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

Guido V Janssen, Susan Zhang, Remco Merkx, Christa Schiesswohl, Champak Chatterjee, K Heran Darwin, Paul P Geurink, Gerbrand J van der Heden van Noort, Huib Ovaa

Chembiochem : a European journal of chemical biology 2021 Nov 03

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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.

Citation

Guido V Janssen, Susan Zhang, Remco Merkx, Christa Schiesswohl, Champak Chatterjee, K Heran Darwin, Paul P Geurink, Gerbrand J van der Heden van Noort, Huib Ovaa. Development of Tyrphostin Analogues to Study Inhibition of the Mycobacterium tuberculosis Pup Proteasome System*. Chembiochem : a European journal of chemical biology. 2021 Nov 03;22(21):3082-3089