1. Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System*.
- Author
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Janssen GV, Zhang S, Merkx R, Schiesswohl C, Chatterjee C, Darwin KH, Geurink PP, van der Heden van Noort GJ, and Ovaa H
- Subjects
- Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Bacterial Proteins metabolism, Dose-Response Relationship, Drug, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Microbial Sensitivity Tests, Molecular Structure, Mycobacterium tuberculosis enzymology, Structure-Activity Relationship, Tyrphostins chemical synthesis, Tyrphostins chemistry, Ubiquitins metabolism, Anti-Bacterial Agents pharmacology, Bacterial Proteins antagonists & inhibitors, Drug Development, Enzyme Inhibitors pharmacology, Mycobacterium tuberculosis drug effects, Tyrphostins pharmacology, Ubiquitins antagonists & inhibitors
- 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., (© 2021 The Authors. ChemBioChem published by Wiley-VCH GmbH.)
- Published
- 2021
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