publications of the research group drug design and optimization(HIPS]DDOP)
http://hdl.handle.net/10033/620657
2024-03-29T00:49:18Z
2024-03-29T00:49:18Z
Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters
Kiefer, Alexander F.
Bousis, Spyridon
Hamed, Mostafa M.
Diamanti, Eleonora
Haupenthal, Jörg
Hirsch, Anna K.H.
http://hdl.handle.net/10033/623250
2022-10-06T03:22:54Z
2022-07-14T00:00:00Z
Structure-Guided Optimization of Small-Molecule Folate Uptake Inhibitors Targeting the Energy-Coupling Factor Transporters
Kiefer, Alexander F.; Bousis, Spyridon; Hamed, Mostafa M.; Diamanti, Eleonora; Haupenthal, Jörg; Hirsch, Anna K.H.
Here, we report on a potent class of substituted ureidothiophenes targeting energy-coupling factor (ECF) transporters, an unexplored target that is not addressed by any antibiotic in the market. Since the ECF module is crucial for the vitamin transport mechanism, the prevention of substrate uptake should ultimately lead to cell death. By utilizing a combination of virtual and functional whole-cell screening of our in-house library, the membrane-bound protein mediated uptake of folate could be effectively inhibited. Structure-based optimization of our hit yielded low-micromolar inhibitors, whereby the most active compounds showed in addition potent antimicrobial activities against a panel of clinically relevant Gram-positive pathogens without significant cytotoxic effects. © 2022 American Chemical Society.
2022-07-14T00:00:00Z
7-Hydroxycoumarins Are Affinity-Based Fluorescent Probes for Competitive Binding Studies of Macrophage Migration Inhibitory Factor.
Xiao, Zhangping
Chen, Deng
Song, Shanshan
van der Vlag, Ramon
van der Wouden, Petra E
van Merkerk, Ronald
Cool, Robbert H
Hirsch, Anna K H
Melgert, Barbro N
Quax, Wim J
Poelarends, Gerrit J
Dekker, Frank J
http://hdl.handle.net/10033/623224
2022-06-15T02:53:25Z
2020-10-13T00:00:00Z
7-Hydroxycoumarins Are Affinity-Based Fluorescent Probes for Competitive Binding Studies of Macrophage Migration Inhibitory Factor.
Xiao, Zhangping; Chen, Deng; Song, Shanshan; van der Vlag, Ramon; van der Wouden, Petra E; van Merkerk, Ronald; Cool, Robbert H; Hirsch, Anna K H; Melgert, Barbro N; Quax, Wim J; Poelarends, Gerrit J; Dekker, Frank J
Macrophage migration inhibitory factor (MIF) is a cytokine with key roles in inflammation and cancer, which qualifies it as a potential drug target. Apart from its cytokine activity, MIF also harbors enzyme activity for keto-enol tautomerization. MIF enzymatic activity has been used for identification of MIF binding molecules that also interfere with its biological activity. However, MIF tautomerase activity assays are troubled by irregularities, thus creating a need for alternative methods. In this study, we identified a 7-hydroxycoumarin fluorophore with high affinity for the MIF tautomerase active site (Ki = 18 ± 1 nM) that binds with concomitant quenching of its fluorescence. This property enabled development of a novel competition-based assay format to quantify MIF binding. We also demonstrated that the 7-hydroxycoumarin fluorophore interfered with the MIF-CD74 interaction and inhibited proliferation of A549 cells. Thus, we provide a high-affinity MIF binder as a novel tool to advance MIF-oriented research.
2020-10-13T00:00:00Z
Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Modification of the benzenoid part.
Megahed, Sarah H
Rasheed, Sari
Herrmann, Jennifer
El-Hossary, Ebaa M
El-Shabrawy, Yahia I
Abadi, Ashraf H
Engel, Matthias
Müller, Rolf
Abdel-Halim, Mohammad
Hamed, Mostafa M
http://hdl.handle.net/10033/623169
2022-02-18T01:54:25Z
2022-01-07T00:00:00Z
Novel 2,4-disubstituted quinazoline analogs as antibacterial agents with improved cytotoxicity profile: Modification of the benzenoid part.
Megahed, Sarah H; Rasheed, Sari; Herrmann, Jennifer; El-Hossary, Ebaa M; El-Shabrawy, Yahia I; Abadi, Ashraf H; Engel, Matthias; Müller, Rolf; Abdel-Halim, Mohammad; Hamed, Mostafa M
Bacterial resistance to currently used antibiotics demands the development of novel antibacterial agents with good safety margins and sufficient efficacy against multi-drug resistant isolates. We have previously described the synthesis of N-butyl-2-(butylthio)quinazolin-4-amine (I) as an optimized hit with broad-spectrum antibacterial activity and low cytotoxicity. In addition, we have identified a potential growing vector for this series of compounds. Herein, we describe further hit optimization which includes systematic diversifications of both the benzenoid part and the substituents at position 6 and 7 of compound I. Growing of the molecule beside the core modifications yielded several compounds with remarkable anti(myco)bacterial activity against a panel of pathogenic bacteria, including drug-resistant strains. Compound 12 showed a 2-4 fold improvement in activity than I against S. aureus Newman, S. pneumoniae DSM-20566 and E. faecalis DSM-20478. The compounds also showed a good safety profile towards human HepG2 cells.
2022-01-07T00:00:00Z
Bacteriomimetic Liposomes Improve Antibiotic Activity of a Novel Energy-Coupling Factor Transporter Inhibitor.
Drost, Menka
Diamanti, Eleonora
Fuhrmann, Kathrin
Goes, Adriely
Shams, Atanaz
Haupenthal, Jörg
Koch, Marcus
Hirsch, Anna K H
Fuhrmann, Gregor
http://hdl.handle.net/10033/623163
2022-02-12T01:55:14Z
2021-12-21T00:00:00Z
Bacteriomimetic Liposomes Improve Antibiotic Activity of a Novel Energy-Coupling Factor Transporter Inhibitor.
Drost, Menka; Diamanti, Eleonora; Fuhrmann, Kathrin; Goes, Adriely; Shams, Atanaz; Haupenthal, Jörg; Koch, Marcus; Hirsch, Anna K H; Fuhrmann, Gregor
Liposomes have been studied for decades as nanoparticulate drug delivery systems for cytostatics, and more recently, for antibiotics. Such nanoantibiotics show improved antibacterial efficacy compared to the free drug and can be effective despite bacterial recalcitrance. In this work, we present a loading method of bacteriomimetic liposomes for a novel, hydrophobic compound (HIPS5031) inhibiting energy-coupling factor transporters (ECF transporters), an underexplored antimicrobial target. The liposomes were composed of DOPG (18:1 (Δ9-cis) phosphatidylglycerol) and CL (cardiolipin), resembling the cell membrane of Gram-positive Staphylococcus aureus and Streptococcus pneumoniae, and enriched with cholesterol (Chol). The size and polydispersity of the DOPG/CL/± Chol liposomes remained stable over 8 weeks when stored at 4 °C. Loading of the ECF transporter inhibitor was achieved by thin film hydration and led to a high encapsulation efficiency of 33.19% ± 9.5% into the DOPG/CL/Chol liposomes compared to the phosphatidylcholine liposomes (DMPC/DPPC). Bacterial growth inhibition assays on the model organism Bacillus subtilis revealed liposomal HIPS5031 as superior to the free drug, showing a 3.5-fold reduction in CFU/mL at a concentration of 9.64 µM. Liposomal HIPS5031 was also shown to reduce B. subtilis biofilm. Our findings present an explorative basis for bacteriomimetic liposomes as a strategy against drug-resistant pathogens by surpassing the drug-formulation barriers of innovative, yet unfavorably hydrophobic, antibiotics.
2021-12-21T00:00:00Z