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Phosphonate as a Stable Zinc‐Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
Author(s) -
Voos Katrin,
Schönauer Esther,
Alhayek Alaa,
Haupenthal Jörg,
Andreas Anastasia,
Müller Rolf,
Hartmann Rolf W.,
Brandstetter Hans,
Hirsch Anna K. H.,
Ducho Christian
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000994
Subject(s) - phosphonate , prodrug , collagenase , chemistry , metalloproteinase , extracellular , thiol , biochemistry , microbiology and biotechnology , zinc , antibiotics , drug , biology , enzyme , pharmacology , organic chemistry
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.