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Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System

Tuberculosis is a global health problem caused by infection with the Mycobacterium tuberculosis (Mtb) bacteria. Although antibiotic treatment has dramatically reduced the impact of tuberculosis on the population, the existence and spreading of drug resistant strains urgently demands the development...

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Autores principales: Janssen, Guido V., Zhang, Susan, Merkx, Remco, Schiesswohl, Christa, Chatterjee, Champak, Darwin, K. Heran, Geurink, Paul P., van der Heden van Noort, Gerbrand J., Ovaa, Huib
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/PMC8596589/
https://www.ncbi.nlm.nih.gov/pubmed/34387015
http://dx.doi.org/10.1002/cbic.202100333
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author Janssen, Guido V.
Zhang, Susan
Merkx, Remco
Schiesswohl, Christa
Chatterjee, Champak
Darwin, K. Heran
Geurink, Paul P.
van der Heden van Noort, Gerbrand J.
Ovaa, Huib
author_facet Janssen, Guido V.
Zhang, Susan
Merkx, Remco
Schiesswohl, Christa
Chatterjee, Champak
Darwin, K. Heran
Geurink, Paul P.
van der Heden van Noort, Gerbrand J.
Ovaa, Huib
author_sort Janssen, Guido V.
collection PubMed
description Tuberculosis is a global health problem caused by infection with the Mycobacterium tuberculosis (Mtb) bacteria. Although antibiotic treatment has dramatically reduced the impact of tuberculosis on the population, the existence and spreading of drug resistant strains urgently demands the development of new drugs that target Mtb in a different manner than currently used antibiotics. The prokaryotic ubiquitin‐like protein (Pup) proteasome system is an attractive target for new drug development as it is unique to Mtb and related bacterial genera. Using a Pup‐based fluorogenic substrate, we screened for inhibitors of Dop, the Mtb depupylating protease, and identified I‐OMe‐Tyrphostin AG538 (1) and Tyrphostin AG538 (2). The hits were validated and determined to be fast‐reversible, non‐ATP competitive inhibitors. We synthesized >25 analogs of 1 and 2 and show that several of the synthesized compounds also inhibit the depupylation actions of Dop on native substrate, FabD‐Pup. Importantly, the pupylation activity of PafA, the sole Pup ligase in Mtb, was also inhibited by some of these compounds.
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spelling pubmed-85965892021-11-22 Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System Janssen, Guido V. Zhang, Susan Merkx, Remco Schiesswohl, Christa Chatterjee, Champak Darwin, K. Heran Geurink, Paul P. van der Heden van Noort, Gerbrand J. Ovaa, Huib Chembiochem Full Papers Tuberculosis is a global health problem caused by infection with the Mycobacterium tuberculosis (Mtb) bacteria. Although antibiotic treatment has dramatically reduced the impact of tuberculosis on the population, the existence and spreading of drug resistant strains urgently demands the development of new drugs that target Mtb in a different manner than currently used antibiotics. The prokaryotic ubiquitin‐like protein (Pup) proteasome system is an attractive target for new drug development as it is unique to Mtb and related bacterial genera. Using a Pup‐based fluorogenic substrate, we screened for inhibitors of Dop, the Mtb depupylating protease, and identified I‐OMe‐Tyrphostin AG538 (1) and Tyrphostin AG538 (2). The hits were validated and determined to be fast‐reversible, non‐ATP competitive inhibitors. We synthesized >25 analogs of 1 and 2 and show that several of the synthesized compounds also inhibit the depupylation actions of Dop on native substrate, FabD‐Pup. Importantly, the pupylation activity of PafA, the sole Pup ligase in Mtb, was also inhibited by some of these compounds. John Wiley and Sons Inc. 2021-09-12 2021-11-03 /pmc/articles/PMC8596589/ /pubmed/34387015 http://dx.doi.org/10.1002/cbic.202100333 Text en © 2021 The Authors. ChemBioChem published by Wiley-VCH GmbH https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Full Papers
Janssen, Guido V.
Zhang, Susan
Merkx, Remco
Schiesswohl, Christa
Chatterjee, Champak
Darwin, K. Heran
Geurink, Paul P.
van der Heden van Noort, Gerbrand J.
Ovaa, Huib
Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System
title Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System
title_full Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System
title_fullStr Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System
title_full_unstemmed Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System
title_short Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System
title_sort development of tyrphostin analogues to study inhibition of the mycobacterium tuberculosis pup proteasome system
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8596589/
https://www.ncbi.nlm.nih.gov/pubmed/34387015
http://dx.doi.org/10.1002/cbic.202100333
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