2.50
Hdl Handle:
http://hdl.handle.net/10033/344574
Title:
Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD.
Authors:
Allegretta, Giuseppe; Weidel, Elisabeth; Empting, Martin; Hartmann, Rolf W
Abstract:
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.
Affiliation:
Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), PO Box 15 11 50, D-66041 Saarbrücken, Germany.
Citation:
Catechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD. 2015, 90:351-9 Eur J Med Chem
Journal:
European journal of medicinal chemistry
Issue Date:
27-Jan-2015
URI:
http://hdl.handle.net/10033/344574
DOI:
10.1016/j.ejmech.2014.11.055
PubMed ID:
25437621
Type:
Article
Language:
en
ISSN:
1768-3254
Appears in Collections:
publications of the department drug design and optimization (HIPS]DDOP)

Full metadata record

DC FieldValue Language
dc.contributor.authorAllegretta, Giuseppeen
dc.contributor.authorWeidel, Elisabethen
dc.contributor.authorEmpting, Martinen
dc.contributor.authorHartmann, Rolf Wen
dc.date.accessioned2015-02-18T13:48:22Z-
dc.date.available2015-02-18T13:48:22Z-
dc.date.issued2015-01-27-
dc.identifier.citationCatechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD. 2015, 90:351-9 Eur J Med Chemen
dc.identifier.issn1768-3254-
dc.identifier.pmid25437621-
dc.identifier.doi10.1016/j.ejmech.2014.11.055-
dc.identifier.urihttp://hdl.handle.net/10033/344574-
dc.description.abstractA 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
dc.language.isoenen
dc.titleCatechol-based substrates of chalcone synthase as a scaffold for novel inhibitors of PqsD.en
dc.typeArticleen
dc.contributor.departmentHelmholtz Institute for Pharmaceutical Research Saarland (HIPS), PO Box 15 11 50, D-66041 Saarbrücken, Germany.en
dc.identifier.journalEuropean journal of medicinal chemistryen

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