Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System*.
Anti-Bacterial Agents
/ chemical synthesis
Bacterial Proteins
/ antagonists & inhibitors
Dose-Response Relationship, Drug
Drug Development
Enzyme Inhibitors
/ chemical synthesis
Microbial Sensitivity Tests
Molecular Structure
Mycobacterium tuberculosis
/ drug effects
Structure-Activity Relationship
Tyrphostins
/ chemical synthesis
Ubiquitins
/ antagonists & inhibitors
Mycobacterium tuberculosis
inhibitor screen
pup proteasome system
tuberculosis
Journal
Chembiochem : a European journal of chemical biology
ISSN: 1439-7633
Titre abrégé: Chembiochem
Pays: Germany
ID NLM: 100937360
Informations de publication
Date de publication:
03 11 2021
03 11 2021
Historique:
revised:
12
08
2021
received:
08
07
2021
pubmed:
14
8
2021
medline:
22
2
2022
entrez:
13
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34387015
doi: 10.1002/cbic.202100333
pmc: PMC8596589
mid: NIHMS1755596
doi:
Substances chimiques
Anti-Bacterial Agents
0
Bacterial Proteins
0
Enzyme Inhibitors
0
Pup protein, Mycobacterium tuberculosis
0
Tyrphostins
0
Ubiquitins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3082-3089Subventions
Organisme : VIDI
Organisme : Off-Road grant
Organisme : NIGMS NIH HHS
ID : R01 GM110430
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI088075
Pays : United States
Organisme : Burroughs Wellcome Fund
Informations de copyright
© 2021 The Authors. ChemBioChem published by Wiley-VCH GmbH.
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