4.5 Article

Phosphonate as a Stable Zinc-Binding Group for Pathoblocker Inhibitors of Clostridial Collagenase H (ColH)

期刊

CHEMMEDCHEM
卷 16, 期 8, 页码 1257-1267

出版社

WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.202000994

关键词

anti-infectives; drug design; medicinal chemistry; metalloenzymes; structure– activity relationships

资金

  1. Austrian Science Fund (FWF) [P 31843, W 01213]
  2. Austrian Federal Ministry of Science, Research, and Economy
  3. European Research Council (ERC) [757913]
  4. Helmholtz Association's Initiative and Networking Fund
  5. Projekt DEAL

向作者/读者索取更多资源

Microbial infections pose a significant threat to public health, and the rise in resistance calls for urgently needed new antibiotics. The zinc metalloprotease collagenase H (ColH) from Clostridium histolyticum is a virulence factor that catalyses tissue damage, making it an attractive target for new antivirulence agents. A phosphonate motif as a zinc-binding group showed promising activity against ColH, improved selectivity, and higher stability, making it a promising candidate for future drug development.
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.

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