1. Phosphonate as a Stable Zinc-Binding Group for "Pathoblocker" Inhibitors of Clostridial Collagenase H (ColH).
- Author
-
Voos K, Schönauer E, Alhayek A, Haupenthal J, Andreas A, Müller R, Hartmann RW, Brandstetter H, Hirsch AKH, and Ducho C
- Subjects
- Acetanilides chemical synthesis, Acetanilides toxicity, Animals, Bacillus cereus enzymology, Bacterial Proteins metabolism, Cell Line, Tumor, Chelating Agents chemical synthesis, Chelating Agents toxicity, Clostridium histolyticum enzymology, Collagen metabolism, Collagenases metabolism, HEK293 Cells, Humans, Matrix Metalloproteinase Inhibitors chemical synthesis, Matrix Metalloproteinase Inhibitors toxicity, Organophosphonates chemical synthesis, Organophosphonates toxicity, Swine, Zebrafish, Zinc chemistry, Acetanilides pharmacology, Bacterial Proteins antagonists & inhibitors, Chelating Agents pharmacology, Matrix Metalloproteinase Inhibitors pharmacology, Organophosphonates pharmacology
- Abstract
Microbial infections are a significant threat to public health, and resistance is on the rise, so new antibiotics with novel modes of action are urgently needed. The extracellular zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyses tissue damage, leading to improved host invasion and colonisation. Besides the major role of ColH in pathogenicity, its extracellular localisation makes it a highly attractive target for the development of new antivirulence agents. Previously, we had found that a highly selective and potent thiol prodrug (with a hydrolytically cleavable thiocarbamate unit) provided efficient ColH inhibition. We now report the synthesis and biological evaluation of a range of zinc-binding group (ZBG) variants of this thiol-derived inhibitor, with the mercapto unit being replaced by other zinc ligands. Among these, an analogue with a phosphonate motif as ZBG showed promising activity against ColH, an improved selectivity profile, and significantly higher stability than the thiol reference compound, thus making it an attractive candidate for future drug development., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)
- Published
- 2021
- Full Text
- View/download PDF