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dc.contributor.authorSchönauer, Esther
dc.contributor.authorKany, Andreas M
dc.contributor.authorHaupenthal, Jörg
dc.contributor.authorHüsecken, Kristina
dc.contributor.authorHoppe, Isabel J
dc.contributor.authorVoos, Katrin
dc.contributor.authorYahiaoui, Samir
dc.contributor.authorElsässer, Brigitta
dc.contributor.authorDucho, Christian
dc.contributor.authorBrandstetter, Hans
dc.contributor.authorHartmann, Rolf W.
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.
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
refterms.dateFOA2018-06-13T01:19:46Z
html.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.


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