2.50
Hdl Handle:
http://hdl.handle.net/10033/621153
Title:
Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases.
Authors:
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
Abstract:
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.
Affiliation:
Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
Citation:
Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases. 2017, 139 (36):12696-12703 J. Am. Chem. Soc.
Journal:
Journal of the American Chemical Society
Issue Date:
13-Sep-2017
URI:
http://hdl.handle.net/10033/621153
DOI:
10.1021/jacs.7b06935
PubMed ID:
28820255
Type:
Article
Language:
en
ISSN:
1520-5126
Appears in Collections:
publications of the department drug design and optimization (HIPS]DDOP)

Full metadata record

DC FieldValue Language
dc.contributor.authorSchönauer, Estheren
dc.contributor.authorKany, Andreas Men
dc.contributor.authorHaupenthal, Jörgen
dc.contributor.authorHüsecken, Kristinaen
dc.contributor.authorHoppe, Isabel Jen
dc.contributor.authorVoos, Katrinen
dc.contributor.authorYahiaoui, Samiren
dc.contributor.authorElsässer, Brigittaen
dc.contributor.authorDucho, Christianen
dc.contributor.authorBrandstetter, Hansen
dc.contributor.authorHartmann, Rolf Wen
dc.date.accessioned2017-11-02T10:29:34Z-
dc.date.available2017-11-02T10:29:34Z-
dc.date.issued2017-09-13-
dc.identifier.citationDiscovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases. 2017, 139 (36):12696-12703 J. Am. Chem. Soc.en
dc.identifier.issn1520-5126-
dc.identifier.pmid28820255-
dc.identifier.doi10.1021/jacs.7b06935-
dc.identifier.urihttp://hdl.handle.net/10033/621153-
dc.description.abstractSecreted 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
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.titleDiscovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.en
dc.identifier.journalJournal of the American Chemical Societyen

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