Discovery of a Potent Inhibitor Class with High Selectivity toward Clostridial Collagenases

• Published in: Journal of the American Chemical Society Vol. 139; no. 36; pp. 12696 - 12703
• Main 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
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 13.09.2017
• Subjects: Collagenases - drug effects; Crystallography, X-Ray; Drug Discovery; Humans; Inhibitory Concentration 50; Matrix Metalloproteinases - drug effects; Molecular Structure; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Substrate Specificity; Surface Plasmon Resonance; Virulence Factors
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.7b06935

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.