1. Academic Validation
  2. Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome

Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome

  • Molecules. 2020 Mar 12;25(6):1305. doi: 10.3390/molecules25061305.
Kaja Rožman 1 2 Evan M Alexander 2 Eva Ogorevc 1 Krištof Bozovičar 1 Izidor Sosič 1 Courtney C Aldrich 2 Stanislav Gobec 1
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, SI-1000 Ljubljana, Slovenia.
  • 2 Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street Southeast, Minneapolis, MN 55455, USA.
Abstract

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 (Ki = 5.6 µM) and carboxaldehyde-based derivative 15 (Ki = 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 Ki 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 (Ki = 5.2 ± 1.9 µM, kinact/Ki = 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.

Keywords

Mycobacterium tuberculosis; nonpeptidic proteasome inhibitors; proteasome; protein degradation; psoralens.

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