2024-03-28T11:54:39Zhttp://repository.helmholtz-hzi.de/oai/requestoai:repository.helmholtz-hzi.de:10033/2006692019-08-30T11:30:31Zcom_10033_620656col_10033_620657
Xu, Kuiying
Wetzel, Marie
W. Hartmann, Rolf
Marchais-Oberwinkler, Sandrine
2012-01-06T08:51:56Z
2012-01-06T08:51:56Z
2012-01-06T08:51:56Z
Synthesis and Biological Evaluation of Spiro-δ-lactones as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 2 (17β-HSD2) 2011, 8 (5):406 Letters in Drug Design & Discovery
15701808
10.2174/157018011795514230
http://hdl.handle.net/10033/200669
Letters in Drug Design & Discovery
Synthesis and Biological Evaluation of Spiro-δ-lactones as Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 2 (17β-HSD2)
Article
oai:repository.helmholtz-hzi.de:10033/2039492019-08-30T11:25:43Zcom_10033_620656col_10033_620657
Klein, Tobias
Henn, Claudia
Negri, Matthias
Frotscher, Martin
2012-01-20T13:41:17Z
2012-01-20T13:41:17Z
2011
Structural basis for species specific inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1): computational study and biological validation. 2011, 6 (8):e22990 PLoS ONE
1932-6203
21857977
10.1371/journal.pone.0022990
http://hdl.handle.net/10033/203949
PloS one
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the reduction of estrone to estradiol, which is the most potent estrogen in humans. Inhibition of 17β-HSD1 and thereby reducing the intracellular estradiol concentration is thus a promising approach for the treatment of estrogen dependent diseases. In the past, several steroidal and non-steroidal inhibitors of 17β-HSD1 have been described but so far there is no cocrystal structure of the latter in complex with 17β-HSD1. However, a distinct knowledge of active site topologies and protein-ligand interactions is a prerequisite for structure-based drug design and optimization. An elegant strategy to enhance this knowledge is to compare inhibition values obtained for one compound toward ortholog proteins from various species, which are highly conserved in sequence and differ only in few residues. In this study the inhibitory potencies of selected members of different non-steroidal inhibitor classes toward marmoset 17β-HSD1 were determined and the data were compared with the values obtained for the human enzyme. A species specific inhibition profile was observed in the class of the (hydroxyphenyl)naphthols. Using a combination of computational methods, including homology modelling, molecular docking, MD simulation, and binding energy calculation, a reasonable model of the three-dimensional structure of marmoset 17β-HSD1 was developed and inhibition data were rationalized on the structural basis. In marmoset 17β-HSD1, residues 190 to 196 form a small α-helix, which induces conformational changes compared to the human enzyme. The docking poses suggest these conformational changes as determinants for species specificity and energy decomposition analysis highlighted the outstanding role of Asn152 as interaction partner for inhibitor binding. In summary, this strategy of comparing the biological activities of inhibitors toward highly conserved ortholog proteins might be an alternative to laborious x-ray or site-directed mutagenesis experiments in certain cases. Additionally, it facilitates inhibitor design and optimization by offering new information on protein-ligand interactions.
en
Structural basis for species specific inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1): computational study and biological validation.
Article
oai:repository.helmholtz-hzi.de:10033/2146512019-08-30T11:26:42Zcom_10033_620656col_10033_620657
Klein, Tobias
Henn, Claudia
Negri, Matthias
Frotscher, Martin
2012-03-07T15:35:23Z
2012-03-07T15:35:23Z
2011
Structural basis for species specific inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1): computational study and biological validation. 2011, 6 (8):e22990 PLoS ONE
1932-6203
21857977
10.1371/journal.pone.0022990
http://hdl.handle.net/10033/214651
PloS one
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the reduction of estrone to estradiol, which is the most potent estrogen in humans. Inhibition of 17β-HSD1 and thereby reducing the intracellular estradiol concentration is thus a promising approach for the treatment of estrogen dependent diseases. In the past, several steroidal and non-steroidal inhibitors of 17β-HSD1 have been described but so far there is no cocrystal structure of the latter in complex with 17β-HSD1. However, a distinct knowledge of active site topologies and protein-ligand interactions is a prerequisite for structure-based drug design and optimization. An elegant strategy to enhance this knowledge is to compare inhibition values obtained for one compound toward ortholog proteins from various species, which are highly conserved in sequence and differ only in few residues. In this study the inhibitory potencies of selected members of different non-steroidal inhibitor classes toward marmoset 17β-HSD1 were determined and the data were compared with the values obtained for the human enzyme. A species specific inhibition profile was observed in the class of the (hydroxyphenyl)naphthols. Using a combination of computational methods, including homology modelling, molecular docking, MD simulation, and binding energy calculation, a reasonable model of the three-dimensional structure of marmoset 17β-HSD1 was developed and inhibition data were rationalized on the structural basis. In marmoset 17β-HSD1, residues 190 to 196 form a small α-helix, which induces conformational changes compared to the human enzyme. The docking poses suggest these conformational changes as determinants for species specificity and energy decomposition analysis highlighted the outstanding role of Asn152 as interaction partner for inhibitor binding. In summary, this strategy of comparing the biological activities of inhibitors toward highly conserved ortholog proteins might be an alternative to laborious x-ray or site-directed mutagenesis experiments in certain cases. Additionally, it facilitates inhibitor design and optimization by offering new information on protein-ligand interactions.
en
Structural basis for species specific inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1): computational study and biological validation.
Article
oai:repository.helmholtz-hzi.de:10033/2142382019-08-30T11:36:32Zcom_10033_620656col_10033_620657
Bihrer, Verena
Friedrich-Rust, Mireen
Kronenberger, Bernd
Forestier, Nicole
Haupenthal, Jörg
Shi, Ying
Peveling-Oberhag, Jan
Radeke, Heinfried H
Sarrazin, Christoph
Herrmann, Eva
Zeuzem, Stefan
Waidmann, Oliver
Piiper, Albrecht
2012-03-05T14:52:18Z
2012-03-05T14:52:18Z
2011-09
Serum miR-122 as a biomarker of necroinflammation in patients with chronic hepatitis C virus infection. 2011, 106 (9):1663-9 Am. J. Gastroenterol.
1572-0241
21606975
10.1038/ajg.2011.161
http://hdl.handle.net/10033/214238
The American journal of gastroenterology
The liver contains large amounts of microRNA-122 (miR-122), whereas other tissues contain only marginal amounts of this miRNA. MicroRNAs have also been found to circulate in the blood in a cell-free form; their potential as readily accessible disease markers is currently evaluated. Here, we investigated if the serum levels of miR-122 might be useful as disease parameter in patients with chronic hepatitis C virus (HCV) infection.
en
Serum miR-122 as a biomarker of necroinflammation in patients with chronic hepatitis C virus infection.
Article
oai:repository.helmholtz-hzi.de:10033/2163012019-08-30T11:26:13Zcom_10033_620656col_10033_620657
Negri, Matthias
Recanatini, Maurizio
Hartmann, Rolf W
2012-03-22T15:11:27Z
2012-03-22T15:11:27Z
2011-09
Computational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps. 2011, 25 (9):795-811 J. Comput. Aided Mol. Des.
1573-4951
21822722
10.1007/s10822-011-9464-7
http://hdl.handle.net/10033/216301
Journal of computer-aided molecular design
17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyzes the last step of the estrogen biosynthesis, namely the reduction of estrone to the biologically potent estradiol. As such it is a potentially attractive drug target for the treatment of estrogen-dependent diseases like breast cancer and endometriosis. 17β-HSD1 belongs to the bisubstrate enzymes and exists as an ensemble of conformations. These principally differ in the region of the βFαG'-loop, suggesting a prominent role in substrate and inhibitor binding. Although several classes of potent non-steroidal 17β-HSD1 inhibitors currently exist, their binding mode is still unclear. We aimed to elucidate the binding mode of bis(hydroxyphenyl)arenes, a highly potent class of 17β-HSD1 inhibitors, and to rank these compounds correctly with respect to their inhibitory potency, two essential aspects in drug design. Ensemble docking experiments resulted in a steroidal binding mode for the closed enzyme conformations and in an alternative mode for the opened and occluded conformers with the inhibitors placed below the NADPH interacting with it synergically via π-π stacking and H-bond formation. Both binding modes were investigated by MD simulations and MM-PBSA binding free energy estimations using as representative member for this class compound 1 (50 nM). Notably, only the alternative binding mode proved stable and was energetically more favorable, while when simulated in the steroidal binding mode compound 1 was displaced from the active site. In parallel, ab initio studies of small NADPH-inhibitor complexes were performed, which supported the importance of the synergistic interaction between inhibitors and cofactor.
en
Archived with thanks to Journal of computer-aided molecular design
Computational investigation of the binding mode of bis(hydroxylphenyl)arenes in 17β-HSD1: molecular dynamics simulations, MM-PBSA free energy calculations, and molecular electrostatic potential maps.
Article
oai:repository.helmholtz-hzi.de:10033/2371532019-08-30T11:34:48Zcom_10033_620656col_10033_620657
Bihrer, Verena
Waidmann, Oliver
Friedrich-Rust, Mireen
Forestier, Nicole
Susser, Simone
Haupenthal, Jörg
Welker, Martin
Shi, Ying
Peveling-Oberhag, Jan
Polta, Andreas
von Wagner, Michael
Radeke, Heinfried H
Sarrazin, Christoph
Trojan, Jörg
Zeuzem, Stefan
Kronenberger, Bernd
Piiper, Albrecht
2012-08-03T12:25:14Z
2012-08-03T12:25:14Z
2011
Serum microRNA-21 as marker for necroinflammation in hepatitis C patients with and without hepatocellular carcinoma. 2011, 6 (10):e26971 PLoS ONE
1932-6203
22066022
10.1371/journal.pone.0026971
http://hdl.handle.net/10033/237153
PloS one
MicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC.
en
Archived with thanks to PloS one
Serum microRNA-21 as marker for necroinflammation in hepatitis C patients with and without hepatocellular carcinoma.
Article
oai:repository.helmholtz-hzi.de:10033/2375552019-08-30T11:30:32Zcom_10033_620656col_10033_620657
Lu, Cenbin
Kirsch, Benjamin
Zimmer, Christina
de Jong, Johannes C
Henn, Claudia
Maurer, Christine K
Müsken, Mathias
Häussler, Susanne
Steinbach, Anke
Hartmann, Rolf W
2012-08-07T13:35:08Z
2012-08-07T13:35:08Z
2012-03-23
Discovery of antagonists of PqsR, a key player in 2-alkyl-4-quinolone-dependent quorum sensing in Pseudomonas aeruginosa. 2012, 19 (3):381-90 Chem. Biol.
1879-1301
22444593
10.1016/j.chembiol.2012.01.015
http://hdl.handle.net/10033/237555
Chemistry & biology
The pqs quorum sensing communication system of Pseudomonas aeruginosa controls virulence factor production and is involved in biofilm formation, therefore playing an important role for pathogenicity. In order to attenuate P. aeruginosa pathogenicity, we followed a ligand-based drug design approach and synthesized a series of compounds targeting PqsR, the receptor of the pqs system. In vitro evaluation using a reporter gene assay in Escherichia coli led to the discovery of the first competitive PqsR antagonists, which are highly potent (K(d,app) of compound 20: 7 nM). These antagonists are able to reduce the production of the virulence factor pyocyanin in P. aeruginosa. Our finding offers insights into the ligand-receptor interaction of PqsR and provides a promising starting point for further drug design.
en
Archived with thanks to Chemistry & biology
Discovery of antagonists of PqsR, a key player in 2-alkyl-4-quinolone-dependent quorum sensing in Pseudomonas aeruginosa.
Article
oai:repository.helmholtz-hzi.de:10033/2462112019-08-30T11:25:11Zcom_10033_620656col_10033_620657
Bansal, Ranju
Guleria, Sheetal
Thota, Sridhar
Bodhankar, Subhash L
Patwardhan, Moreshwar R
Zimmer, Christina
Hartmann, Rolf W
Harvey, Alan L
2012-09-28T08:27:23Z
2012-09-28T08:27:23Z
2012-05
Design, synthesis and evaluation of novel 16-imidazolyl substituted steroidal derivatives possessing potent diversified pharmacological properties. 2012, 77 (6):621-9 Steroids
1878-5867
22366075
10.1016/j.steroids.2012.02.005
http://hdl.handle.net/10033/246211
Steroids
As a part of our investigations into the structural-activity relationship studies of a novel class of medicinally active 16-substituted steroids, several new 16-imidazolyl substituted steroidal derivatives have been synthesized and pharmacologically evaluated in the current study. The new steroidal analogues 5, 6, 8, 9, 11 and 12 exhibited moderate cytotoxic effects in sixty cancer cell lines derived from nine cancers types. The imidazolyl substituted steroidal derivatives 6 (DPJ-RG-1241) and 7 (RB-401) were obtained as the powerful inhibitors of aromatase with IC50=0.18 μM and IC50=0.168 μM, respectively, approximately 1.2 and 1.4 times more potent in comparison to standard drug exemestane. The bis-quaternary steroids 13 and 14 displayed potent skeletal muscle relaxant properties. An affinity constant of 0.007 μM was observed for compound 14 on frog rectus abdominis muscle preparation and 13 displayed a very high anticholinesterase activity K(i)=25 nM, approximately 115-fold higher in comparison to standard drug galanthamine (K(i)=2.9 μM).
en
Archived with thanks to Steroids
Design, synthesis and evaluation of novel 16-imidazolyl substituted steroidal derivatives possessing potent diversified pharmacological properties.
Article
oai:repository.helmholtz-hzi.de:10033/2493562019-08-30T11:27:46Zcom_10033_620656col_10033_620657
Spadaro, Alessandro
Negri, Matthias
Marchais-Oberwinkler, Sandrine
Bey, Emmanuel
Frotscher, Martin
2012-10-18T11:35:47Z
2012-10-18T11:35:47Z
2012
Hydroxybenzothiazoles as new nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). 2012, 7 (1):e29252 PLoS ONE
1932-6203
22242164
10.1371/journal.pone.0029252
http://hdl.handle.net/10033/249356
PloS one
17β-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17β-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17β-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17β-HSD1 inhibitors bearing a benzothiazole-scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC₅₀-values in the nanomolar range for the transformation of E1 to E2 by 17β-HSD1, reasonable selectivity against 17β-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17β-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17β-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17β-HSD1 inhibitors for the development of potential therapeutics.
en
Archived with thanks to PloS one
Hydroxybenzothiazoles as new nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1).
Article
oai:repository.helmholtz-hzi.de:10033/2667122019-08-30T11:30:32Zcom_10033_620656col_10033_620657
Bansal, Ranju
Thota, Sridhar
Karkra, Nalin
Minu, Maninder
Zimmer, Christina
Hartmann, Rolf W
2013-01-23T15:18:03Z
2013-01-23T15:18:03Z
2012-12
Synthesis and aromatase inhibitory activity of some new 16E-arylidenosteroids. 2012, 45:36-40 Bioorg. Chem.
1090-2120
23064126
10.1016/j.bioorg.2012.08.005
http://hdl.handle.net/10033/266712
Bioorganic chemistry
A new series of 16E-arylidene androstene derivatives has been synthesized and evaluated for aromatase inhibitory activity. The impact of various aryl substituents at 16 position of the steroid skeleton on aromatase inhibitory activity has been observed. The 16E-arylidenosteroids 6, 10 and 11 exhibited significant inhibition of the aromatase enzyme. 16-(4-Pyridylmethylene)-4-androstene-3,17-dione (6, IC(50): 5.2 μM) and 16-(benzo-[1,3]dioxol-5-ylmethylene)androsta-1,4-diene-3,17-dione (11, IC(50): 6.4 μM) were found to be approximately five times more potent in comparison to aminoglutethimide.
en
Archived with thanks to Bioorganic chemistry
Synthesis and aromatase inhibitory activity of some new 16E-arylidenosteroids.
Article
oai:repository.helmholtz-hzi.de:10033/2699122019-08-30T11:28:24Zcom_10033_620656col_10033_620657
Yin, Lina
Hu, Qingzhong
Hartmann, Rolf W
2013-02-21T08:04:32Z
2013-02-21T08:04:32Z
2012
3-Pyridyl substituted aliphatic cycles as CYP11B2 inhibitors: aromaticity abolishment of the core significantly increased selectivity over CYP1A2. 2012, 7 (11):e48048 PLoS ONE
1932-6203
23133610
10.1371/journal.pone.0048048
http://hdl.handle.net/10033/269912
PloS one
Aldosterone synthase (CYP11B2) is a promising therapeutic target for the treatment of cardiovascular diseases related to abnormally high aldosterone levels. On the basis of our previously identified lead compounds I-III, a series of 3-pyridinyl substituted aliphatic cycles were designed, synthesized and tested as CYP11B2 inhibitors. Aromaticity abolishment of the core was successfully applied to overcome the undesired CYP1A2 inhibition. This study resulted in a series of potent and selective CYP11B2 inhibitors, with compound 12 (IC(50) = 21 nM, SF = 50) as the most promising one, which shows no inhibition toward CYP1A2 at 2 µM. The design conception demonstrated in this study can be helpful in the optimization of CYP inhibitor drugs regarding CYP1A2 selectivity.
en
Archived with thanks to PloS one
3-Pyridyl substituted aliphatic cycles as CYP11B2 inhibitors: aromaticity abolishment of the core significantly increased selectivity over CYP1A2.
Article
oai:repository.helmholtz-hzi.de:10033/2971952019-08-30T11:29:47Zcom_10033_620656col_10033_620657
Yin, Lina
Hu, Qingzhong
Hartmann, Rolf W
2013-08-01T09:32:52Z
2013-08-01T09:32:52Z
2013
Recent progress in pharmaceutical therapies for castration-resistant prostate cancer. 2013, 14 (7):13958-78 Int J Mol Sci
1422-0067
23880851
10.3390/ijms140713958
http://hdl.handle.net/10033/297195
International journal of molecular sciences
Since 2010, six drugs have been approved for the treatment of castration-resistant prostate cancer, i.e., CYP17 inhibitor Abiraterone, androgen receptor antagonist Enzalutamide, cytotoxic agent Cabazitaxel, vaccine Sipuleucel-T, antibody Denosumab against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin. All these drugs demonstrate improvement on overall survival, expect for Denosumab, which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone-metastasis-free survival. Besides further CYP17 inhibitors (Orteronel, Galeterone, VT-464 and CFG920), androgen receptor antagonists (ARN-509, ODM-201, AZD-3514 and EZN-4176) and vaccine Prostvac, more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials, including various kinase inhibitors and platinum complexes. Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments. Under these flourishing circumstances, more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients.
en
Archived with thanks to International journal of molecular sciences
Recent progress in pharmaceutical therapies for castration-resistant prostate cancer.
Article
oai:repository.helmholtz-hzi.de:10033/2982522019-08-30T11:28:51Zcom_10033_620656col_10033_620657
Krug, Sebastian J
Hu, Qingzhong
Hartmann, Rolf W
2013-08-14T14:20:01Z
2013-08-14T14:20:01Z
2013-03
Hits identified in library screening demonstrate selective CYP17A1 lyase inhibition. 2013, 134:75-9 J. Steroid Biochem. Mol. Biol.
1879-1220
23142656
10.1016/j.jsbmb.2012.10.019
http://hdl.handle.net/10033/298252
The Journal of steroid biochemistry and molecular biology
A screening of structurally different steroid hormone synthesis inhibitors was performed in order to find a starting point for the development of a new inhibitor of the bifunctional steroidogenic enzyme CYP17A1. Emphasis was placed on determination of selectivity between the two catalytic steps, namely 17α-hydroxylase and C(17,20)-lyase. For that purpose a new inhibition assay has been developed. Hits identified within this novel assay demonstrated selective inhibition of CYP17A1 lyase activity, and thus mark the basis for the development of selective C(17,20)-lyase inhibitors for the treatment of prostate cancer.
en
Archived with thanks to The Journal of steroid biochemistry and molecular biology
Hits identified in library screening demonstrate selective CYP17A1 lyase inhibition.
Article
oai:repository.helmholtz-hzi.de:10033/2983752019-08-30T11:26:42Zcom_10033_620656col_10033_620657
Berényi, Agnes
Frotscher, Martin
Marchais-Oberwinkler, Sandrine
Hartmann, Rolf W
Minorics, Renáta
Ocsovszki, Imre
Falkay, George
Zupkó, István
2013-08-15T09:51:45Z
2013-08-15T09:51:45Z
2013-08
Direct antiproliferative effect of nonsteroidal 17β-hydroxysteroid dehydrogenase type 1 inhibitors in vitro. 2013, 28 (4):695-703 J Enzyme Inhib Med Chem
1475-6374
22471733
10.3109/14756366.2012.672414
http://hdl.handle.net/10033/298375
Journal of enzyme inhibition and medicinal chemistry
Inhibition of the local formation of estrogens seems to be an attractive strategy for pharmacological intervention in hormone-dependent disorders. The direct antiproliferative properties of ten nonsteroidal 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) inhibitors were investigated on human cancer cell lines of gynecological origin. The mechanism of the antiproliferative action was approximated by cell cycle analysis, fluorescent microscopy, BrdU assay, determination of caspase-3 activity and quantification of the expression of cell cycle regulators at mRNA level. Treatment of HeLa cells with some of the compounds resulted in a concentration-dependent inhibition of the G1-S transition and an increase in the apoptotic population. The most effective agents increased the expression of tumor suppressors p21 and p53, while CDK2 and Rb were down-regulated. The reported anticancer actions of the tested compounds are independent of the 17β-HSD1-inhibiting capacity. These results indicate that it is possible to combine direct antiproliferative activity and 17β-HSD1 inhibition resulting in novel agents with dual mode of action.
en
Archived with thanks to Journal of enzyme inhibition and medicinal chemistry
Direct antiproliferative effect of nonsteroidal 17β-hydroxysteroid dehydrogenase type 1 inhibitors in vitro.
Article
oai:repository.helmholtz-hzi.de:10033/2992512019-08-30T11:26:06Zcom_10033_620656col_10033_620657
Hamed, Mostafa M.
Abou El Ella, Dalal A.
Keeton, Adam B.
Piazza, Gary A.
Engel, Matthias
Hartmann, Rolf W.
Abadi, Ashraf H.
2013-08-20T12:39:00Z
2013-08-20T12:39:00Z
2013-08-20
Quinazoline and tetrahydropyridothieno[2,3-d]pyrimidine derivatives as irreversible EGFR tyrosine kinase inhibitors: influence of the position 4 substituent 2013, 4 (8):1202 MedChemComm
2040-2503
2040-2511
10.1039/c3md00118k
http://hdl.handle.net/10033/299251
MedChemComm
Archived with thanks to MedChemComm
Quinazoline and tetrahydropyridothieno[2,3-d]pyrimidine derivatives as irreversible EGFR tyrosine kinase inhibitors: influence of the position 4 substituent
Article
oai:repository.helmholtz-hzi.de:10033/2995042019-08-30T11:32:16Zcom_10033_620656col_10033_620657
Perspicace, Enrico
Marchais-Oberwinkler, Sandrine
Hartmann, Rolf W
2013-08-22T12:14:57Z
2013-08-22T12:14:57Z
2013
Synthesis and biological evaluation of thieno[3,2-d]- pyrimidinones, thieno[3,2-d]pyrimidines and quinazolinones: conformationally restricted 17b-hydroxysteroid dehydrogenase type 2 (17b-HSD2) inhibitors. 2013, 18 (4):4487-509 Molecules
1420-3049
23591928
10.3390/molecules18044487
http://hdl.handle.net/10033/299504
Molecules (Basel, Switzerland)
In this study, a series of conformationally restricted thieno[3,2-d]pyrimidinones, thieno[3,2-d]pyrimidines and quinazolinones was designed and synthesized with the goal of improving the biological activity as 17b-hydroxysteroid dehydrogenase type 2 inhibitors of the corresponding amidothiophene derivatives. Two moderately active compounds were discovered and this allowed the identification of the biologically active open conformer as well as the extension of the enzyme binding site characterisation.
en
Archived with thanks to Molecules (Basel, Switzerland)
Synthesis and biological evaluation of thieno[3,2-d]- pyrimidinones, thieno[3,2-d]pyrimidines and quinazolinones: conformationally restricted 17b-hydroxysteroid dehydrogenase type 2 (17b-HSD2) inhibitors.
Article
oai:repository.helmholtz-hzi.de:10033/3037382019-08-30T11:28:51Zcom_10033_620656col_10033_620657
Köberle, Verena
Pleli, Thomas
Schmithals, Christian
Augusto Alonso, Eduardo
Haupenthal, Jörg
Bönig, Halvard
Peveling-Oberhag, Jan
Biondi, Ricardo M
Zeuzem, Stefan
Kronenberger, Bernd
Waidmann, Oliver
Piiper, Albrecht
2013-10-21T14:39:02Z
2013-10-21T14:39:02Z
2013
Differential Stability of Cell-Free Circulating microRNAs: Implications for Their Utilization as Biomarkers. 2013, 8 (9):e75184 PLoS ONE
1932-6203
24073250
10.1371/journal.pone.0075184
http://hdl.handle.net/10033/303738
PloS one
MicroRNAs circulating in the blood, stabilized by complexation with proteins and/or additionally by encapsulation in lipid vesicles, are currently being evaluated as biomarkers. The consequences of their differential association with lipids/vesicles for their stability and use as biomarkers are largely unexplored and are subject of the present study.
en
Archived with thanks to PloS one
Differential Stability of Cell-Free Circulating microRNAs: Implications for Their Utilization as Biomarkers.
Article
oai:repository.helmholtz-hzi.de:10033/3063732019-08-30T11:33:57Zcom_10033_620656col_10033_620657
Maurer, Christine K
Steinbach, Anke
Hartmann, Rolf W
2013-12-05T12:46:06Z
2013-12-05T12:46:06Z
2013-12
Development and validation of a UHPLC-MS/MS procedure for quantification of the Pseudomonas Quinolone Signal in bacterial culture after acetylation for characterization of new quorum sensing inhibitors. 2013, 86:127-34 J Pharm Biomed Anal
1873-264X
24001903
10.1016/j.jpba.2013.07.047
http://hdl.handle.net/10033/306373
Journal of pharmaceutical and biomedical analysis
The appearance of antibiotic resistance requires novel therapeutic strategies. One approach is to selectively attenuate bacterial pathogenicity by interfering with bacterial cell-to-cell communication known as quorum sensing. The PQS quorum sensing system of Pseudomonas aeruginosa employs as signal molecule the Pseudomonas Quinolone Signal (PQS; 2-heptyl-3-hydroxy-4-(1H)-quinolone), a key contributor to virulence and biofilm formation. Thus, interference with PQS production is considered as promising approach for the development of novel anti-infectives. Therefore, in this study, we developed and validated an ultra-high performance liquid chromatographic-tandem mass spectrometric approach for reliable quantification of PQS in P. aeruginosa cultures for activity determination of new quorum sensing inhibitors. The poor chromatographic properties of PQS reported by others could be overcome by fast microwave-assisted acetylation. The validation procedure including matrix effects, recovery, process efficiency, selectivity, carry-over, accuracy and precision, stability of the processed sample, and limit of quantification demonstrated that the method fulfilled all requirements of common validation guidelines. Its applicability was successfully proven in routine testing. In addition, two-point calibration was shown to be applicable for fast and reliable PQS quantification saving time and resources. In summary, the described method provides a powerful tool for the discovery of new quorum sensing inhibitors as potential anti-infectives and illustrated the usefulness of chemical derivatization, acetylation, in liquid chromatography-mass spectrometry analysis.
en
Archived with thanks to Journal of pharmaceutical and biomedical analysis
Development and validation of a UHPLC-MS/MS procedure for quantification of the Pseudomonas Quinolone Signal in bacterial culture after acetylation for characterization of new quorum sensing inhibitors.
Article
oai:repository.helmholtz-hzi.de:10033/3114212019-08-30T11:26:42Zcom_10033_620656col_10033_620657
Steinbach, Anke
Maurer, Christine K
Weidel, Elisabeth
Henn, Claudia
Brengel, Christian
Hartmann, Rolf W
Negri, Matthias
2014-01-16T14:53:04Z
2014-01-16T14:53:04Z
2013
Molecular basis of HHQ biosynthesis: molecular dynamics simulations, enzyme kinetic and surface plasmon resonance studies. 2013, 6 (1):10 BMC Biophys
2046-1682
23916145
10.1186/2046-1682-6-10
http://hdl.handle.net/10033/311421
BMC biophysics
PQS (PseudomonasQuinolone Signal) and its precursor HHQ are signal molecules of the P. aeruginosa quorum sensing system. They explicate their role in mammalian pathogenicity by binding to the receptor PqsR that induces virulence factor production and biofilm formation. The enzyme PqsD catalyses the biosynthesis of HHQ.
en
Archived with thanks to BMC biophysics
Molecular basis of HHQ biosynthesis: molecular dynamics simulations, enzyme kinetic and surface plasmon resonance studies.
Article
oai:repository.helmholtz-hzi.de:10033/3116762019-08-30T11:26:42Zcom_10033_620656col_10033_620657
Elgaher, Walid A. M.
Fruth, Martina
Groh, Matthias
Haupenthal, Jörg
Hartmann, Rolf W.
2014-01-22T14:47:34Z
2014-01-22T14:47:34Z
2014-01-22
Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure–activity relationships of ureido-heterocyclic-carboxylic acids 2014, 4 (5):2177 RSC Advances
2046-2069
10.1039/c3ra45820b
http://hdl.handle.net/10033/311676
RSC Advances
Archived with thanks to RSC Advances
Expanding the scaffold for bacterial RNA polymerase inhibitors: design, synthesis and structure–activity relationships of ureido-heterocyclic-carboxylic acids
Article
oai:repository.helmholtz-hzi.de:10033/3119292019-08-30T11:33:01Zcom_10033_620656col_10033_620657
Grombein, Cornelia M.
Hu, Qingzhong
Heim, Ralf
Huch, Volker
Hartmann, Rolf W.
2014-01-27T13:53:31Z
2014-01-27T13:53:31Z
2014-01-27
Unexpected results of a SNAr-reaction. A novel synthetic approach to 1-arylthio-2-naphthols 2013, 54 (48):6615 Tetrahedron Letters
404039
10.1016/j.tetlet.2013.09.111
http://hdl.handle.net/10033/311929
Tetrahedron Letters
Archived with thanks to Tetrahedron Letters
Unexpected results of a SNAr-reaction. A novel synthetic approach to 1-arylthio-2-naphthols
Article
oai:repository.helmholtz-hzi.de:10033/3167182019-08-30T11:33:57Zcom_10033_620656col_10033_620657
Lu, Cenbin
Maurer, Christine K
Kirsch, Benjamin
Steinbach, Anke
Hartmann, Rolf W
2014-05-12T09:42:12Z
2014-05-12T09:42:12Z
2014-01-20
Overcoming the unexpected functional inversion of a PqsR antagonist in Pseudomonas aeruginosa: an in vivo potent antivirulence agent targeting pqs quorum sensing. 2014, 53 (4):1109-12 Angew. Chem. Int. Ed. Engl.
1521-3773
24338917
10.1002/anie.201307547
http://hdl.handle.net/10033/316718
Angewandte Chemie (International ed. in English)
The virulence regulator PqsR of Pseudomonas aeruginosa is considered as an attractive target for attenuating the bacterial pathogenicity without eliciting resistance. However, despite efforts and desires, no promising PqsR antagonist has been discovered thus far. Now, a surprising functionality change of a highly affine PqsR antagonist in P. aeruginosa is revealed, which is mediated by a bacterial signal molecule synthase and responsible for low cellular potency. Blockade of the susceptible position led to the discovery of the first antivirulence compound that is potent in vivo and targets PqsR, thus providing a proof of concept for this novel antivirulence therapy.
en
Archived with thanks to Angewandte Chemie (International ed. in English)
Overcoming the unexpected functional inversion of a PqsR antagonist in Pseudomonas aeruginosa: an in vivo potent antivirulence agent targeting pqs quorum sensing.
Article
oai:repository.helmholtz-hzi.de:10033/3227012019-08-30T11:34:48Zcom_10033_620656col_10033_620657
Hinsberger, Stefan
de Jong, Johannes C
Groh, Matthias
Haupenthal, Jörg
Hartmann, Rolf W
2014-07-09T14:37:21Z
2014-07-09T14:37:21Z
2014-04-09
Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections. 2014, 76:343-51 Eur J Med Chem
1768-3254
24589489
10.1016/j.ejmech.2014.02.014
http://hdl.handle.net/10033/322701
European journal of medicinal chemistry
Targeting PqsD is a promising novel approach to disrupt bacterial cell-to-cell-communication in Pseudomonas aeruginosa. In search of selective PqsD inhibitors, two series of benzamidobenzoic acids - one published as RNAP inhibitors and the other as PqsD inhibitors - were investigated for inhibitory activity toward the respective other enzyme. Additionally, novel derivatives were synthesized and biologically evaluated. By this means, the structural features needed for benzamidobenzoic acids to be potent and, most notably, selective PqsD inhibitors were identified. The most interesting compound of this study was the 3-Cl substituted compound 5 which strongly inhibits PqsD (IC₅₀ 6.2 μM) while exhibiting no inhibition of RNAP.
en
Archived with thanks to European journal of medicinal chemistry
Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections.
Article
oai:repository.helmholtz-hzi.de:10033/3249672019-08-30T11:34:48Zcom_10033_620656col_10033_620657
Abdelsamie, Ahmed S
Bey, Emmanuel
Hanke, Nina
Empting, Martin
Hartmann, Rolf W
Frotscher, Martin
2014-08-19T09:52:53Z
2014-08-19T09:52:53Z
2014-07-23
Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker. 2014, 82:394-406 Eur J Med Chem
1768-3254
24929290
10.1016/j.ejmech.2014.05.074
http://hdl.handle.net/10033/324967
European journal of medicinal chemistry
Estradiol is the most potent estrogen in humans. It is known to be involved in the development and proliferation of estrogen dependent diseases such as breast cancer and endometriosis. The last step of its biosynthesis is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β- HSD1) which consequently is a promising target for the treatment of these diseases. Recently, we reported on bicyclic substituted hydroxyphenylmethanones as potent inhibitors of 17β-HSD1. The present study focuses on rational structural modifications in this compound class with the aim of gaining more insight into its structure-activity relationship (SAR). (4-Hydroxyphenyl)-(5-(3-hydroxyphenylsulfanyl)-thiophen-2-yl)methanone (25) was discovered as a member of a novel potent class of human 17β-HSD1 inhibitors. Computational methods were used to elucidate its interactions with the target protein. The compound showed activity also towards the murine 17β-HSD1 enzyme and thus is a starting point for the design of compounds suitable for evaluation in an animal disease model.
en
Archived with thanks to European journal of medicinal chemistry
Inhibition of 17β-HSD1: SAR of bicyclic substituted hydroxyphenylmethanones and discovery of new potent inhibitors with thioether linker.
Article
oai:repository.helmholtz-hzi.de:10033/3250052019-08-30T11:34:48Zcom_10033_620656col_10033_620657
Lu, Cenbin
Kirsch, Benjamin
Maurer, Christine K
de Jong, Johannes C
Braunshausen, Andrea
Steinbach, Anke
Hartmann, Rolf W
2014-08-20T09:16:05Z
2014-08-20T09:16:05Z
2014-05-22
Optimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships. 2014, 79:173-83 Eur J Med Chem
1768-3254
24735643
10.1016/j.ejmech.2014.04.016
http://hdl.handle.net/10033/325005
European journal of medicinal chemistry
Increasing antibiotic resistance urgently requires novel therapeutic options to combat bacterial infections. The anti-virulence therapy selectively intervening with pathogenicity without affecting bacterial viability is such a strategy to overcome resistance. We consider the virulence regulator PqsR as an attractive target in the human pathogen Pseudomonas aeruginosa, and recently discovered the first PqsR antagonists, which, however, suffered from poor aqueous solubility. In this work, the antagonists were structurally modified to become more soluble, and their structure-activity as well as structure-property relationships were studied. A novel promising compound with improved solubility and enhanced anti-virulence activity was discovered (IC50: 3.8 μM, pyocyanin). Our findings emphasize the crucial role of substituents at the 3-position and the carbonyl group at the 4-position for ligand-receptor interactions, and illuminate the way for further optimization of PqsR antagonists as anti-virulence agents.
en
Archived with thanks to European journal of medicinal chemistry
Optimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships.
Article
oai:repository.helmholtz-hzi.de:10033/3261742019-08-30T11:27:16Zcom_10033_620656col_10033_620657
Zhu, Weixing
Haupenthal, Jörg
Groh, Matthias
Fountain, Michelle
Hartmann, Rolf W
2014-09-16T12:41:07Z
2014-09-16T12:41:07Z
2014-07
New insights into the bacterial RNA polymerase inhibitor CBR703 as a starting point for optimization as an anti-infective agent. 2014, 58 (7):4242-5 Antimicrob. Agents Chemother.
1098-6596
24820077
10.1128/AAC.02600-14
http://hdl.handle.net/10033/326174
Antimicrobial agents and chemotherapy
CBR703 was reported to inhibit bacterial RNA polymerase (RNAP) and biofilm formation, considering it to be a good candidate for further optimization. While synthesized derivatives of CBR703 did not result in more-active RNAP inhibitors, we observed promising antibacterial activities. These again correlated with a significant cytotoxicity toward mammalian cells. Furthermore, we suspect the promising effects on biofilm formation to be artifacts. Consequently, this class of compounds can be considered unattractive as antibacterial agents.
en
Archived with thanks to Antimicrobial agents and chemotherapy
New insights into the bacterial RNA polymerase inhibitor CBR703 as a starting point for optimization as an anti-infective agent.
Article
oai:repository.helmholtz-hzi.de:10033/3445702019-08-30T11:30:58Zcom_10033_620656col_10033_620657
Stefanachi, Angela
Hanke, Nina
Pisani, Leonardo
Leonetti, Francesco
Nicolotti, Orazio
Catto, Marco
Cellamare, Saverio
Hartmann, Rolf W
Carotti, Angelo
2015-02-18T13:39:43Z
2015-02-18T13:39:43Z
2015-01-07
Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase. 2015, 89:106-14 Eur J Med Chem
1768-3254
25462231
10.1016/j.ejmech.2014.10.021
http://hdl.handle.net/10033/344570
European journal of medicinal chemistry
Diseases triggered by an abnormally high level of cortisol (hypercortisolism), such as the Cushing's and metabolic syndromes, could be successfully tackled by inhibitors of CYP11B1, a steroidal cytochrome P450 enzyme that catalyzes the last hydroxylation step of the cortisol biosynthesis. Structural optimization of 7-(benzyloxy)-4-(1H-imidazol-1-ylmethyl)-2H-chromen-2-one 2, a selective aromatase inhibitor, afforded the 4-(1H-imidazol-1-ylmethyl)-7-{[3-(trifluoromethoxy)benzyl]oxy}-2H-chromen-2-one 7, with improved inhibitory potency at human CYP11B1 (IC50 = 5 nM) and an enhanced selectivity over human CYP11B2 (SIB = 25) compared to lead compound 2 (IC50 = 72 nM, SIB = 4.0) and metyrapone (IC50 = 15 nM, SIB = 4.8), a non-selective drug used in the therapy of the Cushing's syndrome. Structure-activity relationship studies allowed the design and optimization of a novel series of potent and selective compounds, that can be regarded as open analogues of 2H-chromen-2-one derivatives. Compound 23, 2-(1H-imidazol-1-yl)-1-(4-{[3(trifluoromethoxy)benzyl]oxy}phenyl) ethanone, was the most interesting inhibitor of the series displaying a high potency at CYP11B1 (IC50 = 15 nM), increased selectivities over CYP11B2 (SIB = 33), CYP19 (SIB = 390) and CYP17 (5% inhibition at 2.5 μM concentration).
en
Discovery of new 7-substituted-4-imidazolylmethyl coumarins and 4'-substituted-2-imidazolyl acetophenones open analogues as potent and selective inhibitors of steroid-11β-hydroxylase.
Article
oai:repository.helmholtz-hzi.de:10033/3445742019-08-30T11:30:58Zcom_10033_620656col_10033_620657
Allegretta, Giuseppe
Weidel, Elisabeth
Empting, Martin
Hartmann, Rolf W
2015-02-18T13:48:22Z
2015-02-18T13:48:22Z
2015-01-27
Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD. 2015, 90:351-9 Eur J Med Chem
1768-3254
25437621
10.1016/j.ejmech.2014.11.055
http://hdl.handle.net/10033/344574
European journal of medicinal chemistry
A new strategy for treating Pseudomonas aeruginosa infections could be disrupting the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system. The goal is to impair communication among the cells and, hence, reduce the expression of virulence factors and the formation of biofilms. PqsD is an essential enzyme for the synthesis of PQS and shares some features with chalcone synthase (CHS2), an enzyme expressed in Medicago sativa. Both proteins are quite similar concerning the size of the active site, the catalytic residues and the electrostatic surface potential at the entrance of the substrate tunnel. Hence, we evaluated selected substrates of the vegetable enzyme as potential inhibitors of the bacterial protein. This similarity-guided approach led to the identification of a new class of PqsD inhibitors having a catechol structure as an essential feature for activity, a saturated linker with two or more carbons and an ester moiety bearing bulky substituents. The developed compounds showed PqsD inhibition with IC50 values in the single-digit micromolar range. The binding mode of these compounds was investigated by Surface Plasmon Resonance (SPR) experiments revealing that their interaction with the protein is not influenced by the presence of the anthranilic acid bound to active site cysteine. Importantly, some compounds reduced the signal molecule production in cellulo.
en
Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD.
Article
oai:repository.helmholtz-hzi.de:10033/3452912019-08-30T11:31:23Zcom_10033_620656col_10033_620657
Grombein, Cornelia M
Hu, Qingzhong
Heim, Ralf
Rau, Sabrina
Zimmer, Christina
Hartmann, Rolf W
2015-02-25T10:38:26Z
2015-02-25T10:38:26Z
2015-01-07
1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: a new class of potent and selective aldosterone synthase inhibitors. 2015, 89:597-605 Eur J Med Chem
1768-3254
25462268
10.1016/j.ejmech.2014.10.027
http://hdl.handle.net/10033/345291
European journal of medicinal chemistry
1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11β-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.
en
1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols: a new class of potent and selective aldosterone synthase inhibitors.
Article
oai:repository.helmholtz-hzi.de:10033/3458232019-08-30T11:37:44Zcom_10033_620656col_10033_620657
Weidel, Elisabeth
Negri, Matthias
Empting, Martin
Hinsberger, Stefan
Hartmann, Rolf W
2015-03-02T13:39:14Z
2015-03-02T13:39:14Z
2014
Composing compound libraries for hit discovery--rationality-driven preselection or random choice by structural diversity? 2014, 6 (18):2057-72 Future Med Chem
1756-8927
25531968
10.4155/fmc.14.142
http://hdl.handle.net/10033/345823
Future medicinal chemistry
In order to identify new scaffolds for drug discovery, surface plasmon resonance is frequently used to screen structurally diverse libraries. Usually, hit rates are low and identification processes are time consuming. Hence, approaches which improve hit rates and, thus, reduce the library size are required.
en
Composing compound libraries for hit discovery--rationality-driven preselection or random choice by structural diversity?
Article
oai:repository.helmholtz-hzi.de:10033/3461342019-08-30T11:31:23Zcom_10033_620656col_10033_620657
Gargano, Emanuele M
Perspicace, Enrico
Hanke, Nina
Carotti, Angelo
Marchais-Oberwinkler, Sandrine
Hartmann, Rolf W
2015-03-04T10:43:11Z
2015-03-04T10:43:11Z
2014-11-24
Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors. 2014, 87:203-19 Eur J Med Chem
1768-3254
25259513
10.1016/j.ejmech.2014.09.061
http://hdl.handle.net/10033/346134
European journal of medicinal chemistry
17β-HSD2 is a promising new target for the treatment of osteoporosis. In this paper, a rational strategy to overcome the metabolic liability in the 2,5-thiophene amide class of 17β-HSD2 inhibitors is described, and the biological activity of the new inhibitors. Applying different strategies, as lowering the cLogP or modifying the structures of the molecules, compounds 27, 31 and 35 with strongly improved metabolic stability were obtained. For understanding biotransformation in the 2,5-thiophene amide class the main metabolic pathways of three properly selected compounds were elucidated.
en
Metabolic stability optimization and metabolite identification of 2,5-thiophene amide 17β-hydroxysteroid dehydrogenase type 2 inhibitors.
Article
oai:repository.helmholtz-hzi.de:10033/3466022019-08-30T11:27:46Zcom_10033_620656col_10033_620657
Beber, T C
Andrade, D F
Kann, B
Fontana, M C
Coradini, K
Windbergs, M
Beck, R C R
2015-03-13T14:53:24Z
2015-03-13T14:53:24Z
2014-11
Submicron polymeric particles prepared by vibrational spray-drying: Semisolid formulation and skin penetration/permeation studies. 2014, 88 (3):602-13 Eur J Pharm Biopharm
1873-3441
25078859
10.1016/j.ejpb.2014.07.008
http://hdl.handle.net/10033/346602
European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft für Pharmazeutische Verfahrenstechnik e.V
Topical glucocorticoids (TG) such as dexamethasone (DEX) have been used for decades for the treatment of skin diseases. However, TG present well-documented side effects and their delivery to the skin is often insufficient. Therefore, many efforts have been undergone to improve the amount of drug delivered to the skin and to reduce side effects at the same time. In this work, the feasibility of DEX-submicron polymeric particles (SP) prepared by vibrational spray-drying as an approach to overcome the challenges associated with the topical administration of this drug class was evaluated. DEX was homogeneously dispersed in the SP matrix, according to confocal Raman microscopy analysis. Drug-loaded SP were incorporated into the oil phase of oil-in-water emulsions (creams). The formulation containing polymeric submicron particles (C-SP) showed controlled drug release kinetics and a significant drug accumulation in skin compared to formulations containing non-polymeric particles or free drug. DEX accumulation in the stratum corneum was evaluated by tape stripping and a depot effect over time was observed for C-SP, while the formulation containing the free drug showed a decrease over time. Similarly, C-SP presented higher drug retention in epidermis and dermis in skin penetration studies performed on pig skin in Franz diffusion cells, while drug permeation into the receptor compartment was negligible. It was demonstrated, for the first time, the advantageous application of submicron polymeric particles obtained by vibrational spray-drying in semisolid formulations for cutaneous administration to overcome challenges related to the therapy with TG such as DEX.
en
Submicron polymeric particles prepared by vibrational spray-drying: Semisolid formulation and skin penetration/permeation studies.
Article
oai:repository.helmholtz-hzi.de:10033/3469152019-08-30T11:28:23Zcom_10033_620656col_10033_620657
Grombein, Cornelia M
Hu, Qingzhong
Rau, Sabrina
Zimmer, Christina
Hartmann, Rolf W
2015-03-19T15:21:26Z
2015-03-19T15:21:26Z
2015-01-27
Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase. 2015, 90:788-96 Eur J Med Chem
1768-3254
25528333
10.1016/j.ejmech.2014.12.022
http://hdl.handle.net/10033/346915
European journal of medicinal chemistry
Aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 < 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2 μM).
en
Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase.
Article
oai:repository.helmholtz-hzi.de:10033/3470622019-08-30T11:26:13Zcom_10033_620656col_10033_620657
Laggai, Stephan
Kessler, Sonja M
Boettcher, Stefan
Lebrun, Valérie
Gemperlein, Katja
Lederer, Eva
Leclercq, Isabelle A
Mueller, Rolf
Hartmann, Rolf W
Haybaeck, Johannes
Kiemer, Alexandra K
2015-03-24T12:10:17Z
2015-03-24T12:10:17Z
2014-04-22
The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis. 2014, 55 (6):1087-1097 J. Lipid Res.
0022-2275
24755648
10.1194/jlr.M045500
http://hdl.handle.net/10033/347062
Journal of lipid research
Liver-specific overexpression of the insulin-like growth factor 2 (IGF2) mRNA binding protein p62/IGF2BP2-2 induces a fatty liver, which highly expresses IGF2. Because IGF2 expression is elevated in patients with steatohepatitis, the aim of our study was to elucidate the role and interconnection of p62 and IGF2 in lipid metabolism. Expression of p62 and IGF2 highly correlated in human liver disease. p62 induced an elevated ratio of C18:C16 and increased fatty acid elongase 6 (ELOVL6) protein, the enzyme catalyzing the elongation of C16 to C18 fatty acids and promoting nonalcoholic steatohepatitis in mice and humans. The p62 overexpression induced the activation of the ELOVL6 transcriptional activator sterol regulatory element binding transcription factor 1 (SREBF1). Recombinant IGF2 induced the nuclear translocation of SREBF1 and a neutralizing IGF2 antibody reduced ELOVL6 and mature SREBF1 protein levels. Concordantly, p62 and IGF2 correlated with ELOVL6 in human livers. Decreased palmitoyl-CoA levels, as found in p62 transgenic livers, can explain the lipogenic action of ELOVL6. Accordingly, p62 represents an inducer of hepatic C18 fatty acid production via a SREBF1-dependent induction of ELOVL6. These findings underline the detrimental role of p62 in liver disease.
The IGF2 mRNA binding protein p62/IGF2BP2-2 induces fatty acid elongation as a critical feature of steatosis.
Article
oai:repository.helmholtz-hzi.de:10033/5562022019-08-30T11:28:51Zcom_10033_620656col_10033_620657
Sahner, J Henning
Empting, Martin
Kamal, Ahmed
Weidel, Elisabeth
Groh, Matthias
Börger, Carsten
Hartmann, Rolf W
2015-06-03T12:40:11Z
2015-06-03T12:40:11Z
2015-05-26
Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa. 2015, 96:14-21 Eur J Med Chem
1768-3254
25874327
10.1016/j.ejmech.2015.04.007
http://hdl.handle.net/10033/556202
European journal of medicinal chemistry
Pseudomonas aeruginosa employs a quorum sensing (QS) communication system that makes use of small diffusible molecules. Among other effects, the QS system coordinates the formation of biofilm which decisively contributes to difficulties in the therapy of Pseudomonas infections. The present work deals with the structure-activity exploration of ureidothiophene-2-carboxylic acids as inhibitors of PqsD, a key enzyme in the biosynthetic pathway of signal molecules in the Pseudomonas QS system. We describe an improvement of the inhibitory activity by successfully combining features from two different PqsD inhibitor classes. Furthermore the functional groups, which are responsible for the inhibitory potency, were identified. Moreover, the inability of the new inhibitors, to prevent signal molecule formation in whole cell assays, is discussed.
en
Exploring the chemical space of ureidothiophene-2-carboxylic acids as inhibitors of the quorum sensing enzyme PqsD from Pseudomonas aeruginosa.
Article
oai:repository.helmholtz-hzi.de:10033/5562032019-08-30T11:28:51Zcom_10033_620656col_10033_620657
Hu, Qingzhong
Kunde, Jessica
Hanke, Nina
Hartmann, Rolf W
2015-06-03T12:52:31Z
2015-06-03T12:52:31Z
2015-05-26
Identification of 4-(4-nitro-2-phenethoxyphenyl)pyridine as a promising new lead for discovering inhibitors of both human and rat 11β-Hydroxylase. 2015, 96:139-50 Eur J Med Chem
1768-3254
25874338
10.1016/j.ejmech.2015.04.013
http://hdl.handle.net/10033/556203
European journal of medicinal chemistry
The inhibition of 11β-hydroxylase is a promising strategy for the treatment of Cushing's syndrome, in particular for the recurrent and subclinical cases. To achieve proof of concept in rats, efforts were paid to identify novel lead compounds inhibiting both human and rat CYP11B1. Modifications on a potent promiscuous inhibitor of hCYP11B1, hCYP11B2 and hCYP19 (compound IV) that exhibited moderate rCYP11B1 inhibition led to compound 8 as a new promising lead compound. Significant improvements compared to starting point IV were achieved regarding inhibitory potency against both human and rat CYP11B1 (IC50 values of 2 and 163 nM, respectively) as well as selectivity over hCYP19 (IC50 = 1900 nM). Accordingly, compound 8 was around 7- and 28-fold more potent than metyrapone regarding the inhibition of human and rat CYP11B1 and exhibited a comparable selectivity over hCYP11B2 (SF of 3.5 vs 4.9). With further optimizations on this new lead compound 8, drug candidates with satisfying profiles are expected to be discovered.
en
Identification of 4-(4-nitro-2-phenethoxyphenyl)pyridine as a promising new lead for discovering inhibitors of both human and rat 11β-Hydroxylase.
Article
oai:repository.helmholtz-hzi.de:10033/5610552019-08-30T11:35:39Zcom_10033_620656col_10033_620657
Zielonka, Stefan
Empting, Martin
Könning, Doreen
Grzeschik, Julius
Krah, Simon
Becker, Stefan
Dickgießer, Stephan
Kolmar, Harald
2015-07-27T09:50:38Z
2015-07-27T09:50:38Z
2015-08
The Shark Strikes Twice: Hypervariable Loop 2 of Shark IgNAR Antibody Variable Domains and Its Potential to Function as an Autonomous Paratope. 2015, 17 (4):386-92 Mar. Biotechnol.
1436-2236
26003538
10.1007/s10126-015-9642-z
http://hdl.handle.net/10033/561055
Marine biotechnology (New York, N.Y.)
In this present study, we engineered hypervariable loop 2 (HV2) of the IgNAR variable domain in a way that it solely facilitates antigen binding, potentially functioning as an autonomous paratope. For this, the surface-exposed loop corresponding to HV2 was diversified and antigen-specific variable domain of IgNAR antibody (vNAR) molecules were isolated by library screening using yeast surface display (YSD) as platform technology. An epithelial cell adhesion molecule (EpCAM)-specific vNAR was used as starting material, and nine residues in HV2 were randomized. Target-specific clones comprising a new HV2-mediated paratope were isolated against cluster of differentiation 3ε (CD3ε) and human Fcγ while retaining high affinity for EpCAM. Essentially, we demonstrate that a new paratope comprising moderate affinities against a given target molecule can be engineered into the vNAR scaffold that acts independent of the original antigen-binding site, composed of complementarity-determining region 3 (CDR3) and CDR1.
en
The Shark Strikes Twice: Hypervariable Loop 2 of Shark IgNAR Antibody Variable Domains and Its Potential to Function as an Autonomous Paratope.
Article
oai:repository.helmholtz-hzi.de:10033/5759332019-08-30T11:33:30Zcom_10033_620656col_10033_620657
Müller, Stefan
Rachid, Shwan
Hoffmann, Thomas
Surup, Frank
Volz, Carsten
Zaburannyi, Nestor
Müller, Rolf
2015-08-25T13:54:50Z
2015-08-25T13:54:50Z
2014-07-17
Biosynthesis of crocacin involves an unusual hydrolytic release domain showing similarity to condensation domains. 2014, 21 (7):855-65 Chem. Biol.
1879-1301
24981773
10.1016/j.chembiol.2014.05.012
http://hdl.handle.net/10033/575933
Chemistry & biology
The crocacins are potent antifungal and cytotoxic natural compounds from myxobacteria of the genus Chondromyces. Although total synthesis approaches have been reported, the molecular and biochemical basis guiding the formation of the linear crocacin scaffold has remained unknown. Along with the identification and functional analysis of the crocacin biosynthetic gene cluster from Chondromyces crocatus Cm c5, we here present the identification and biochemical characterization of an unusual chain termination domain homologous to condensation domains responsible for hydrolytic release of the product from the assembly line. In particular, gene inactivation studies and in vitro experiments using the heterologously produced domain CroK-C2 confirm this surprising role giving rise to the linear carboxylic acid. Additionally, we determined the kinetic parameters of CroK-C2 by monitoring hydrolytic cleavage of the substrate mimic N-acetylcysteaminyl-crocacin B using an innovative high-performance liquid chromatography mass spectrometry-based assay.
en
Biosynthesis of crocacin involves an unusual hydrolytic release domain showing similarity to condensation domains.
Article
oai:repository.helmholtz-hzi.de:10033/6209482019-08-30T11:36:32Zcom_10033_620656col_10033_620657
Steinbach, Anke
Maurer, Christine K
Weidel, Elisabeth
Henn, Claudia
Brengel, Christian
Hartmann, Rolf W
Negri, Matthias
2017-06-15T08:44:04Z
2017-06-15T08:44:04Z
2013-08-01
BMC Biophysics. 2013 Aug 01;6(1):10
http://dx.doi.org/10.1186/2046-1682-6-10
http://hdl.handle.net/10033/620948
Abstract Background PQS (P seudomonas Quinolone Signal) and its precursor HHQ are signal molecules of the P. aeruginosa quorum sensing system. They explicate their role in mammalian pathogenicity by binding to the receptor PqsR that induces virulence factor production and biofilm formation. The enzyme PqsD catalyses the biosynthesis of HHQ. Results Enzyme kinetic analysis and surface plasmon resonance (SPR) biosensor experiments were used to determine mechanism and substrate order of the biosynthesis. Comparative analysis led to the identification of domains involved in functionality of PqsD. A kinetic cycle was set up and molecular dynamics (MD) simulations were used to study the molecular bases of the kinetics of PqsD. Trajectory analysis, pocket volume measurements, binding energy estimations and decompositions ensured insights into the binding mode of the substrates anthraniloyl-CoA and β-ketodecanoic acid. Conclusions Enzyme kinetics and SPR experiments hint at a ping-pong mechanism for PqsD with ACoA as first substrate. Trajectory analysis of different PqsD complexes evidenced ligand-dependent induced-fit motions affecting the modified ACoA funnel access to the exposure of a secondary channel. A tunnel-network is formed in which Ser317 plays an important role by binding to both substrates. Mutagenesis experiments resulting in the inactive S317F mutant confirmed the importance of this residue. Two binding modes for β-ketodecanoic acid were identified with distinct catalytic mechanism preferences.
en
Steinbach et al.; licensee BioMed Central Ltd.
Molecular basis of HHQ biosynthesis: molecular dynamics simulations, enzyme kinetic and surface plasmon resonance studies
Journal Article
oai:repository.helmholtz-hzi.de:10033/5774382019-08-30T11:34:48Zcom_10033_620656col_10033_620657
Adam, Oliver
Zimmer, Christina
Hanke, Nina
Hartmann, Rolf W
Klemmer, Birgit
Böhm, Michael
Laufs, Ulrich
2015-09-17T15:17:44Z
2015-09-17T15:17:44Z
2015-08
Inhibition of aldosterone synthase (CYP11B2) by torasemide prevents atrial fibrosis and atrial fibrillation in mice. 2015, 85:140-50 J. Mol. Cell. Cardiol.
1095-8584
26047574
10.1016/j.yjmcc.2015.05.019
http://hdl.handle.net/10033/577438
Journal of molecular and cellular cardiology
Loop diuretics are used for fluid control in patients with heart failure. Furosemide and torasemide may exert differential effects on myocardial fibrosis. Here, we studied the effects of torasemide and furosemide on atrial fibrosis and remodeling during atrial fibrillation. In primary neonatal cardiac fibroblasts, torasemide (50μM, 24h) but not furosemide (50μM, 24h) reduced the expression of connective tissue growth factor (CTGF; 65±6%) and the pro-fibrotic miR-21 (44±23%), as well as the expression of lysyl oxidase (LOX; 57±8%), a regulator of collagen crosslinking. Mineralocorticoid receptor (MR) expression and activity were not altered. Torasemide but not furosemide inhibited human aldosterone synthase (CYP11B2) activity in transfected lung fibroblasts (V79MZ cells) by 75±1.8%. The selective CYP11B2 inhibitor SL242 mimicked the torasemide effects. Mice with cardiac overexpression of Rac1 GTPase (RacET), which develop atrial fibrosis and spontaneous AF with aging, were treated long-term (8months) with torasemide (10mg/kg/day), furosemide (40mg/kg/day) or vehicle. Treatment with torasemide but not furosemide prevented atrial fibrosis in RacET as well as the up-regulation of CTGF, LOX, and miR-2, whereas MR expression and activity remained unaffected. These effects correlated with a reduced prevalence of atrial fibrillation (33% RacET+Tora vs. 80% RacET). Torasemide but not furosemide inhibits CYP11B2 activity and reduces the expression of CTGF, LOX, and miR-21. These effects are associated with prevention of atrial fibrosis and a reduced prevalence of atrial fibrillation in mice.
en
Inhibition of aldosterone synthase (CYP11B2) by torasemide prevents atrial fibrosis and atrial fibrillation in mice.
Article
oai:repository.helmholtz-hzi.de:10033/5796122019-08-30T11:34:48Zcom_10033_620656col_10033_620657
Abdelsamie, Ahmed S
Bey, Emmanuel
Gargano, Emanuele M
van Koppen, Chris J
Empting, Martin
Frotscher, Martin
2015-10-14T08:24:30Z
2015-10-14T08:24:30Z
2015-10-20
Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme. 2015, 103:56-68 Eur J Med Chem
1768-3254
26322835
10.1016/j.ejmech.2015.08.030
http://hdl.handle.net/10033/579612
European journal of medicinal chemistry
17β-Estradiol (E2), the most potent human estrogen, is known to be involved in the etiology of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step of E2 biosynthesis and is thus a promising target for the treatment of EDD. The previously described bicyclic substituted hydroxyphenylmethanones (BSHs) display high inhibitory potency towards human 17β-HSD1, but marginal activity towards rodent 17β-HSD1, precluding a proof of principle study in an animal endometriosis model. The aim of this work was to perform structural optimizations in the BSHs class to enhance inhibitory activity against rodent (mouse and rat) 17β-HSD1 while maintaining activity against the human enzyme. The introduction of fluorine atoms on the benzoyl moiety resulted in compounds with the desired properties. Molecular docking and homology modeling were applied to elucidate the binding mode and interspecies differences in activity. Compound 33 is the most potent inhibitor of both human and rat 17β-HSD1 up to date (IC50 = 2 nM and 97 nM, respectively).
en
Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme.
Article
oai:repository.helmholtz-hzi.de:10033/5931012019-08-30T11:34:17Zcom_10033_620656col_10033_620657
Thomann, Andreas
Eberhard, Jens
Allegretta, Giuseppe
Empting, Martin
Hartmann, Rolf
2016-01-08T15:36:42Z
2016-01-08T15:36:42Z
2015-10-21
Mild and Catalyst-Free Microwave-Assisted Synthesis of 4,6-Disubstituted 2-Methylthiopyrimidines – Exploiting Tetrazole as an Efficient Leaving Group 2015, 26 (18):2606 Synlett
0936-5214
1437-2096
10.1055/s-0035-1560577
http://hdl.handle.net/10033/593101
Synlett
Mild and Catalyst-Free Microwave-Assisted Synthesis of 4,6-Disubstituted 2-Methylthiopyrimidines – Exploiting Tetrazole as an Efficient Leaving Group
Article
oai:repository.helmholtz-hzi.de:10033/5957132019-08-30T11:37:23Zcom_10033_620656col_10033_620657
Reuter, Kerstin
Steinbach, Anke
Helms, Volkhard
2016-02-05T14:20:00Z
2016-02-05T14:20:00Z
2016
Interfering with Bacterial Quorum Sensing. 2016, 8:1-15 Perspect Medicin Chem
1177-391X
26819549
10.4137/PMC.S13209
http://hdl.handle.net/10033/595713
Perspectives in medicinal chemistry
Quorum sensing (QS) describes the exchange of chemical signals in bacterial populations to adjust the bacterial phenotypes according to the density of bacterial cells. This serves to express phenotypes that are advantageous for the group and ensure bacterial survival. To do so, bacterial cells synthesize autoinducer (AI) molecules, release them to the environment, and take them up. Thereby, the AI concentration reflects the cell density. When the AI concentration exceeds a critical threshold in the cells, the AI may activate the expression of virulence-associated genes or of luminescent proteins. It has been argued that targeting the QS system puts less selective pressure on these pathogens and should avoid the development of resistant bacteria. Therefore, the molecular components of QS systems have been suggested as promising targets for developing new anti-infective compounds. Here, we review the QS systems of selected gram-negative and gram-positive bacteria, namely, Vibrio fischeri, Pseudomonas aeruginosa, and Staphylococcus aureus, and discuss various antivirulence strategies based on blocking different components of the QS machinery.
en
Interfering with Bacterial Quorum Sensing.
Article
oai:repository.helmholtz-hzi.de:10033/5966492019-08-30T11:37:24Zcom_10033_620656col_10033_620657
Thomann, Andreas
Huch, Volker
Hartmann, Rolf W
2016-02-18T15:35:30Z
2016-02-18T15:35:30Z
2015-12-01
Crystal structure of 4-methyl-sulfanyl-2-(2H-tetra-zol-2-yl)pyrimidine. 2015, 71 (Pt 12):o1051-2 Acta Crystallogr E Crystallogr Commun
2056-9890
26870493
10.1107/S2056989015023634
http://hdl.handle.net/10033/596649
Acta crystallographica. Section E, Crystallographic communications
The title compound, C6H6N6S, crystallized with two independent mol-ecules (A and B) in the asymmetric unit. The conformation of the two mol-ecules differs slightly. While the tetra-zole ring is inclined to the pyrim-idene ring by 5.48 (7) and 4.24 (7)° in mol-ecules A and B, respectively, the N-C-S-C torsion angles of the thio-methyl groups differ by ca 180°. In the crystal, the A and B mol-ecules are linked via a C-H⋯N hydrogen bond. They stack along the b-axis direction forming columns within which there are weak π-π inter-actions present [shortest inter-centroid distance = 3.6933 (13) Å].
en
Crystal structure of 4-methyl-sulfanyl-2-(2H-tetra-zol-2-yl)pyrimidine.
Article
oai:repository.helmholtz-hzi.de:10033/6043822019-08-30T11:35:39Zcom_10033_620656col_10033_620657
Krah, Simon
Schröter, Christian
Zielonka, Stefan
Empting, Martin
Valldorf, Bernhard
Kolmar, Harald
2016-04-04T14:22:16Z
2016-04-04T14:22:16Z
2016-02
Single-domain antibodies for biomedical applications. 2016, 38 (1):21-8 Immunopharmacol Immunotoxicol
1532-2513
26551147
10.3109/08923973.2015.1102934
http://hdl.handle.net/10033/604382
Immunopharmacology and immunotoxicology
Single-domain antibodies are the smallest antigen-binding units of antibodies, consisting either only of one variable domain or one engineered constant domain that solely facilitates target binding. This class of antibody derivatives comprises naturally occurring variable domains derived from camelids and sharks as well as engineered human variable or constant antibody domains of the heavy or light chain. Because of their high affinity and specificity as well as stability, small size and benefit of multiple re-formatting opportunities, those molecules emerged as promising candidates for biomedical applications and some of these entities have already proven to be successful in clinical development.
en
Single-domain antibodies for biomedical applications.
Article
oai:repository.helmholtz-hzi.de:10033/6112272019-08-30T11:32:59Zcom_10033_620656col_10033_620657
Barthold, S.
Kletting, S.
Taffner, J.
de Souza Carvalho-Wodarz, C.
Lepeltier, E.
Loretz, B.
Lehr, Claus Michael
2016-05-31T12:16:24Z
2016-05-31T12:16:24Z
2016
Preparation of nanosized coacervates of positive and negative starch derivatives intended for pulmonary delivery of proteins 2016, 4 (13):2377 J. Mater. Chem. B
2050-750X
2050-7518
10.1039/C6TB00178E
http://hdl.handle.net/10033/611227
J. Mater. Chem. B
Preparation of nanosized coacervates of positive and negative starch derivatives intended for pulmonary delivery of proteins
Article
oai:repository.helmholtz-hzi.de:10033/6156132019-08-30T11:30:58Zcom_10033_620656col_10033_620657
Gargano, Emanuele M
Allegretta, Giuseppe
Perspicace, Enrico
Carotti, Angelo
Van Koppen, Chris
Frotscher, Martin
Marchais-Oberwinkler, Sandrine
Hartmann, Rolf W
2016-07-06T09:39:32Z
2016-07-06T09:39:32Z
2015
17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog. 2015, 10 (7):e0134754 PLoS ONE
1932-6203
26230928
10.1371/journal.pone.0134754
http://hdl.handle.net/10033/615613
PloS one
Design and synthesis of a new class of inhibitors for the treatment of osteoporosis and its comparative h17β-HSD2 and m17β-HSD2 SAR study are described. 17a is the first compound to show strong inhibition of both h17β-HSD2 and m17β-HSD2, intracellular activity, metabolic stability, selectivity toward h17β-HSD1, m17β-HSD1 and estrogen receptors α and β as well as appropriate physicochemical properties for oral bioavailability. These properties make it eligible for pre-clinical animal studies, prior to human studies.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
17β-Hydroxysteroid Dehydrogenase Type 2 Inhibition: Discovery of Selective and Metabolically Stable Compounds Inhibiting Both the Human Enzyme and Its Murine Ortholog.
Article
oai:repository.helmholtz-hzi.de:10033/6159092019-08-30T11:30:58Zcom_10033_620656col_10033_620657
Elgaher, Walid A M
Sharma, Kamal K
Haupenthal, Jörg
Saladini, Francesco
Pires, Manuel
Real, Eleonore
Mély, Yves
Hartmann, Rolf W
2016-07-11T14:26:33Z
2016-07-11T14:26:33Z
2016-07-07
Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors. 2016: J. Med. Chem.
1520-4804
27339173
10.1021/acs.jmedchem.6b00730
http://hdl.handle.net/10033/615909
Journal of medicinal chemistry
We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure-activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity.
http://creativecommons.org/licenses/by-nc-sa/4.0/
Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors.
Article
oai:repository.helmholtz-hzi.de:10033/6185992019-08-30T11:35:39Zcom_10033_620656col_10033_620657
Maurer, Christine K
Fruth, Martina
Empting, Martin
Avrutina, Olga
Hoßmann, Jörn
Nadmid, Suvd
Gorges, Jan
Herrmann, Jennifer
Kazmaier, Uli
Dersch, Petra
Müller, Rolf
Hartmann, Rolf W
2016-08-19T12:59:04Z
2016-08-19T12:59:04Z
2016-06
Discovery of the first small-molecule CsrA-RNA interaction inhibitors using biophysical screening technologies. 2016, 8 (9):931-47 Future Med Chem
1756-8927
27253623
10.4155/fmc-2016-0033
http://hdl.handle.net/10033/618599
Future medicinal chemistry
CsrA is a global post-transcriptional regulator protein affecting mRNA translation and/or stability. Widespread among bacteria, it is essential for their full virulence and thus represents a promising anti-infective drug target. Therefore, we aimed at the discovery of CsrA-RNA interaction inhibitors. Results & methodology: We followed two strategies: a screening of small molecules (A) and an RNA ligand-based approach (B). Using surface plasmon resonance-based binding and fluorescence polarization-based competition assays, (A) yielded seven small-molecule inhibitors, among them MM14 (IC50 of 4 µM). (B) resulted in RNA-based inhibitor GGARNA (IC50 of 113 µM).
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Discovery of the first small-molecule CsrA-RNA interaction inhibitors using biophysical screening technologies.
Article
oai:repository.helmholtz-hzi.de:10033/6205942019-08-30T11:34:48Zcom_10033_620656col_10033_620657
Thomann, Andreas
Brengel, Christian
Börger, Carsten
Kail, Dagmar
Steinbach, Anke
Empting, Martin
Hartmann, Rolf W
2016-11-25T11:41:20Z
2016-11-25T11:41:20Z
2016-11-21
Structure-Activity Relationships of 2-Sufonylpyrimidines as Quorum-Sensing Inhibitors to Tackle Biofilm Formation and eDNA Release of Pseudomonas aeruginosa. 2016, 11 (22):2522-2533 ChemMedChem
1860-7187
27731921
10.1002/cmdc.201600419
http://hdl.handle.net/10033/620594
ChemMedChem
Drug-resistant Pseudomonas aeruginosa (PA) strains are on the rise, making treatment with current antibiotics ineffective. Hence, circumventing resistance or restoring the activity of antibiotics by novel approaches is of high demand. Targeting the Pseudomonas quinolone signal quorum sensing (PQS-QS) system is an intriguing strategy to abolish PA pathogenicity without affecting the viability of the pathogen. Herein we report the structure-activity relationships of 2-sulfonylpyrimidines, which were previously identified as dual-target inhibitors of the PQS receptor PqsR and the PQS synthase PqsD. The SAR elucidation was guided by a combined approach using ligand efficiency and ligand lipophilicity efficiency to select the most promising compounds. In addition, the most effective inhibitors were rationally modified by the guidance of QSAR using Hansch analyses. Finally, these inhibitors showed the capacity to decrease biofilm mass and extracellular DNA, which are important determinants for antibiotic resistance.
http://creativecommons.org/licenses/by-nc-sa/4.0/
Structure-Activity Relationships of 2-Sufonylpyrimidines as Quorum-Sensing Inhibitors to Tackle Biofilm Formation and eDNA Release of Pseudomonas aeruginosa.
Article
oai:repository.helmholtz-hzi.de:10033/6209172019-08-30T11:29:47Zcom_10033_620656col_10033_620657
Fazli, Mustafa
Rybtke, Morten
Steiner, Elisabeth
Weidel, Elisabeth
Berthelsen, Jens
Groizeleau, Julie
Bin, Wu
Zhi, Boo Zhao
Yaming, Zhang
Kaever, Volkhard
Givskov, Michael
Hartmann, Rolf W.
Eberl, Leo
Tolker-Nielsen, Tim
2017-05-12T14:47:05Z
2017-05-12T14:47:05Z
2017-04-16
Regulation of Burkholderia cenocepacia biofilm formation by RpoN and the c-di-GMP effector BerB. 2017 Microbiologyopen
2045-8827
28419759
10.1002/mbo3.480
http://hdl.handle.net/10033/620917
MicrobiologyOpen
Knowledge about the molecular mechanisms that are involved in the regulation of biofilm formation is essential for the development of biofilm-control measures. It is well established that the nucleotide second messenger cyclic diguanosine monophosphate (c-di-GMP) is a positive regulator of biofilm formation in many bacteria, but more knowledge about c-di-GMP effectors is needed. We provide evidence that c-di-GMP, the alternative sigma factor RpoN (σ54), and the enhancer-binding protein BerB play a role in biofilm formation of Burkholderia cenocepacia by regulating the production of a biofilm-stabilizing exopolysaccharide. Our findings suggest that BerB binds c-di-GMP, and activates RpoN-dependent transcription of the berA gene coding for a c-di-GMP-responsive transcriptional regulator. An increased level of the BerA protein in turn induces the production of biofilm-stabilizing exopolysaccharide in response to high c-di-GMP levels. Our findings imply that the production of biofilm exopolysaccharide in B. cenocepacia is regulated through a cascade involving two consecutive transcription events that are both activated by c-di-GMP. This type of regulation may allow tight control of the expenditure of cellular resources.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Regulation of Burkholderia cenocepacia biofilm formation by RpoN and the c-di-GMP effector BerB.
Article
oai:repository.helmholtz-hzi.de:10033/6209652019-08-30T11:34:22Zcom_10033_620656col_10033_620657
Allegretta, Giuseppe
Maurer, Christine K
Eberhard, Jens
Maura, Damien
Hartmann, Rolf W
Rahme, Laurence
Empting, Martin
2017-06-21T08:51:17Z
2017-06-21T08:51:17Z
2017
In-depth Profiling of MvfR-Regulated Small Molecules in Pseudomonas aeruginosa after Quorum Sensing Inhibitor Treatment. 2017, 8:924 Front Microbiol
28596760
10.3389/fmicb.2017.00924
http://hdl.handle.net/10033/620965
Frontiers in microbiology
Pseudomonas aeruginosa is a Gram-negative bacterium, which causes opportunistic infections in immuno-compromised individuals. Due to its multiple resistances toward antibiotics, the development of new drugs is required. Interfering with Quorum Sensing (QS), a cell-to-cell communication system, has shown to be highly efficient in reducing P. aeruginosa pathogenicity. One of its QS systems employs Pseudomonas Quinolone Signal (PQS) and 4-hydroxy-2-heptylquinoline (HHQ) as signal molecules. Both activate the transcriptional regulator MvfR (Multiple Virulence Factor Regulator), also called PqsR, driving the production of QS molecules as well as toxins and biofilm formation. The aim of this work was to elucidate the effects of QS inhibitors (QSIs), such as MvfR antagonists and PqsBC inhibitors, on the biosynthesis of the MvfR-regulated small molecules 2'-aminoacetophenone (2-AA), dihydroxyquinoline (DHQ), HHQ, PQS, and 4-hydroxy-2-heptylquinoline-N-oxide (HQNO). The employed synthetic MvfR antagonist fully inhibited pqs small molecule formation showing expected sigmoidal dose-response curves for 2-AA, HQNO, HHQ and PQS. Surprisingly, DHQ levels were enhanced at lower antagonist concentrations followed by a full suppression at higher QSI amounts. This particular bi-phasic profile hinted at the accumulation of a biosynthetic intermediate resulting in the observed overproduction of the shunt product DHQ. Additionally, investigations on PqsBC inhibitors showed a reduction of MvfR natural ligands, while increased 2-AA, DHQ and HQNO levels compared to the untreated cells were detected. Moreover, PqsBC inhibitors did not show any significant effect in PA14 pqsC mutant demonstrating their target selectivity. As 2-AA is important for antibacterial tolerance, the QSIs were evaluated in their capability to attenuate persistence. Indeed, persister cells were reduced along with 2-AA inhibition resulting from MvfR antagonism, but not from PqsBC inhibition. In conclusion, antagonizing MvfR using a dosage capable of fully suppressing this QS system will lead to a favorable therapeutic outcome as DHQ overproduction is avoided and bacterial persistence is reduced.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
In-depth Profiling of MvfR-Regulated Small Molecules in Pseudomonas aeruginosa after Quorum Sensing Inhibitor Treatment.
Article
oai:repository.helmholtz-hzi.de:10033/6210192019-08-30T11:26:42Zcom_10033_620656col_10033_620657
Schmitt, Christian
Kail, Dagmar
Mariano, Marica
Empting, Martin
Weber, Nadja
Paul, Tamara
Hartmann, Rolf W.
Engel, Matthias
2017-07-25T13:56:49Z
2017-07-25T13:56:49Z
2014
Design and synthesis of a library of lead-like 2,4-bisheterocyclic substituted thiophenes as selective Dyrk/Clk inhibitors. 2014, 9 (3):e87851 PLoS ONE
1932-6203
24676346
10.1371/journal.pone.0087851
http://hdl.handle.net/10033/621019
PloS one
The Dyrk family of protein kinases is implicated in the pathogenesis of several diseases, including cancer and neurodegeneration. Pharmacological inhibitors were mainly described for Dyrk1A so far, but in fewer cases for Dyrk1B, Dyrk2 or other isoforms. Herein, we report the development and optimization of 2,4-bisheterocyclic substituted thiophenes as a novel class of Dyrk inhibitors. The optimized hit compounds displayed favorable pharmacokinetic properties and high ligand efficiencies, and inhibited Dyrk1B in intact cells. In a larger selectivity screen, only Clk1 and Clk4 were identified as additional targets of compound 48, but no other kinases frequently reported as off-targets. Interestingly, Dyrk1A is implicated in the regulation of alternative splicing, a function shared with Clk1/Clk4; thus, some of the dual inhibitors might be useful as efficient splicing modulators. A further compound (29) inhibited Dyrk1A and 1B with an IC50 of 130 nM, showing a moderate selectivity over Dyrk2. Since penetration of the central nervous system (CNS) seems possible based on the physicochemical properties, this compound might serve as a lead for the development of potential therapeutic agents against glioblastoma. Furthermore, an inhibitor selective for Dyrk2 (24) was also identified, which might be are suitable as a pharmacological tool to dissect Dyrk2 isoform-mediated functions.
en
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Design and synthesis of a library of lead-like 2,4-bisheterocyclic substituted thiophenes as selective Dyrk/Clk inhibitors.
Article
oai:repository.helmholtz-hzi.de:10033/6210892019-08-30T11:27:16Zcom_10033_620656col_10033_620657
Gobbi, Silvia
Hu, Qingzhong
Zimmer, Christina
Belluti, Federica
Rampa, Angela
Hartmann, Rolf W.
Bisi, Alessandra
2017-09-04T13:33:12Z
2017-09-04T13:33:12Z
2017-08-02
Drifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1. 2017, 139:60-67 Eur J Med Chem
1768-3254
28797884
10.1016/j.ejmech.2017.07.078
http://hdl.handle.net/10033/621089
European journal of medicinal chemistry
An abnormal increase in glucocorticoid levels is responsible for pathological disorders affecting different organs and systems, and the selective inhibition of appropriate steroidogenic enzymes represents a validated strategy to restore their physiological levels. In continuing our studies on CYP11B inhibitors, in this paper a small series of 6-substituted 3-imidazolylmethylxanthones was designed and synthesized, according to the data acquired from previously reported series of derivatives and from a purposely-performed docking study. The new compounds proved to be potent inhibitors of CYP11B isoforms, being effective on CYP11B1 in the low nanomolar range and improving selectivity with respect to CYP11B2, compared to previously reported related compounds. These data further confirmed that a suitable mutual arrangement of the imidazolylmethyl pharmacophore and a properly selected substituent on the xanthone core allows a fine tuning of the activity towards the different CYPs and further corroborate the role of the xanthone scaffold as a privileged structure in this field.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Drifting of heme-coordinating group in imidazolylmethylxanthones leading to improved selective inhibition of CYP11B1.
Article
oai:repository.helmholtz-hzi.de:10033/6211122019-08-30T11:33:05Zcom_10033_620656col_10033_620657
Kamal, Ahmed A M
Petrera, Lucia
Eberhard, Jens
Hartmann, Rolf W.
2017-09-18T12:58:35Z
2017-09-18T12:58:35Z
2017-05-31
Structure-functionality relationship and pharmacological profiles of Pseudomonas aeruginosa alkylquinolone quorum sensing modulators. 2017, 15 (21):4620-4630 Org. Biomol. Chem.
1477-0539
28513746
10.1039/c7ob00263g
http://hdl.handle.net/10033/621112
Organic & biomolecular chemistry
An important paradigm in anti-infective research is the antivirulence concept. Pathoblockers are compounds which disarm bacteria of their arsenal of virulence factors. PqsR is a transcriptional regulator controlling the production of such factors in Pseudomonas aeruginosa, most prominently pyocyanin. In this work, a series of tool compounds based on the structure of the natural ligand 2-heptyl-4-quinolone (HHQ) were used for probing the structure-functionality relationship. Four different profiles are identified namely agonists, antagonists, inverse agonists and biphasic modulators. Molecular docking studies revealed that each class of the PqsR modulators showed distinctive interactions in the PqsR binding domain. It was found that the substituents in position 3 of the quinolone core act as a switch between the different profiles, according to their ability to donate or accept a hydrogen bond, or form a hydrophobic interaction. Finally, it was shown that only inverse agonists were able to strongly inhibit pyocyanin production.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Structure-functionality relationship and pharmacological profiles of Pseudomonas aeruginosa alkylquinolone quorum sensing modulators.
Article
oai:repository.helmholtz-hzi.de:10033/6211232019-08-30T11:31:49Zcom_10033_620656col_10033_620657
Könning, Doreen
Rhiel, Laura
Empting, Martin
Grzeschik, Julius
Sellmann, Carolin
Schröter, Christian
Zielonka, Stefan
Dickgießer, Stephan
Pirzer, Thomas
Yanakieva, Desislava
Becker, Stefan
Kolmar, Harald
2017-09-26T13:22:25Z
2017-09-26T13:22:25Z
2017-08-29
Semi-synthetic vNAR libraries screened against therapeutic antibodies primarily deliver anti-idiotypic binders. 2017, 7 (1):9676 Sci Rep
2045-2322
28852148
10.1038/s41598-017-10513-9
http://hdl.handle.net/10033/621123
Scientific reports
Anti-idiotypic binders which specifically recognize the variable region of monoclonal antibodies have proven to be robust tools for pharmacokinetic studies of antibody therapeutics and for the development of cancer vaccines. In the present investigation, we focused on the identification of anti-idiotypic, shark-derived IgNAR antibody variable domains (vNARs) targeting the therapeutic antibodies matuzumab and cetuximab for the purpose of developing specific capturing ligands. Using yeast surface display and semi-synthetic, CDR3-randomized libraries, we identified several highly specific binders targeting both therapeutic antibodies in their corresponding variable region, without applying any counter selections during screening. Importantly, anti-idiotypic vNAR binders were not cross-reactive towards cetuximab or matuzumab, respectively, and comprised good target recognition in the presence of human and mouse serum. When coupled to magnetic beads, anti-idiotypic vNAR variants could be used as efficient capturing tools. Moreover, a two-step procedure involving vNAR-functionalized beads was employed for the enrichment of potentially bispecific cetuximab × matuzumab antibody constructs. In conclusion, semi-synthetic and CDR3-randomized vNAR libraries in combination with yeast display enable the fast and facile identification of anti-idiotypic vNAR domains targeting monoclonal antibodies primarily in an anti-idiotypic manner.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Semi-synthetic vNAR libraries screened against therapeutic antibodies primarily deliver anti-idiotypic binders.
Article
oai:repository.helmholtz-hzi.de:10033/6211472019-08-30T11:31:23Zcom_10033_620656col_10033_620657
Liu, Yun
Stuart, Marc C A
Witte, Martin D
Buhler, Eric
Hirsch, Anna K H
2017-11-01T08:31:27Z
2017-11-01T08:31:27Z
2017-10-05
Saccharide-Containing Dynamic Proteoids. 2017 Chemistry
1521-3765
28981987
10.1002/chem.201703584
http://hdl.handle.net/10033/621147
Chemistry (Weinheim an der Bergstrasse, Germany)
Dynamic proteoids are dynamic covalent analogues of proteins, which can be used as new adaptive biomaterials. We designed and synthesized a range of sugar-containing dynamic proteoid biodynamers based on the polycondensation of different types of amino acid and dipeptide hydrazides with a biological aliphatic dialdehyde and a nonbiological aromatic dialdehyde. By using the saccharide-based dialdehyde, the biocompatibility of biodynamers should be enhanced compared to previously reported biodynamers.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Saccharide-Containing Dynamic Proteoids.
Article
oai:repository.helmholtz-hzi.de:10033/6211532019-08-30T11:31:23Zcom_10033_620656col_10033_620657
Schönauer, Esther
Kany, Andreas M
Haupenthal, Jörg
Hüsecken, Kristina
Hoppe, Isabel J
Voos, Katrin
Yahiaoui, Samir
Elsässer, Brigitta
Ducho, Christian
Brandstetter, Hans
Hartmann, Rolf W.
2017-11-02T10:29:34Z
2017-11-02T10:29:34Z
2017-09-13
Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases. 2017, 139 (36):12696-12703 J. Am. Chem. Soc.
1520-5126
28820255
10.1021/jacs.7b06935
http://hdl.handle.net/10033/621153
Journal of the American Chemical Society
Secreted virulence factors like bacterial collagenases are conceptually attractive targets for fighting microbial infections. However, previous attempts to develop potent compounds against these metalloproteases failed to achieve selectivity against human matrix metalloproteinases (MMPs). Using a surface plasmon resonance-based screening complemented with enzyme inhibition assays, we discovered an N-aryl mercaptoacetamide-based inhibitor scaffold that showed sub-micromolar affinities toward collagenase H (ColH) from the human pathogen Clostridium histolyticum. Moreover, these inhibitors also efficiently blocked the homologous bacterial collagenases, ColG from C. histolyticum, ColT from C. tetani, and ColQ1 from the Bacillus cereus strain Q1, while showing negligible activity toward human MMPs-1, -2, -3, -7, -8, and -14. The most active compound displayed a more than 1000-fold selectivity over human MMPs. This selectivity can be rationalized by the crystal structure of ColH with this compound, revealing a distinct non-primed binding mode to the active site. The non-primed binding mode presented here paves the way for the development of selective broad-spectrum bacterial collagenase inhibitors with potential therapeutic application in humans.
en
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Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases.
Article
oai:repository.helmholtz-hzi.de:10033/6211712019-08-30T11:33:05Zcom_10033_620656col_10033_620657
Monjas, Leticia
Swier, Lotteke J Y M
Setyawati, Inda
Slotboom, Dirk J
Hirsch, Anna K H
2017-11-08T13:08:39Z
2017-11-08T13:08:39Z
2017-10-20
Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S-Component of the Energy-Coupling Factor Transporter for Thiamine. 2017, 12 (20):1693-1696 ChemMedChem
1860-7187
28960943
10.1002/cmdc.201700440
http://hdl.handle.net/10033/621171
ChemMedChem
We applied dynamic combinatorial chemistry (DCC) to identify ligands of ThiT, the S-component of the energy-coupling factor (ECF) transporter for thiamine in Lactococcus lactis. We used a pre-equilibrated dynamic combinatorial library (DCL) and saturation-transfer difference (STD) NMR spectroscopy to identify ligands of ThiT. This is the first report in which DCC is used for fragment growing to an ill-defined pocket, and one of the first reports for its application with an integral membrane protein as target.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Dynamic Combinatorial Chemistry to Identify Binders of ThiT, an S-Component of the Energy-Coupling Factor Transporter for Thiamine.
Article
oai:repository.helmholtz-hzi.de:10033/6212352019-08-30T11:32:16Zcom_10033_620656col_10033_620657
Marcozzi, Alessio
Masini, Tiziana
Zhu, Di
Pesce, Diego
Illarionov, Boris
Fischer, Markus
Herrmann, Andreas
Hirsch, Anna Katharina Herta
2018-01-17T11:44:13Z
2018-01-17T11:44:13Z
2018-01-04
Phage Display on the Anti-infective Target 1-Deoxy-d-xylulose-5-phosphate Synthase Leads to an Acceptor-Substrate Competitive Peptidic Inhibitor. 2018, 19 (1):58-65 Chembiochem
1439-7633
29119720
10.1002/cbic.201700402
http://hdl.handle.net/10033/621235
Chembiochem : a European journal of chemical biology
Enzymes of the 2-C-methyl-d-erythritol-4-phosphate pathway for the biosynthesis of isoprenoid precursors are validated drug targets. By performing phage display on 1-deoxy-d-xylulose-5-phosphate synthase (DXS), which catalyzes the first step of this pathway, we discovered several peptide hits and recognized false-positive hits. The enriched peptide binder P12 emerged as a substrate (d-glyceraldehyde-3-phosphate)-competitive inhibitor of Deinococcus radiodurans DXS. The results indicate possible overlap of the cofactor- and acceptor-substrate-binding pockets and provide inspiration for the design of inhibitors of DXS with a unique and novel mechanism of inhibition.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
Phage Display on the Anti-infective Target 1-Deoxy-d-xylulose-5-phosphate Synthase Leads to an Acceptor-Substrate Competitive Peptidic Inhibitor.
Article
oai:repository.helmholtz-hzi.de:10033/6213382019-08-30T11:33:57Zcom_10033_338554com_10033_620656com_10033_311308col_10033_621050col_10033_620721col_10033_620657
Bussey, Kendra A
Lau, Ulrike
Schumann, Sophie
Gallo, Antonio
Osbelt, Lisa
Stempel, Markus
Arnold, Christine
Wissing, Josef
Gad, Hans Henrik
Hartmann, Rune
Brune, Wolfram
Jänsch, Lothar
Whitehouse, Adrian
Brinkmann, Melanie M
2018-04-06T11:02:25Z
2018-04-06T11:02:25Z
2018-03
The interferon-stimulated gene product oligoadenylate synthetase-like protein enhances replication of Kaposi's sarcoma-associated herpesvirus (KSHV) and interacts with the KSHV ORF20 protein. 2018, 14 (3):e1006937 PLoS Pathog.
1553-7374
29499066
10.1371/journal.ppat.1006937
http://hdl.handle.net/10033/621338
PLoS pathogens
Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the few oncogenic human viruses known to date. Its large genome encodes more than 85 proteins and includes both unique viral proteins as well as proteins conserved amongst herpesviruses. KSHV ORF20 is a member of the herpesviral core UL24 family, but the function of ORF20 and its role in the viral life cycle is not well understood. ORF20 encodes three largely uncharacterized isoforms, which we found were localized predominantly in the nuclei and nucleoli. Quantitative affinity purification coupled to mass spectrometry (q-AP-MS) identified numerous specific interacting partners of ORF20, including ribosomal proteins and the interferon-stimulated gene product (ISG) oligoadenylate synthetase-like protein (OASL). Both endogenous and transiently transfected OASL co-immunoprecipitated with ORF20, and this interaction was conserved among all ORF20 isoforms and multiple ORF20 homologs of the UL24 family in other herpesviruses. Characterization of OASL interacting partners by q-AP-MS identified a very similar interactome to that of ORF20. Both ORF20 and OASL copurified with 40S and 60S ribosomal subunits, and when they were co-expressed, they associated with polysomes. Although ORF20 did not have a global effect on translation, ORF20 enhanced RIG-I induced expression of endogenous OASL in an IRF3-dependent but IFNAR-independent manner. OASL has been characterized as an ISG with antiviral activity against some viruses, but its role for gammaherpesviruses was unknown. We show that OASL and ORF20 mRNA expression were induced early after reactivation of latently infected HuARLT-rKSHV.219 cells. Intriguingly, we found that OASL enhanced infection of KSHV. During infection with a KSHV ORF20stop mutant, however, OASL-dependent enhancement of infectivity was lost. Our data have characterized the interaction of ORF20 with OASL and suggest ORF20 usurps the function of OASL to benefit KSHV infection.
en
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The interferon-stimulated gene product oligoadenylate synthetase-like protein enhances replication of Kaposi's sarcoma-associated herpesvirus (KSHV) and interacts with the KSHV ORF20 protein.
Article
oai:repository.helmholtz-hzi.de:10033/6214022019-08-30T11:26:38Zcom_10033_620656col_10033_620657
Liu, Yun
Stuart, Marc C A
Buhler, Eric
Hirsch, Anna K H
2018-06-18T11:57:38Z
2018-06-18T11:57:38Z
2018-05-28
1521-3927
29806088
10.1002/marc.201800099
http://hdl.handle.net/10033/621402
Dynamic proteoids are dynamic covalent analogues of proteins which are generated through the reversible polymerization of amino-acid- or peptide-derived monomers. The authors design and prepare a series of dynamic proteoids based on the reversible polycondensation of six types of dipeptide hydrazides bearing different categories of side chains. The polymerization and structures of biodynamers generated by
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Attribution-NonCommercial-ShareAlike 3.0 United States
biodynamers
dynamic proteoids
polycondensation
reversible polymerization
supramolecular structures
Dynamic Proteoids Generated From Dipeptide-Based Monomers.
Article
oai:repository.helmholtz-hzi.de:10033/6214742018-09-11T01:30:01Zcom_10033_620656col_10033_620657
Liu, Yun
Stuart, Marc C A
Witte, Martin D
Buhler, Eric
Hirsch, Anna K H
2018-09-10T14:06:00Z
2018-09-10T14:06:00Z
2017-11-16
1521-3765
28981987
10.1002/chem.201703584
http://hdl.handle.net/10033/621474
Dynamic proteoids are dynamic covalent analogues of proteins, which can be used as new adaptive biomaterials. We designed and synthesized a range of sugar-containing dynamic proteoid biodynamers based on the polycondensation of different types of amino acid and dipeptide hydrazides with a biological aliphatic dialdehyde and a nonbiological aromatic dialdehyde. By using the saccharide-based dialdehyde, the biocompatibility of biodynamers should be enhanced compared to previously reported biodynamers.
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
openAccess
Attribution-NonCommercial-ShareAlike 3.0 United States
biodynamers
dynamic proteoids
equilibrium polymerization
nanostructures
supramolecular chemistry
Saccharide-Containing Dynamic Proteoids.
Article
oai:repository.helmholtz-hzi.de:10033/6214752019-08-30T11:27:44Zcom_10033_620656col_10033_620657
Liu, Yun
de Vries, Jan Willem
Liu, Qing
Hartman, Alwin M
Wieland, Gerhard D
Wieczorek, Sebastian
Börner, Hans G
Wiehe, Arno
Buhler, Eric
Stuart, Marc C A
Browne, Wesley R
Herrmann, Andreas
Hirsch, Anna K H
2018-09-11T11:54:22Z
2018-09-11T11:54:22Z
2018-01-19
1521-3765
29194834
10.1002/chem.201705206
http://hdl.handle.net/10033/621475
Hydrophobic drug candidates require innovative formulation agents. We designed and synthesized lipid-DNA polymers containing varying numbers of hydrophobic alkyl chains. The hydrophobicity of these amphiphiles is easily tunable by introducing a defined number of alkyl chain-modified nucleotides during standard solid-phase synthesis of DNA using an automated DNA synthesizer. We observed that the resulting self-assembled micelles solubilize the poorly water-soluble drug, meta-tetra-hydroxyphenyl-chlorin (mTHPC) used in photodynamic therapy (PDT) with high loading concentrations and loading capacities. A cell viability study showed that mTHPC-loaded micelles exhibit good biocompatibility without irradiation, and high PDT efficacy upon irradiation. Lipid-DNAs provide a novel class of drug-delivery vehicle, and hybridization of DNA offers a potentially facile route for further functionalization of the drug-delivery system with, for instance, targeting or imaging moieties.
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
amphiphiles
drug delivery
lipid-DNA
micelles
photodynamic therapy
Lipid-DNAs as Solubilizers of mTHPC.
Article
oai:repository.helmholtz-hzi.de:10033/6214822019-11-20T02:02:10Zcom_10033_620613com_10033_620656col_10033_620614col_10033_620685col_10033_620657
Frank, Julia
Richter, Maximilian
de Rossi, Chiara
Lehr, Claus-Michael
Fuhrmann, Kathrin
Fuhrmann, Gregor
2018-09-17T07:54:12Z
2018-09-17T07:54:12Z
2018-08-17
2045-2322
30120298
10.1038/s41598-018-30786-y
http://hdl.handle.net/10033/621482
Extracellular vesicles (EVs) are natural nanoparticles that play important roles in intercellular communication and are increasingly studied for biosignalling, pathogenesis and therapy. Nevertheless, little is known about optimal conditions for their transfer and storage, and the potential impact on preserving EV-loaded cargoes. We present the first comprehensive stability assessment of different widely available types of EVs during various storage conditions including -80 °C, 4 °C, room temperature, and freeze-drying (lyophilisation). Lyophilisation of EVs would allow easy handling at room temperature and thus significantly enhance their expanded investigation. A model enzyme, β-glucuronidase, was loaded into different types of EVs derived from mesenchymal stem cells, endothelial cells and cancer cells. Using asymmetric flow field-flow fractionation we proved that the model enzyme is indeed stably encapsulated into EVs. When assessing enzyme activity as indicator for EV stability, and in comparison to liposomes, we show that EVs are intrinsically stable during lyophilisation, an effect further enhanced by cryoprotectants. Our findings provide new insight for exploring lyophilisation as a novel storage modality and we create an important basis for standardised and advanced EV applications in biomedical research.
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Attribution-NonCommercial-ShareAlike 3.0 United States
Extracellular vesicles protect glucuronidase model enzymes during freeze-drying.
Article
oai:repository.helmholtz-hzi.de:10033/6214892019-08-30T11:33:04Zcom_10033_620656col_10033_620657
Liu, Yun
Bos, I Sophie T
Oenema, Tjitske A
Meurs, Herman
Maarsingh, Harm
Hirsch, Anna K H
2018-09-19T08:08:09Z
2018-09-19T08:08:09Z
2018-09-01
1873-3441
29908939
10.1016/j.ejpb.2018.06.012
http://hdl.handle.net/10033/621489
Budesonide is a hydrophobic glucocorticoid with high anti-inflammatory activity for the treatment of asthma, inflammatory bowel disease and rheumatoid arthritis. A micellar drug-delivery system based on lipid-DNA may provide a strategy to maximize its drug efficacy and reduce adverse effects. In this work, we report the use of lipid-DNAA (UU11mer), featuring two hydrophobic alkyl chains and forming micelles at a comparatively low critical micelle concentration, to render budesonide water-soluble with a high loading capacity (LC). The inhibition of interleukin-8 (IL-8) release shows that the new delivery system retains the inhibitory activity in cell-based assays. In conclusion, this research provides a novel approach to formulate and administer budesonide in a non-invasive manner, which dramatically improves its water-solubility while retaining its bioavailability.
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Anti-inflammatory
Budesonide
Drug delivery
Lipid-DNA
Solubility
Delivery system for budesonide based on lipid-DNA.
Article
oai:repository.helmholtz-hzi.de:10033/6214932018-09-25T06:51:10Zcom_10033_620656col_10033_620657
Liu, Yun
Bos, I Sophie T
Oenema, Tjitske A
Meurs, Herman
Maarsingh, Harm
Hirsch, Anna K H
2018-09-24T14:01:09Z
2018-09-24T14:01:09Z
2018-09-01
1873-3441
29908939
10.1016/j.ejpb.2018.06.012
http://hdl.handle.net/10033/621493
Budesonide is a hydrophobic glucocorticoid with high anti-inflammatory activity for the treatment of asthma, inflammatory bowel disease and rheumatoid arthritis. A micellar drug-delivery system based on lipid-DNA may provide a strategy to maximize its drug efficacy and reduce adverse effects. In this work, we report the use of lipid-DNAA (UU11mer), featuring two hydrophobic alkyl chains and forming micelles at a comparatively low critical micelle concentration, to render budesonide water-soluble with a high loading capacity (LC). The inhibition of interleukin-8 (IL-8) release shows that the new delivery system retains the inhibitory activity in cell-based assays. In conclusion, this research provides a novel approach to formulate and administer budesonide in a non-invasive manner, which dramatically improves its water-solubility while retaining its bioavailability.
http://creativecommons.org/licenses/by-nc-sa/3.0/us/
Attribution-NonCommercial-ShareAlike 3.0 United States
Anti-inflammatory
Budesonide
Drug delivery
Lipid-DNA
Solubility
Delivery system for budesonide based on lipid-DNA.
Article
oai:repository.helmholtz-hzi.de:10033/6215152019-08-30T11:29:46Zcom_10033_620656col_10033_620657
Brengel, Christian
Thomann, Andreas
Schifrin, Alexander
Allegretta, Giuseppe
Kamal, Ahmed A M
Haupenthal, Jörg
Schnorr, Isabell
Cho, Sang Hyun
Franzblau, Scott G
Empting, Martin
Eberhard, Jens
Hartmann, Rolf W
2018-10-11T14:07:57Z
2018-10-11T14:07:57Z
2017-10-09
1860-7187
28815923
10.1002/cmdc.201700363
http://hdl.handle.net/10033/621515
The development of novel antimycobacterial agents against Mycobacterium tuberculosis (Mtb) is urgently required due to the appearance of multidrug resistance (MDR) combined with complicated long-term treatment. CYP121 was shown to be a promising novel target for inhibition of mycobacterial growth. In this study, we describe the rational discovery of new CYP121 inhibitors by a systematic screening based on biophysical and microbiological methods. The best hits originating from only one structural class gave initial information about molecular motifs required for binding and activity. The initial screening procedure was followed by mode-of-action studies and further biological characterizations. The results demonstrate superior antimycobacterial efficacy and a decreased toxicity profile of our frontrunner compound relative to the reference compound econazole. Due to its low molecular weight, promising biological profile, and physicochemical properties, this compound is an excellent starting point for further rational optimization.
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Attribution-NonCommercial-ShareAlike 3.0 United States
Mycobacterium tuberculosis
anti-infectives
biophysics
inhibitors
screening
Biophysical Screening of a Focused Library for the Discovery of CYP121 Inhibitors as Novel Antimycobacterials.
Article
oai:repository.helmholtz-hzi.de:10033/6215552019-08-30T11:31:44Zcom_10033_620656col_10033_620657
Vasile, Francesca
Della Volpe, Serena
Ambrosio, Francesca Alessandra
Costa, Giosuè
Unver, M Yagiz
Zucal, Chiara
Rossi, Daniela
Martino, Emanuela
Provenzani, Alessandro
Hirsch, Anna K H
Alcaro, Stefano
Potenza, Donatella
Collina, Simona
2018-11-13T11:41:25Z
2018-11-13T11:41:25Z
2018-09-13
2045-2322
30214075
10.1038/s41598-018-32084-z
http://hdl.handle.net/10033/621555
Post-transcriptional processes have been recognised as pivotal in the control of gene expression, and impairments in RNA processing are reported in several pathologies (i.e., cancer and neurodegeneration). Focusing on RNA-binding proteins (RBPs), the involvement of Embryonic Lethal Abnormal Vision (ELAV) or Hu proteins and their complexes with target mRNAs in the aetiology of various dysfunctions, has suggested the great potential of compounds able to interfere with the complex stability as an innovative pharmacological strategy for the treatment of numerous diseases. Here, we present a rational follow-up investigation of the interaction between ELAV isoform HuR and structurally-related compounds (i.e., flavonoids and coumarins), naturally decorated with different functional groups, by means of STD-NMR and Molecular Modelling. Our results represent the foundation for the development of potent and selective ligands able to interfere with ELAV-RNA complexes.
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Attribution-NonCommercial-ShareAlike 3.0 United States
Exploration of ligand binding modes towards the identification of compounds targeting HuR: a combined STD-NMR and Molecular Modelling approach.
Article
oai:repository.helmholtz-hzi.de:10033/6215692019-08-30T11:29:43Zcom_10033_620656col_10033_620657
Salah, Mohamed
Abdelsamie, Ahmed S
Frotscher, Martin
2018-11-15T14:23:17Z
2018-11-15T14:23:17Z
2018-10-15
1872-8057
30336189
10.1016/j.mce.2018.10.001
http://hdl.handle.net/10033/621569
During the past 25 years, the modulation of estrogen action by inhibition of 17β-hydroxysteroid dehydrogenase types 1 and 2 (17β-HSD1 and 17β-HSD2), respectively, has been pursued intensively. In the search for novel treatment options for estrogen-dependent diseases (EDD) and in order to explore estrogenic signaling pathways, a large number of steroidal and nonsteroidal inhibitors of these enzymes has been described in the literature. The present review gives a survey on the development of inhibitor classes as well as the structural formulas and biological properties of their most interesting representatives. In addition, rationally designed dual inhibitors of both 17β-HSD1 and steroid sulfatase (STS) as well as the first inhibitors of 17β-HSD14 are covered.
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Attribution-NonCommercial-ShareAlike 3.0 United States
Enzyme inhibitors
Estrogen dependent diseases
Hydroxysteroid dehydrogenases
Steroidogenic enzymes
Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges.
Article
oai:repository.helmholtz-hzi.de:10033/6216632019-08-30T11:33:27Zcom_10033_620613com_10033_620656com_10033_620644com_10033_620618col_10033_620614col_10033_620657col_10033_620619col_10033_620646
Castoldi, Arianna
Empting, Martin
De Rossi, Chiara
Mayr, Karsten
Dersch, Petra
Hartmann, Rolf
Müller, Rolf
Gordon, Sarah
Lehr, Claus-Michael
2019-01-18T15:45:31Z
2019-01-18T15:45:31Z
2018-12-05
Pharm Res. 2018 Dec 5;36(1):22. doi: 10.1007/s11095-018-2521-3.
1573-904X
30519925
10.1007/s11095-018-2521-3
http://hdl.handle.net/10033/621663
Pharmaceutical research
The objective of this work was to evaluate the potential of polymeric spherical and aspherical invasive nanocarriers, loaded with antibiotic, to access and treat intracellular bacterial infections. Aspherical nanocarriers were prepared by stretching of spherical precursors, and both aspherical and spherical nanocarriers were surface-functionalized with the invasive protein InvA497. The relative uptake of nanocarriers into HEp-2 epithelial cells was then assessed. Nanocarriers were subsequently loaded with a preparation of the non-permeable antibiotic gentamicin, and tested for their ability to treat HEp-2 cells infected with the enteroinvasive bacterium Shigella flexneri. InvA497-functionalized nanocarriers of both spherical and aspherical shape showed a significantly improved rate and extent of uptake into HEp-2 cells in comparison to non-functionalized nanocarriers. Functionalized and antibiotic-loaded nanocarriers demonstrated a dose dependent killing of intracellular S. flexneri. A slight but significant enhancement of intracellular bacterial killing was also observed with aspherical as compared to spherical functionalized nanocarriers at the highest tested concentration. InvA497-functionalized, polymer-based nanocarriers were able to efficiently deliver a non-permeable antibiotic across host cell membranes to affect killing of intracellular bacteria. Functionalized nanocarriers with an aspherical shape showed an interesting future potential for intracellular infection therapy.
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AOT-gentamicin
aspherical nanoparticles
bacteriomimetic nanocarriers
intracellular infection
invasin
Aspherical and Spherical InvA497-Functionalized Nanocarriers for Intracellular Delivery of Anti-Infective Agents.
Article
oai:repository.helmholtz-hzi.de:10033/6216992019-02-20T01:22:06Zcom_10033_620656col_10033_620657
2019-02-19T15:09:37Z
2019-02-19T15:09:37Z
2018-09-12
2366-3987
10.1002/adtp.201800066
http://hdl.handle.net/10033/621699
Advanced Therapeutics
In an attempt to find new antibiotics, novel ways of interfering with important biological functions should be explored, especially with those which are necessary or even irreplaceable for bacterial survival, growth, and virulence. The purpose of this review is to highlight B‐type vitamin transporters from the energy‐coupling factor (ECF) family, which are not present in humans, as potential antimicrobial targets. In addition, a druggability analysis of an ECF transporter for folic acid and sequence‐conservation studies in seven prominent pathogens revealed new druggable pockets. Evaluation of the presence of de novo biosynthetic routes for the vitamins in question in the seven pathogens confirmed that this target class holds promise for the discovery of antimicrobial drugs with a new mechanism of action, possibly on a broad‐spectrum level.
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openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
Energy‐Coupling Factor Transporters as Novel Antimicrobial Targets
Article
oai:repository.helmholtz-hzi.de:10033/6217002021-07-23T12:59:03Zcom_10033_620656col_10033_620657
Bousis, Spyridon
Diamanti, Eleonora
Slotboom, Dirk J.
Hirsch, Anna K. H.
2019-02-20T10:42:06Z
2019-02-20T10:42:06Z
2019-02
10.1002/adtp.201800066
https://onlinelibrary.wiley.com/doi/epdf/10.1002/adtp.201800066
http://hdl.handle.net/10033/621700
2366-3987
Advanced Therapeutics
In an attempt to find new antibiotics, novel ways of interfering with important biological functions should be explored, especially with those which are necessary or even irreplaceable for bacterial survival, growth, and virulence. The purpose of this review is to highlight B‐type vitamin transporters from the energy‐coupling factor (ECF) family, which are not present in humans, as potential antimicrobial targets. In addition, a druggability analysis of an ECF transporter for folic acid and sequence‐conservation studies in seven prominent pathogens revealed new druggable pockets. Evaluation of the presence of de novo biosynthetic routes for the vitamins in question in the seven pathogens confirmed that this target class holds promise for the discovery of antimicrobial drugs with a new mechanism of action, possibly on a broad‐spectrum level.
en
http://creativecommons.org/licenses/by-nc-sa/4.0/
openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
antimicrobials
B-type vitamins
energy coupling factor transporters
S-components
uptake
Energy‐Coupling Factor Transporters as Novel Antimicrobial Targets
Article
oai:repository.helmholtz-hzi.de:10033/6217282019-08-30T11:31:49Zcom_10033_620656col_10033_620657
Bestgen, Benoît
Kufareva, Irina
Seetoh, Weiguang
Abell, Chris
Hartmann, Rolf W
Abagyan, Ruben
Le Borgne, Marc
Filhol, Odile
Cochet, Claude
Lomberget, Thierry
Engel, Matthias
2019-03-20T10:55:28Z
2019-03-20T10:55:28Z
2019-02-28
J Med Chem. 2019 Feb 28;62(4):1817-1836. doi: 10.1021/acs.jmedchem.8b01765. Epub 2019 Feb 13
1520-4804
30689946
10.1021/acs.jmedchem.8b01765
http://hdl.handle.net/10033/621728
Journal of Medicinal Chemistry
Protein CK2 has gained much interest as an anticancer drug target in the past decade. We had previously described the identification of a new allosteric site on the catalytic α-subunit, along with first small molecule ligands based on the 4-(4-phenylthiazol-2-ylamino)benzoic acid scaffold. In the present work, structure optimizations guided by a binding model led to the identification of the lead compound 2-hydroxy-4-((4-(naphthalen-2-yl)thiazol-2-yl)amino)benzoic acid (27), showing a submicromolar potency against purified CK2α (IC
en
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CK2
kinase inhibitors
allosteric inhibition
kinase selectivity
anti-cancer
2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 2. Structure-Based Optimization and Investigation of Effects Specific to the Allosteric Mode of Action.
Article
oai:repository.helmholtz-hzi.de:10033/6217442019-08-30T11:32:36Zcom_10033_620656col_10033_620657
Schmidt, Nico
Li, Jun
Gottardi, Stefano
Moreno-Lopez, Juan Carlos
Enache, Mihaela
Monjas, Leticia
van der Vlag, Ramon
Havenith, Remco W A
Hirsch, Anna K H
Stöhr, Meike
2019-04-11T11:36:13Z
2019-04-11T11:36:13Z
2019-04-01
Chemistry. 2019 Apr 1;25(19):5065-5070. doi: 10.1002/chem.201806312. Epub 2019 Mar 12.
1521-3765
30657213
10.1002/chem.201806312
http://hdl.handle.net/10033/621744
Chemistry - A European Journal
A comparative study on the self-assembly of sexiphenyl-dicarbonitrile on highly oriented pyrolytic graphite and single-layer graphene on Cu(111) is presented. Despite an overall low molecule-substrate interaction, the close-packed structures exhibit a peculiar shift repeating every four to five molecules. This shift has hitherto not been reported for similar systems and is hence a unique feature induced by the graphitic substrates.
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graphene
nanostructures
scanning probe microscopy
self-assembly
surface analysis
Comparing the Self-Assembly of Sexiphenyl-Dicarbonitrile on Graphite and Graphene on Cu(111).
Article
oai:repository.helmholtz-hzi.de:10033/6218312019-08-30T11:32:13Zcom_10033_620656col_10033_620657
Li, Jun
Solianyk, Leonid
Schmidt, Nico
Baker, Brian
Gottardi, Stefano
Moreno Lopez, Juan Carlos
Enache, Mihaela
Monjas, Leticia
van der Vlag, Ramon
Havenith, Remco W A
Hirsch, Anna K H
Stöhr, Meike
2019-06-26T13:22:47Z
2019-06-26T13:22:47Z
2019-05-23
J Phys Chem C Nanomater Interfaces. 2019 May 23;123(20):12730-12735. doi: 10.1021/acs.jpcc.9b00326. Epub 2019 Apr 30.
1932-7447
31156737
10.1021/acs.jpcc.9b00326
http://hdl.handle.net/10033/621831
Journal of Physical Chemistry C
We report the formation of one- and two-dimensional metal-organic coordination structures from para-hexaphenyl-dicarbonitrile (NC-Ph6-CN) molecules and Cu atoms on graphene epitaxially grown on Ir(111). By varying the stoichiometry between the NC-Ph6-CN molecules and Cu atoms, the dimensionality of the metal-organic coordination structures could be tuned: for a 3:2 ratio, a two-dimensional hexagonal porous network based on threefold Cu coordination was observed, while for a 1:1 ratio, one-dimensional chains based on twofold Cu coordination were formed. The formation of metal-ligand bonds was supported by imaging the Cu atoms within the metal-organic coordination structures with scanning tunneling microscopy. Scanning tunneling spectroscopy measurements demonstrated that the electronic properties of NC-Ph6-CN molecules and Cu atoms were different between the two-dimensional porous network and one-dimensional molecular chains.
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Attribution-NonCommercial-ShareAlike 4.0 International
Low-Dimensional Metal-Organic Coordination Structures on Graphene.
Article
oai:repository.helmholtz-hzi.de:10033/6218442019-08-30T11:26:39Zcom_10033_620656col_10033_620657
Prismawan, Deka
van der Vlag, Ramon
Guo, Hao
Dekker, Frank J
Hirsch, Anna K H
2019-07-03T14:07:18Z
2019-07-03T14:07:18Z
2019-05-01
Helv Chim Acta. 2019 May;102(5):e1900040. doi: 10.1002/hlca.201900040. Epub 2019 May 2.
0018-019X
31231138
10.1002/hlca.201900040
http://hdl.handle.net/10033/621844
Helvetica Chimica Acta
Human 15-lipoxygenase-1 (15-LOX-1) belongs to the class of lipoxygenases, which catalyze oxygenation of polyunsaturated fatty acids, such as arachidonic and linoleic acid. Recent studies have shown that 15-LOX-1 plays an important role in physiological processes linked to several diseases such as airway inflammation disease, coronary artery disease, and several types of cancer such as rectal, colon, breast and prostate cancer. In this study, we aimed to extend the structural diversity of 15-LOX-1 inhibitors, starting from the recently identified indolyl core. In order to find new scaffolds, we employed a combinatorial approach using various aromatic aldehydes and an aliphatic hydrazide tail. This scaffold-hopping study resulted in the identification of the 3-pyridylring as a suitable replacement of the indolyl core with an inhibitory activity in the micromolar range (IC50=16±6 μm) and a rapid and efficient structure-activity relationship investigation.
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15-lipoxygenase-1
acylhydrazone
combinatorial chemistry
enzyme inhibitors
structure–activity relationships
Replacement of an Indole Scaffold Targeting Human 15-Lipoxygenase-1 Using Combinatorial Chemistry.
Article
oai:repository.helmholtz-hzi.de:10033/6218462019-08-30T11:24:27Zcom_10033_620656col_10033_620657
Hartman, Alwin M.
Gierse, Robin M.
Hirsch, Anna K. H.
2019-07-04T12:52:19Z
2019-07-04T12:52:19Z
2019-05-03
http://hdl.handle.net/10033/621846
European Journal of Organic Chemistry
Dynamic combinatorial chemistry (DCC) is a powerful tool to identify bioactive compounds. This efficient technique allows the target to select its own binders and circumvents the need for synthesis and biochemical evaluation of all individual derivatives. An ever‐increasing number of publications report the use of DCC on biologically relevant target proteins. This minireview complements previous reviews by focusing on the experimental protocol and giving detailed examples of essential steps and factors that need to be considered, such as protein stability, buffer composition and cosolvents.
en
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Attribution-NonCommercial-ShareAlike 4.0 International
Protein-Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol
Article
oai:repository.helmholtz-hzi.de:10033/6218492019-08-30T11:26:10Zcom_10033_620656col_10033_620657
Kirsch, Philine
Jakob, Valentin
Oberhausen, Kevin
Stein, Saskia C
Cucarro, Ivano
Schulz, Thomas F
Empting, Martin
2019-07-05T14:38:50Z
2019-07-05T14:38:50Z
2019-04-25
J Med Chem. 2019 Apr 25;62(8):3924-3939. doi: 10.1021/acs.jmedchem.8b01827. Epub 2019 Apr 12.
1520-4804
30888817
10.1021/acs.jmedchem.8b01827
http://hdl.handle.net/10033/621849
Journal of Medicinal Chemistry
The latency-associated nuclear antigen (LANA) is required for latent replication and persistence of Kaposi's sarcoma-associated herpesvirus/human herpesvirus 8. It acts via replicating and tethering the virus episome to the host chromatin and exerts other functions. We conceived a new approach for the discovery of antiviral drugs to inhibit the interaction between LANA and the viral genome. We applied a biophysical screening cascade and identified the first LANA binders from small, structurally diverse compound libraries. Starting from a fragment-sized scaffold, we generated optimized hits via fragment growing using a dedicated fluorescence-polarization-based assay as the structure-activity-relationship driver. We improved compound potency to the double-digit micromolar range. Importantly, we qualified the resulting hit through orthogonal methods employing EMSA, STD-NMR, and MST methodologies. This optimized hit provides an ideal starting point for subsequent hit-to-lead campaigns providing evident target-binding, suitable ligand efficiencies, and favorable physicochemical properties.
en
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Fragment-Based Discovery of a Qualified Hit Targeting the Latency-Associated Nuclear Antigen of the Oncogenic Kaposi's Sarcoma-Associated Herpesvirus/Human Herpesvirus 8.
Article
oai:repository.helmholtz-hzi.de:10033/6218792019-08-30T11:26:10Zcom_10033_620656col_10033_620657
Röhrig, Teresa
Kirsch, Verena
Schipp, Dorothea
Galan, Jens
Richling, Elke
2019-07-16T13:28:20Z
2019-07-16T13:28:20Z
2019-06-19
J Agric Food Chem. 2019 Jun 19;67(24):6792-6797. doi: 10.1021/acs.jafc.9b01567. Epub 2019 Jun 10.
1520-5118
31134806
10.1021/acs.jafc.9b01567
http://hdl.handle.net/10033/621879
Journal of agricultural and food chemistry
The dominant anthocyanins in blackcurrant are delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside. Data on their absorption and distribution in the human body are limited. Therefore, we performed a human pilot study on five healthy male volunteers consuming a blackcurrant (Ribes nigrum L.) extract. The rutinosides and their degradation products gallic acid and protocatechuic acid were determined in plasma and urine. The rutinosides’ concentrations peaked in both plasma and urine samples within 2 h of extract ingestion. The recoveries of delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside from urine samples were 0.040 ± 0.011% and 0.048 ± 0.016%, respectively, over a 48 h period. Protocatechuic acid concentration increased significantly after ingestion of the blackcurrant extract. Our results show that after ingestion of a blackcurrant extract containing delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside, significant quantities of biologically active compounds circulated in the plasma and were excreted via urine. Furthermore, these results contribute to the understanding of anthocyanin metabolism in humans.
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L.
anthocyanin
bioavailability
blackcurrant
rutinoside
Absorption of Anthocyanin Rutinosides after Consumption of a Blackcurrant ( Ribes nigrum L.) Extract.
Article
oai:repository.helmholtz-hzi.de:10033/6219132019-08-30T11:27:14Zcom_10033_620656col_10033_620657
Simhadri, Chakravarthi
Daze, Kevin D
Douglas, Sarah F
Milosevich, Natalia
Monjas, Leticia
Dev, Amarjot
Brown, Tyler M
Hirsch, Anna K H
Wulff, Jeremy E
Hof, Fraser
2019-08-21T08:57:28Z
2019-08-21T08:57:28Z
2019-08-06
ChemMedChem. 2019 Aug 6;14(15):1444-1456. doi: 10.1002/cmdc.201900021. Epub 2019
1860-7187
31254321
10.1002/cmdc.201900021
http://hdl.handle.net/10033/621913
ChemMedChem
Chromobox homolog 7 (Cbx7) is an epigenetic modulator that is an important driver of multiple cancers. It is a methyl reader protein that operates by recognizing and binding to methylated lysine residues on specific partners. Herein we report our efforts to create low-molecular-weight inhibitors of Cbx7 by making rational structural adaptations to inhibitors of a different methyl reader protein, L3MBTL1, inhibitors that had previously been reported to be inactive against Cbx7. We evaluated each new inhibitor for Cbx7 inhibition by fluorescence polarization assay, and also confirmed the binding of selected inhibitors to Cbx7 by saturation-transfer difference NMR spectroscopy. This work identified multiple small-molecule inhibitors with modest (IC50 : 257-500 μm) potency.
en
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anticancer agents
bromodomains
chromatin
epigenetics
histones
Rational Adaptation of L3MBTL1 Inhibitors to Create Small-Molecule Cbx7 Antagonists.
Article
oai:repository.helmholtz-hzi.de:10033/6219172019-08-30T11:27:44Zcom_10033_620656col_10033_620657
Bentler, Patrick
Bergander, Klaus
Daniliuc, Constantin G
Mück-Lichtenfeld, Christian
Jumde, Ravindra P
Hirsch, Anna K H
Gilmour, Ryan
2019-08-21T13:19:20Z
2019-08-21T13:19:20Z
2019-08-05
Angew Chem Int Ed Engl. 2019 Aug 5;58(32):10990-10994. doi: 10.1002/anie.201905452. Epub 2019 Jul 3.
1521-3773
31157945
10.1002/anie.201905452
http://hdl.handle.net/10033/621917
Angewandte Chemie - International Edition
Fluorinated motifs have a venerable history in drug discovery, but as C(sp3 )-F-rich 3D scaffolds appear with increasing frequency, the effect of multiple bioisosteric changes on molecular recognition requires elucidation. Herein we demonstrate that installation of a 1,3,5-stereotriad, in the substrate for a commonly used lipase from Pseudomonas fluorescens does not inhibit recognition, but inverts stereoselectivity. This provides facile access to optically active, stereochemically well-defined organofluorine compounds (up to 98 % ee). Whilst orthogonal recognition is observed with fluorine, the trend does not hold for the corresponding chlorinated substrates or mixed halogens. This phenomenon can be placed on a structural basis by considering the stereoelectronic gauche effect inherent to F-C-C-X systems (σ→σ*). Docking reveals that this change in selectivity (H versus F) with a common lipase results from inversion in the orientation of the bound substrate being processed as a consequence of conformation. This contrasts with the stereochemical interpretation of the biogenetic isoprene rule, whereby product divergence from a common starting material is also a consequence of conformation, albeit enforced by two discrete enzymes.
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biocatalysis
conformation
fluorine
gauche effect
molecular recognition
Inverting Small Molecule-Protein Recognition by the Fluorine Gauche Effect: Selectivity Regulated by Multiple H→F Bioisosterism.
Article
oai:repository.helmholtz-hzi.de:10033/6219922019-11-08T12:50:04Zcom_10033_620533com_10033_620656col_10033_620534col_10033_620657col_10033_620658
Sommer, Roman
Rox, Katharina
Wagner, Stefanie
Hauck, Dirk
Henrikus, Sarah S
Newsad, Shelby
Arnold, Tatjana
Ryckmans, Thomas
Brönstrup, Mark
Imberty, Anne
Varrot, Annabelle
Hartmann, Rolf W
Titz, Alexander
2019-10-28T14:39:28Z
2019-10-28T14:39:28Z
2019-10-24
J Med Chem. 2019 Oct 24;62(20):9201-9216. doi: 10.1021/acs.jmedchem.9b01120. Epub 2019 Oct 11.
1520-4804
31553873
10.1021/acs.jmedchem.9b01120
http://hdl.handle.net/10033/621992
Journal of medicinal Chemistry
Biofilm formation is a key mechanism of antimicrobial resistance. We have recently reported two classes of orally bioavailable C-glycosidic inhibitors of the Pseudomonas aeruginosa lectin LecB with antibiofilm activity. They proved efficient in target binding, were metabolically stable, nontoxic, selective, and potent in inhibiting formation of bacterial biofilm. Here, we designed and synthesized six new carboxamides and 24 new sulfonamides for a detailed structure-activity relationship for two clinically representative LecB variants. Sulfonamides generally showed higher inhibition compared to carboxamides, which was rationalized based on crystal structure analyses. Substitutions at the thiophenesulfonamide increased binding through extensive contacts with a lipophilic protein patch. These metabolically stable compounds showed a further increase in potency toward the target and in biofilm inhibition assays. In general, we established the structure-activity relationship for these promising antibiofilm agents and showed that modification of the sulfonamide residue bears future optimization potential.
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Anti-biofilm Agents against Pseudomonas aeruginosa: A Structure-Activity Relationship Study of C-Glycosidic LecB Inhibitors
Article
oai:repository.helmholtz-hzi.de:10033/6219932019-10-29T04:09:40Zcom_10033_620656col_10033_620657
Kohler, Christian
Proctor, Richard A
Bayer, Arnold S
Yeaman, Michael R
Lalk, Michael
Engelmann, Susanne
Mishra, Nagendra N
2019-10-28T14:59:59Z
2019-10-28T14:59:59Z
2019-09-28
Antibiotics (Basel). 2019 Sep 28;8(4). pii: antibiotics8040169. doi: 10.3390/antibiotics8040169.
2079-6382
31569354
10.3390/antibiotics8040169
http://hdl.handle.net/10033/621993
Antibiotics (Basel)
We previously described a transposon mutant in Staphylococcus aureus strain SH1000 that exhibited reduced susceptibility to cationic thrombin-induced platelet microbicidal proteins (tPMPs). The transposon insertion site was mapped to the gene snoD, the staphylococcal nuo orthologue. Hence, further studies have been performed to understand how this mutation impacts susceptibility to tPMP, by comparing proteomics profiling and membrane lipid analyses of the parent vs. mutant strains. Surprisingly, the mutant showed differential regulation of only a single protein when cultivated aerobically (FadB), and only a small number of proteins under anaerobic growth conditions (AdhE, DapE, Ddh, Ald1, IlvA1, AgrA, Rot, SA2366, and SA2367). Corresponding to FadB impact on lipid remodeling, membrane fatty acid analyses showed that the snoD mutant contained more short chain anteiso-, but fewer short chain iso-branched chain fatty acids under both aerobic and anaerobic conditions vs. the parental strain. Based upon these proteomic and membrane compositional data, a hypothetical "network" model was developed to explain the impact of the snoD mutation upon tPMP susceptibility.
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S. aureus
lipids
proteomics
snoD mutant
tPMP resistance
Proteomic and Membrane Lipid Correlates of Reduced Host Defense Peptide.
Article
oai:repository.helmholtz-hzi.de:10033/6219942019-10-30T10:50:30Zcom_10033_620656col_10033_620657
Kamal, Ahmed Ashraf Moustafa
Habib, Monica
Haupenthal, Joerg
Hartmann, Rolf Wolfgang
Empting, Martin
2019-10-29T10:43:18Z
2019-10-29T10:43:18Z
2019-02-25
Biol Chem. 2019 Feb 25;400(3):333-342. doi: 10.1515/hsz-2018-0333.
1437-4315
30657738
10.1515/hsz-2018-0333
http://hdl.handle.net/10033/621994
Biological Chemistry
RNA polymerase (RNAP) remains a relatively underexplored target with only rifampicin and
fidaxomicin in clinical use. Hence, the concurrent rise in bacterial resistance rate urges the
search for novel RNAP inhibitors with novel mode of action. In this work, we investigated the
impact of several systematic modifications including sidechain-to-sidechain macrocylization
in α-helical content and biological activity of a previously identified inhibitory sigma factor
fragment. Ala-scan results, peptide truncation from both the N- and C- terminus, and
modifications inspired by other RNAP inhibitors revealed novel structure activity
relationships but did not yield a superior sequence. Additionally, four insertion points for
non-natural amino acids bearing side chains required for macrocylization were explored.
Linear precursors showed improved stabilization of α-helical content compared to the
original sequence as demonstrated by CD spectroscopy. However, this increase in α-helicity
did not translate into improved biological activity. Instead, complete abolishment of RNAP
inhibitory activity occurred. We hypothesize three possible reasons for such discrepancy and
offer basis for further optimization efforts for this peptidic RNAP inhibitor.
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RNA polymerase
anti-infective
click chemistry
macrocyclic peptides
α-helix
Hit evaluation of an α-helical peptide: Ala-scan, truncation and sidechain-to-sidechain macrocyclization of an RNA polymerase Inhibitor.
Article
oai:repository.helmholtz-hzi.de:10033/6220292020-09-29T12:06:33Zcom_10033_311308com_10033_620656col_10033_620657col_10033_559591
Zender, Michael
Witzgall, Florian
Kiefer, Alexander Felix
Kirsch, Benjamin
Maurer, Christine K
Kany, Andreas M
Xu, Ningna
Schmelz, Stefan
Börger, Carsten
Blankenfeldt, Wulf
Empting, Martin
2019-11-26T10:21:56Z
2019-11-26T10:21:56Z
2019-11-11
ChemMedChem. 2019 Nov 11. doi: 10.1002/cmdc.201900621.
1860-7187
31709767
10.1002/cmdc.201900621
http://hdl.handle.net/10033/622029
ChemMedChem
Hit-to-lead optimization is a critical phase in drug discovery. Herein, we report on the fragment-based discovery and optimization of 2-amino pyridine derivatives as a novel lead-like structure for the treatment of the dangerous opportunistic pathogen Pseudomonas aeruginosa . We pursue an innovative treatment strategy by interfering with the Pseudomonas Quinolone Signal (PQS) Quorum Sensing (QS) system leading to an abolishment of bacterial pathogenicity. Our compounds act on the PQS receptor (PqsR), a key transcription factor controlling the expression of various pathogenicity determinants. In this target-driven approach, we made use of biophysical screening via surface plasmon resonance (SPR) followed by isothermal titration calorimetry (ITC)-enabled enthalpic efficiency (EE) evaluation. Hit optimization then involved growth vector identification and exploitation. Astonishingly, the latter was successfully achieved by introducing flexible linkers rather than rigid motifs leading to a boost in activity on the target receptor and anti-virulence potency.
en
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Enthalpic Efficiency
Fragment-based Drug Discovery
Pathoblocker
Pseudomonas aeruginosa
quorum sensing
Flexible Fragment Growing Boosts Potency of Quorum Sensing Inhibitors against Pseudomonas aeruginosa Virulence.
Article
oai:repository.helmholtz-hzi.de:10033/6220542019-12-21T01:56:52Zcom_10033_620656col_10033_620657
Lababidi, Nashrawan
Ofosu Kissi, Eric
Elgaher, Walid A M
Sigal, Valentin
Haupenthal, Jörg
Schwarz, Bianca C
Hirsch, Anna K H
Rades, Thomas
Schneider, Marc
2019-12-20T09:35:25Z
2019-12-20T09:35:25Z
2019-11-28
Journal of controlled release : official journal of the Controlled Release Society.
1873-4995
31654686
10.1016/j.jconrel.2019.10.038
http://hdl.handle.net/10033/622054
Journal of controlled release
Cystic fibrosis (CF) is a serious lung disease, commonly susceptible to Pseudomonas aeruginosa colonization. The dense mucus together with biofilm formation limit drug permeability and prevent the drug from reaching the site of action, causing treatment failure of the bacterial infection. Besides the use of antibiotics, the mucolytic agent N-acetylcysteine (NAC) is recommended to be co-administered in the treatment of CF. Although several formulations have been developed for inhalation therapy to improve the pulmonary condition in CF patients, there is still no comprehensive study on a combined multifunctional dry powder formulation of antibiotics with NAC. In this work, we developed an innovative multifunctional dry powder inhaler (DPI) formulation based on salt formation between NAC and antibiotics and characterized their solid state properties and physical stability. NAC could be spray dried together with three different antibiotics, azithromycin (Azi), tobramycin (Tobra) and ciprofloxacin (Cipro), without the use of organic solvents to form Azi/NAC, Tobra/NAC and Cipro/NAC DPI formulations. Solid-state characterization of these DPI formulations showed that they were amorphous after spray drying. Azi/NAC and Tobra/NAC form co-amorphous salt systems that were physically stable under storage at stress conditions. For particle characterization, the obtained mass median aerodynamic diameters were in a suitable range for inhalation (< 5.0μm). The multifunctional antibiotic/NAC formulations conserved or improved the antibiotic susceptibility and showed promising results regarding the inhibition of P. aeruginosa PA14 biofilm formation.
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Antibiotics
Bacterial infection
Co-amorphous drug delivery
Dry-powder formulation
Inhalation
Salt formation
Spray-drying of inhalable, multifunctional formulations for the treatment of biofilms formed in cystic fibrosis.
Article
oai:repository.helmholtz-hzi.de:10033/6220552019-12-21T01:56:28Zcom_10033_620656col_10033_620657
Piquero-Zulaica, Ignacio
Li, Jun
Abd El-Fattah, Zakaria M
Solianyk, Leonid
Gallardo, Iker
Monjas, Leticia
Hirsch, Anna K H
Arnau, Andres
Ortega, J Enrique
Stöhr, Meike
Lobo-Checa, Jorge
2019-12-20T13:19:59Z
2019-12-20T13:19:59Z
2019-12-28
Nanoscale. 2019 Dec 28;11(48):23132-23138. doi: 10.1039/c9nr07365e. Epub 2019 Dec 3.
2040-3372
31793595
10.1039/c9nr07365e
http://hdl.handle.net/10033/622055
Nanoscale
Quantum dot arrays in the form of molecular nanoporous networks are renowned for modifying the electronic surface properties through quantum confinement. Here we show that, compared to the pristine surface state, the band bottom of the confined states can exhibit downward shifts accompanied by a lowering of the effective masses simultaneous to the appearance of tiny gaps at the Brillouin zone boundaries. We observed these effects by angle resolved photoemission for two self-assembled homothetic (scalable) Co-coordinated metal-organic networks. Complementary scanning tunneling spectroscopy measurements confirmed these findings. Electron plane wave expansion simulations and density functional theory calculations provide insight into the nature of this phenomenon, which we assign to metal-organic overlayer-substrate interactions in the form of adatom-substrate hybridization. To date, the absence of the experimental band structure resulting from single metal adatom coordinated nanoporous networks has precluded the observation of the significant surface state renormalization reported here, which we infer to be general for low interacting and well-defined adatom arrays.
en
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Surface state tunable energy and mass renormalization from homothetic quantum dot arrays.
Article
oai:repository.helmholtz-hzi.de:10033/6220572020-01-04T02:01:29Zcom_10033_620656col_10033_620657
Elangovan, Saravanakumar
Afanasenko, Anastasiia
Haupenthal, Jörg
Sun, Zhuohua
Liu, Yongzhuang
Hirsch, Anna K H
Barta, Katalin
2020-01-03T10:44:55Z
2020-01-03T10:44:55Z
2019-10-23
ACS Cent Sci. 2019 Oct 23;5(10):1707-1716. doi: 10.1021/acscentsci.9b00781. Epub 2019 Oct 11.
2374-7943
31660439
10.1021/acscentsci.9b00781
http://hdl.handle.net/10033/622057
ACS Central Science
nherently complex, lignin-derived aromatic monomers comprising valuable structural moieties present in many pharmaceuticals would serve as ideal substrates for the construction of biologically active molecules. Here, we describe a strategy that incorporates all intrinsic functional groups present in platform chemicals obtained by lignin depolymerization into value-added amines, using sustainable catalytic methods and benign solvents. Our strikingly efficient protocol provides access to libraries of aminoalkyl-phenol derivatives and seven-membered N-heterocycles directly from wood in two, respectively three, waste-free steps. Several molecules in these libraries have shown promising antibacterial or anticancer activities, emphasizing the advantage of this modular synthetic strategy and the potential for drug discovery. The sustainable catalytic pathways presented here can lead to significant benefits for the pharmaceutical industry where reduction of hazardous waste is a prime concern, and the described strategies that lead to high-value products from non-edible biomass waste streams also markedly increase the economic feasibility of lignocellulosic biorefineries.
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Attribution-NonCommercial-ShareAlike 4.0 International
From Wood to Tetrahydro-2-benzazepines in Three Waste-Free Steps: Modular Synthesis of Biologically Active Lignin-Derived Scaffolds.
Article
oai:repository.helmholtz-hzi.de:10033/6220902020-01-18T02:09:02Zcom_10033_620656col_10033_620657
Hollenhorst, Monika I
Jurastow, Innokentij
Nandigama, Rajender
Appenzeller, Silke
Li, Lei
Vogel, Jörg
Wiederhold, Stephanie
Althaus, Mike
Empting, Martin
Altmüller, Janine
Hirsch, Anna K H
Flockerzi, Veit
Canning, Brendan J
Saliba, Antoine-Emmanuel
Krasteva-Christ, Gabriela
2020-01-17T12:55:58Z
2020-01-17T12:55:58Z
2020-01-01
FASEB J. 2020 Jan;34(1):316-332. doi: 10.1096/fj.201901314RR. Epub 2019 Nov 22.
1530-6860
31914675
10.1096/fj.201901314RR
http://hdl.handle.net/10033/622090
FASEB Journal
For protection from inhaled pathogens many strategies have evolved in the airways such as mucociliary clearance and cough. We have previously shown that protective respiratory reflexes to locally released bacterial bitter "taste" substances are most probably initiated by tracheal brush cells (BC). Our single-cell RNA-seq analysis of murine BC revealed high expression levels of cholinergic and bitter taste signaling transcripts (Tas2r108, Gnat3, Trpm5). We directly demonstrate the secretion of acetylcholine (ACh) from BC upon stimulation with the Tas2R agonist denatonium. Inhibition of the taste transduction cascade abolished the increase in [Ca2+]i in BC and subsequent ACh-release. ACh-release is regulated in an autocrine manner. While the muscarinic ACh-receptors M3R and M1R are activating, M2R is inhibitory. Paracrine effects of ACh released in response to denatonium included increased [Ca2+]i in ciliated cells. Stimulation by denatonium or with Pseudomonas quinolone signaling molecules led to an increase in mucociliary clearance in explanted tracheae that was Trpm5- and M3R-mediated. We show that ACh-release from BC via the bitter taste cascade leads to immediate paracrine protective responses that can be boosted in an autocrine manner. This mechanism represents the initial step for the activation of innate immune responses against pathogens in the airways.
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acetylcholine
brush cells
mucociliary clearance
single‐cell RNA‐seq
taste
Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling.
Article
oai:repository.helmholtz-hzi.de:10033/6221112020-01-31T02:17:32Zcom_10033_620656col_10033_620657
Jumde, Varsha R
Mondal, Milon
Gierse, Robin M
Unver, M Yagiz
Magari, Francesca
van Lier, Roos C W
Heine, Andreas
Klebe, Gerhard
Hirsch, Anna K H
2020-01-30T14:04:46Z
2020-01-30T14:04:46Z
2018-11-06
ChemMedChem. 2018 Nov 6;13(21):2266-2270. doi: 10.1002/cmdc.201800446. Epub 2018 Oct 9.
1860-7187
30178575
10.1002/cmdc.201800446
http://hdl.handle.net/10033/622111
ChemMedChem
Acylhydrazone-based dynamic combinatorial chemistry (DCC) is a powerful strategy for the rapid identification of novel hits. Even though acylhydrazones are important structural motifs in medicinal chemistry, their further progression in development may be hampered by major instability and potential toxicity under physiological conditions. It is therefore of paramount importance to identify stable replacements for acylhydrazone linkers. Herein, we present the first report on the design and synthesis of stable bioisosteres of acylhydrazone-based inhibitors of the aspartic protease endothiapepsin as a follow-up to a DCC study. The most successful bioisostere is equipotent, bears an amide linker, and we confirmed its binding mode by X-ray crystallography. Having some validated bioisosteres of acylhydrazones readily available might accelerate hit-to-lead optimization in future acylhydrazone-based DCC projects.
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acylhydrazones
aspartic proteases
bioisosteres
drug design
dynamic combinatorial chemistry
Design and Synthesis of Bioisosteres of Acylhydrazones as Stable Inhibitors of the Aspartic Protease Endothiapepsin.
Article
oai:repository.helmholtz-hzi.de:10033/6221282020-02-12T12:12:58Zcom_10033_620533com_10033_620618com_10033_620656col_10033_620534col_10033_620657col_10033_620619
Elgaher, Walid A M
Hamed, Mostafa M
Baumann, Sascha
Herrmann, Jennifer
Siebenbürger, Lorenz
Krull, Jana
Cirnski, Katarina
Kirschning, Andreas
Brönstrup, Mark
Müller, Rolf
Hartmann, Rolf W
2020-02-12T09:08:18Z
2020-02-12T09:08:18Z
2020-01-26
Chemistry. 2020 Jan 26. doi: 10.1002/chem.202000117.
1521-3765
31984562
10.1002/chem.202000117
http://hdl.handle.net/10033/622128
Chemistry A European journal
Lack of new antibiotics and increasing antimicrobial resistance are the main concerns of healthcare community nowadays, which necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids - a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe a concise total synthesis of cystobactamid 507, the identification of the bioactive conformation using non-covalently bonded rigid analogs, the first structure–activity relationship (SAR) study for cystobactamid 507 leading to new analogs with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor groove binding as part of the drug–target interaction without showing significant intercalation. By designing a new analog of cystobactamid 919-2 we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.
en
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Bioactive conformation * Cystobactamids * Drug design * Intramolecular hydrogen bond * Total synthesis
Cystobactamid 507: Concise Synthesis, Mode of Action and Optimization toward More Potent Antibiotics.
Article
oai:repository.helmholtz-hzi.de:10033/6221322020-02-14T04:06:08Zcom_10033_620533com_10033_620618com_10033_620656col_10033_620534col_10033_620657col_10033_620619
Kirsch, Philine
Jakob, Valentin
Elgaher, Walid A M
Walt, Christine
Oberhausen, Kevin
Schulz, Thomas F
Empting, Martin
2020-02-13T12:58:25Z
2020-02-13T12:58:25Z
2020-01-24
ACS Chem Biol. 2020 Jan 24. doi: 10.1021/acschembio.9b00845.
1554-8937
31944659
10.1021/acschembio.9b00845
http://hdl.handle.net/10033/622132
ACS Chemical Biology
With the aim to develop novel antiviral agents against Kaposi's Sarcoma Herpesvirus (KSHV), we are targeting the latency-associated nuclear antigen (LANA). This protein plays an important role in viral genome maintenance during latent infection. LANA has the ability to tether the viral genome to the host nucleosomes and, thus, ensures latent persistence of the viral genome in the host cells. By inhibition of the LANA-DNA interaction, we seek to eliminate or reduce the load of the viral DNA in the host. To achieve this goal, we screened our in-house library using a dedicated fluorescence polarization (FP)-based competition assay, which allows for the quantification of LANA-DNA-interaction inhibition by small organic molecules. We successfully identified three different compound classes capable of disrupting this protein-nucleic acid interaction. We characterized these compounds by IC50 dose-response evaluation and confirmed the compound-LANA interaction using surface plasmon resonance (SPR) spectroscopy. Furthermore, two of the three hit scaffolds showed only marginal cytotoxicity in two human cell lines. Finally, we conducted STD-NMR competition experiments with our new hit compounds and a previously described fragment-sized inhibitor. Based on these results, future compound linking approaches could serve as a promising strategy for further optimization studies in order to generate highly potent KSHV inhibitors.
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Discovery of Novel Latency-Associated Nuclear Antigen Inhibitors as Antiviral Agents Against Kaposi's Sarcoma-Associated Herpesvirus.
Article
oai:repository.helmholtz-hzi.de:10033/6222272020-11-25T14:43:42Zcom_10033_620618com_10033_620656col_10033_620657col_10033_620619
Zisopoulou, Stavroula A.
Bousis, Spyridon
Haupenthal, Jörg
Herrmann, Jennifer
Müller, Rolf
Hirsch, Anna K.H.
Komiotis, Dimitri
Gallos, John K.
Stathakis, Christos I.
2020-04-14T11:13:51Z
2020-04-14T11:13:51Z
2020-03-17
09365214
10.1055/s-0039-1690772
http://hdl.handle.net/10033/622227
14372096
Synlett
2-s2.0-85081540129
SCOPUS_ID:85081540129
A library of novel 2-substituted derivatives of the antibiotic natural product pentenomycin I is presented. The new collection of analogues is divided in two main classes, 2-alkynyl- and 2-aryl- derivatives, which are accessed by the appropriate type of palladium-catalyzed cross-coupling reaction of the 2-iodo-protected pentenomycin I with suitable nucleophiles. The new derivatives were tested for their activity against certain types of bacteria and one of them, compound 8h, was found to exhibit significant inhibitory activity against several Gram-positive bacteria but also displayed cytotoxic activity against eukaryotic cell lines.
en
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openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
OpenAccess
(-)-pentenomycin
antimicrobial agents
Gram-positive bacteria
Sonogashira
Suzuki
Synthesis and Biological Evaluation of Novel 2-Substituted Analogues of (-)-Pentenomycin i
Article
Other
oai:repository.helmholtz-hzi.de:10033/6222412020-04-23T11:39:27Zcom_10033_620613com_10033_620656col_10033_620614col_10033_620657
Artzy-Schnirman, Arbel
Lehr, Claus-Michael
Sznitman, Josué
2020-04-23T11:39:27Z
2020-04-23T11:39:27Z
2020-03-11
Expert Opin Drug Deliv. 2020 Mar 11:1-5. doi: 10.1080/17425247.2020.1738380.
32129105
10.1080/17425247.2020.1738380
http://hdl.handle.net/10033/622241
1744-7593
Expert opinion on drug delivery
[No abstracr available]
en
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Attribution-NonCommercial-ShareAlike 4.0 International
Preclinical research
lung diseases
microfluidics
organ-on-chips
respiratory therapy
Advancing human pulmonary disease models in preclinical research: opportunities for .lung-on-chips.
Editorial
Other
oai:repository.helmholtz-hzi.de:10033/6222422020-04-24T01:34:28Zcom_10033_620613com_10033_620656col_10033_620614col_10033_620657
Artzy-Schnirman, Arbel
Lehr, Claus-Michael
Sznitman, Josué
2020-04-23T13:04:17Z
2020-04-23T13:04:17Z
2020-03-11
Expert Opin Drug Deliv. 2020 Mar 11:1-5. doi: 10.1080/17425247.2020.1738380.
32129105
10.1080/17425247.2020.1738380
http://hdl.handle.net/10033/622242
1744-7593
Expert opinion on drug delivery
[No abstracr available]
en
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Attribution-NonCommercial-ShareAlike 4.0 International
Preclinical research
lung diseases
microfluidics
organ-on-chips
respiratory therapy
Advancing human pulmonary disease models in preclinical research: opportunities for lung-on-chips..
Editorial
Other
oai:repository.helmholtz-hzi.de:10033/6222702020-05-26T01:28:59Zcom_10033_620613com_10033_620618com_10033_620656col_10033_620614col_10033_620657col_10033_620619
Ho, Duy-Khiet
Murgia, Xabier
de Rossi, Chiara
Christmann, Rebekka
Hüfner de Mello Martins, Antonio G
Koch, Marcus
Andreas, Anastasia
Herrmann, Jennifer
Müller, Rolf
Empting, Martin
Hartmann, Rolf W
Desmaele, Didier
Loretz, Brigitta
Couvreur, Patrick
Lehr, Claus-Michael
2020-05-25T12:00:20Z
2020-05-25T12:00:20Z
2020-04-03
Angew Chem Int Ed Engl. 2020;10.1002/anie.202001407. doi:10.1002/anie.202001407.
32243047
10.1002/anie.202001407
http://hdl.handle.net/10033/622270
1521-3773
Angewandte Chemie (International ed. in English)
Elimination of pulmonary Pseudomonas aeruginosa (PA) infections is challenging to accomplish with antibiotic therapies, mainly due to resistance mechanisms. Quorum sensing inhibitors (QSIs) interfering with biofilm formation can thus complement antibiotics. For simultaneous and improved delivery of both active agents to the infection sites, self-assembling nanoparticles of a newly synthesized squalenyl hydrogen sulfate (SqNPs) were prepared. These nanocarriers allowed for remarkably high loading capacities of hydrophilic antibiotic tobramycin (Tob) and a novel lipophilic QSI at 30 % and circa 10 %, respectively. The drug-loaded SqNPs showed improved biofilm penetration and enhanced efficacy in relevant biological barriers (mucin/human tracheal mucus, biofilm), leading to complete eradication of PA biofilms at circa 16-fold lower Tob concentration than Tob alone. This study offers a viable therapy optimization and invigorates the research and development of QSIs for clinical use.
en
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Pseudomonas aeruginosa
biofilms
drug delivery
quorum sensing inhibitors
tobramycin
Squalenyl Hydrogen Sulfate Nanoparticles for Simultaneous Delivery of Tobramycin and an Alkylquinolone Quorum Sensing Inhibitor Enable the Eradication of P. aeruginosa Biofilm Infections.
Article
oai:repository.helmholtz-hzi.de:10033/6222772020-05-29T01:30:17Zcom_10033_620656col_10033_620657
Konstantinidou, Markella
Magari, Francesca
Sutanto, Fandi
Haupenthal, Jörg
Jumde, Varsha R
Ünver, M Yagiz
Heine, Andreas
Camacho, Carlos Jamie
Hirsch, Anna K H
Klebe, Gerhard
Dömling, Alexander
2020-05-28T10:01:40Z
2020-05-28T10:01:40Z
2020-03-18
ChemMedChem. 2020;15(8):680‐684. doi:10.1002/cmdc.202000024.
32187447
10.1002/cmdc.202000024
http://hdl.handle.net/10033/622277
1860-7187
ChemMedChem
Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases.
en
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openAccess
Attribution-NonCommercial-ShareAlike 4.0 International
MCR chemistry
aspartic protease
crystal structures
docking protocol
hydrazine-tetrazoles
Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach.
Article
oai:repository.helmholtz-hzi.de:10033/6222812020-06-04T02:29:11Zcom_10033_620533com_10033_620618com_10033_620656col_10033_620534col_10033_620657col_10033_620619
Elgaher, Walid A M
Hamed, Mostafa M
Baumann, Sascha
Herrmann, Jennifer
Siebenbürger, Lorenz
Krull, Jana
Cirnski, Katarina
Kirschning, Andreas
Brönstrup, Mark
Müller, Rolf
Hartmann, Rolf W
2020-06-03T12:35:13Z
2020-06-03T12:35:13Z
2020-01-26
Chemistry. 2020;10.1002/chem.202000117. doi:10.1002/chem.202000117.
31984562
10.1002/chem.202000117
http://hdl.handle.net/10033/622281
1521-3765
Chemistry (Weinheim an der Bergstrasse, Germany)
Lack of new antibiotics and increasing antimicrobial resistance are among the main concerns of healthcare communities nowadays, and these concerns necessitate the search for novel antibacterial agents. Recently, we discovered the cystobactamids-a novel natural class of antibiotics with broad-spectrum antibacterial activity. In this work, we describe 1) a concise total synthesis of cystobactamid 507, 2) the identification of the bioactive conformation using noncovalently bonded rigid analogues, and 3) the first structure-activity relationship (SAR) study for cystobactamid 507 leading to new analogues with high metabolic stability, superior topoisomerase IIA inhibition, antibacterial activity and, importantly, stability toward the resistant factor AlbD. Deeper insight into the mode of action revealed that the cystobactamids employ DNA minor-groove binding as part of the drug-target interaction without showing significant intercalation. By designing a new analogue of cystobactamid 919-2, we finally demonstrated that these findings could be further exploited to obtain more potent hexapeptides against Gram-negative bacteria.
en
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Attribution-NonCommercial-ShareAlike 4.0 International
antibiotics
conformation analysis
drug design
hydrogen bonds
total synthesis
Cystobactamid 507: Concise Synthesis, Mode of Action, and Optimization toward More Potent Antibiotics.
Article
oai:repository.helmholtz-hzi.de:10033/6223562020-07-23T01:25:01Zcom_10033_620656col_10033_620657
Kirsch, Philine
Stein, Saskia C
Berwanger, Aylin
Rinkes, Julia
Jakob, Valentin
Schulz, Thomas F
Empting, Martin
2020-07-22T14:03:12Z
2020-07-22T14:03:12Z
2020-06-28
Eur J Med Chem. 2020;202:112525. doi:10.1016/j.ejmech.2020.112525.
32634628
10.1016/j.ejmech.2020.112525
http://hdl.handle.net/10033/622356
1768-3254
European journal of medicinal chemistry
The Latency-associated nuclear antigen (LANA) plays a central role for the latent persistence of the Kaposi's Sarcoma Herpesvirus (KSHV) in the human host and helps to establish lifelong infections. Herein, we report our efforts towards hit-to-lead generation starting from a previously discovered LANA-DNA inhibitor. By tethering the viral genome to the host nucleosomes, LANA ensures the segregation and persistence of the viral DNA during mitosis. LANA is also required for the replication of the latent viral episome during the S phase of the cell cycle. We aim to inhibit the interaction between LANA and the viral genome to prevent the latent persistence of KSHV in the host organism. Medicinal chemistry-driven optimization studies and structure-activity-relationship investigation led to the discovery of an improved LANA inhibitor. The functional activity of our compounds was evaluated using a fluorescence polarization (FP)-based interaction inhibition assay and electrophoretic mobility shift assay (EMSA). Even though a crystal structure of the ligand protein complex was not available, we successfully conducted hit optimization toward a low micromolar protein-nucleic acid-interaction inhibitor. Additionally, we applied STD-NMR studies to corroborate target binding and to gain insights into the binding orientation of our most potent inhibitor, providing opportunities for further rational design of more efficient LANA-targeting anti KSHV agents in future studies.
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CuAAC
Electrophoretic mobility shift assay (EMSA)
Fluorescence polarization (FP)-Based interaction inhibition assay
Hit-to-lead optimization
Kaposi’s sarcoma herpesvirus (KSHV)
Latency-associated nuclear antigen (LANA)
STD-NMR
Hit-to-lead optimization of a latency-associated nuclear antigen inhibitor against Kaposi's sarcoma-associated herpesvirus infections.
Article
mods///col_10033_620657/100