Back to Search Start Over

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

Authors :
Janssen GV
Zhang S
Merkx R
Schiesswohl C
Chatterjee C
Darwin KH
Geurink PP
van der Heden van Noort GJ
Ovaa H
Source :
Chembiochem : a European journal of chemical biology [Chembiochem] 2021 Nov 03; Vol. 22 (21), pp. 3082-3089. Date of Electronic Publication: 2021 Sep 12.
Publication Year :
2021

Abstract

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.<br /> (© 2021 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Details

Language :
English
ISSN :
1439-7633
Volume :
22
Issue :
21
Database :
MEDLINE
Journal :
Chembiochem : a European journal of chemical biology
Publication Type :
Academic Journal
Accession number :
34387015
Full Text :
https://doi.org/10.1002/cbic.202100333