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

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 dama...

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Autores principales: Voos, Katrin, Schönauer, Esther, Alhayek, Alaa, Haupenthal, Jörg, Andreas, Anastasia, Müller, Rolf, Hartmann, Rolf W., Brandstetter, Hans, Hirsch, Anna K. H., Ducho, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251769/
https://www.ncbi.nlm.nih.gov/pubmed/33506625
http://dx.doi.org/10.1002/cmdc.202000994
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author Voos, Katrin
Schönauer, Esther
Alhayek, Alaa
Haupenthal, Jörg
Andreas, Anastasia
Müller, Rolf
Hartmann, Rolf W.
Brandstetter, Hans
Hirsch, Anna K. H.
Ducho, Christian
author_facet Voos, Katrin
Schönauer, Esther
Alhayek, Alaa
Haupenthal, Jörg
Andreas, Anastasia
Müller, Rolf
Hartmann, Rolf W.
Brandstetter, Hans
Hirsch, Anna K. H.
Ducho, Christian
author_sort Voos, Katrin
collection PubMed
description 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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spelling pubmed-82517692021-07-07 Phosphonate as a Stable Zinc‐Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH) Voos, Katrin Schönauer, Esther Alhayek, Alaa Haupenthal, Jörg Andreas, Anastasia Müller, Rolf Hartmann, Rolf W. Brandstetter, Hans Hirsch, Anna K. H. Ducho, Christian ChemMedChem Full Papers 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. John Wiley and Sons Inc. 2021-03-16 2021-04-20 /pmc/articles/PMC8251769/ /pubmed/33506625 http://dx.doi.org/10.1002/cmdc.202000994 Text en © 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Full Papers
Voos, Katrin
Schönauer, Esther
Alhayek, Alaa
Haupenthal, Jörg
Andreas, Anastasia
Müller, Rolf
Hartmann, Rolf W.
Brandstetter, Hans
Hirsch, Anna K. H.
Ducho, Christian
Phosphonate as a Stable Zinc‐Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
title Phosphonate as a Stable Zinc‐Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
title_full Phosphonate as a Stable Zinc‐Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
title_fullStr Phosphonate as a Stable Zinc‐Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
title_full_unstemmed Phosphonate as a Stable Zinc‐Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
title_short Phosphonate as a Stable Zinc‐Binding Group for “Pathoblocker” Inhibitors of Clostridial Collagenase H (ColH)
title_sort phosphonate as a stable zinc‐binding group for “pathoblocker” inhibitors of clostridial collagenase h (colh)
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251769/
https://www.ncbi.nlm.nih.gov/pubmed/33506625
http://dx.doi.org/10.1002/cmdc.202000994
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