Rxivist logo

Discovery and Optimization of Inhibitors for the Pup Proteasome System in Mycobacterium tuberculosis

By Guido V. Janssen, Susan Zhang, Remco Merkx, Christa Schiesswohl, Champak Chatterjee, Kuan Hu, Huib Ovaa

Posted 07 Oct 2019
bioRxiv DOI: 10.1101/796359

Tuberculosis is a global health problem with the existence and spreading of multidrug resistant and extensive drug resistant strains. The development of new drugs for tuberculosis that inhibit different activities than the current drugs is thus urgent. The prokaryotic ubiquitin like protein proteasome system is an attractive target for the development of new drugs. Using a Pup-based fluorogenic substrate, we screened for inhibitors of Dop, a depupylase, and identified I-OMe-Tyrphostin AG538 (1) and Tyrphostin AG53 (2). The hits were validated and determined to be fast reversible non-ATP competitive inhibitors. The SAR was established by testing 27 synthesized analogs of 1 and 2. Several of the synthesized compounds also inhibited the depupylation of a native substrate, FabD~Pup. Importantly, the pupylation and depupylation activities of PafA, the sole Pup ligase in M. tuberculosis, was also inhibited by some of these compounds. With the identification of the first described lead compounds for Dop and PafA inhibition, this study shows that high throughput screening can be a successful strategy for this purpose.

Download data

  • Downloaded 259 times
  • Download rankings, all-time:
    • Site-wide: 61,434 out of 92,466
    • In microbiology: 4,716 out of 8,033
  • Year to date:
    • Site-wide: 32,457 out of 92,466
  • Since beginning of last month:
    • Site-wide: 32,095 out of 92,466

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

Sign up for the Rxivist weekly newsletter! (Click here for more details.)


News