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Phosphonate as Stable Zinc-binding Group for Inhibitors of Clostridial Collagenase H (ColH) as Pathoblocker Agents.
Voos, Katrin Schönauer, Esther Alhayek, Alaa Haupenthal, Jörg Andreas, Anastasia Müller, Rolf Hartmann, Rolf W Brandstetter, Hans Hirsch, Anna K H Ducho, Christian
Voos, Katrin
Schönauer, Esther
Alhayek, Alaa
Haupenthal, Jörg
Andreas, Anastasia
Müller, Rolf
Hartmann, Rolf W
Brandstetter, Hans
Hirsch, Anna K H
Ducho, Christian
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2021-01-27
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Abstract
Microbial infections are a significant threat to public health and resistances are 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 catalyzes 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.
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ChemMedChem. 2021 Jan 27. doi: 10.1002/cmdc.202000994. Epub ahead of print.
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en
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1860-7187
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Attribution-NonCommercial-NoDerivatives 4.0 International