Phosphonate as a Stable Zinc-Binding Group for "Pathoblocker" Inhibitors of Clostridial Collagenase H (ColH).
Acetanilides
/ chemical synthesis
Animals
Bacillus cereus
/ enzymology
Bacterial Proteins
/ antagonists & inhibitors
Cell Line, Tumor
Chelating Agents
/ chemical synthesis
Clostridium histolyticum
/ enzymology
Collagen
/ metabolism
Collagenases
/ metabolism
HEK293 Cells
Humans
Matrix Metalloproteinase Inhibitors
/ chemical synthesis
Organophosphonates
/ chemical synthesis
Swine
Zebrafish
Zinc
/ chemistry
anti-infectives
drug design
medicinal chemistry
metalloenzymes
structure-activity relationships
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
20 04 2021
20 04 2021
Historique:
received:
23
12
2020
pubmed:
29
1
2021
medline:
12
1
2022
entrez:
28
1
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33506625
doi: 10.1002/cmdc.202000994
pmc: PMC8251769
doi:
Substances chimiques
Acetanilides
0
Bacterial Proteins
0
Chelating Agents
0
Matrix Metalloproteinase Inhibitors
0
Organophosphonates
0
Collagen
9007-34-5
ColH protein, Clostridium histolyticum
EC 3.4.24.-
Collagenases
EC 3.4.24.-
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1257-1267Subventions
Organisme : Austrian Science Fund
ID : P 31843
Organisme : Austrian Science Fund
ID : W 01213
Organisme : Austrian Federal Ministry of Science, Research, and Economy
Organisme : Helmholtz Association's Initiative and Networking Fund
Organisme : European Research Council
ID : 757913
Pays : International
Informations de copyright
© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.
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