Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
Kany, Andreas M
Hoppe, Isabel J
Hartmann, Rolf W.
MetadataShow full item record
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.
CitationDiscovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases. 2017, 139 (36):12696-12703 J. Am. Chem. Soc.
AffiliationHelmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
The following license files are associated with this item:
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by-nc-sa/4.0/
- Structures of three polycystic kidney disease-like domains from Clostridium histolyticum collagenases ColG and ColH.
- Authors: Bauer R, Janowska K, Taylor K, Jordan B, Gann S, Janowski T, Latimer EC, Matsushita O, Sakon J
- Issue date: 2015 Mar
- Structural basis for activity regulation and substrate preference of clostridial collagenases G, H, and T.
- Authors: Eckhard U, Schönauer E, Brandstetter H
- Issue date: 2013 Jul 12
- Biochemical characterization of the catalytic domains of three different Clostridial collagenases.
- Authors: Eckhard U, Schönauer E, Ducka P, Briza P, Nüss D, Brandstetter H
- Issue date: 2009 Jan
- Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa.
- Authors: Kany AM, Sikandar A, Haupenthal J, Yahiaoui S, Maurer CK, Proschak E, Köhnke J, Hartmann RW
- Issue date: 2018 Jun 8
- Cloning, Purification and Characterization of the Collagenase ColA Expressed by Bacillus cereus ATCC 14579.
- Authors: Abfalter CM, Schönauer E, Ponnuraj K, Huemer M, Gadermaier G, Regl C, Briza P, Ferreira F, Huber CG, Brandstetter H, Posselt G, Wessler S
- Issue date: 2016