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Psoralen derivatives as inhibitors of mycobacterium tuberculosis proteasome

  • Rožman, Kaja
  • Alexander, Evan M.
  • Ogorevc, Eva
  • Bozovičar, Krištof
  • Sosič, Izidor
  • Aldrich, Courtney C.
  • Gobec, Stanislav
Publication Date
Nov 26, 2021
University of Ljubljana
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Protein degradation is a fundamental process in all living organisms. An important part of this system is a multisubunit, barrel-shaped protease complex called the proteasome. This enzyme is directly responsible for the proteolysis of ubiquitin- or pup-tagged proteins to smaller peptides. In this study, we present a series of 92 psoralen derivatives, of which 15 displayed inhibitory potency against the Mycobacterium tuberculosis proteasome in low micromolar concentrations. The best inhibitors, i.e., 8, 11, 13 and 15, exhibited a mixed type of inhibition and overall good inhibitory potency in biochemical assays. N-(cyanomethyl)acetamide 8 (K$_i$ = 5.6 µM) and carboxaldehyde-based derivative 15 (K$_i$ = 14.9 µM) were shown to be reversible inhibitors of the enzyme. On the other hand, pyrrolidine-2,5-dione esters 11 and 13 irreversibly inhibited the enzyme with K$_i$ values of 4.2 µM and 1.1 µM, respectively. In addition, we showed that an established immunoproteasome inhibitor, PR-957, is a noncompetitive irreversible inhibitor of the mycobacterial proteasome (K$_i$ = 5.2 ± 1.9 µM, k$_{inact}$/K$_i$ = 96 ± 41 M$^{−1}$·s$^{−1}$). These compounds represent interesting hit compounds for further optimization in the development of new drugs for the treatment of tuberculosis.

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