Kaja Rožman (Author), Evan M. Alexander (Author), Eva Ogorevc (Author), Krištof Bozovičar (Author), Izidor Sosič (Author), Courtney C. Aldrich (Author), Stanislav Gobec (Author)

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 microM) and carboxaldehyde-based derivative 15 (Ki = 14.9 microM) 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 microM and 1.1 microM, 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 microM, 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

sinteza beljakovin;zaviralci Mycobacterium tuberculosis;imunoproteasom;protein degradation;proteasome;Mycobacterium tuberculosis;psoralens;nonpeptidic proteasome inhibitors;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 547.96.057:615.4
COBISS: 4894321 Link will open in a new window
ISSN: 1420-3049
Views: 188
Downloads: 80
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Other data

Secondary language: Slovenian
Secondary keywords: Farmacevtska kemija;Beljakovine;
Type (COBISS): Article
Pages: str. 1-14
Volume: ǂVol. ǂ25
Issue: ǂno. ǂ6
Chronology: 2020
DOI: 10.3390/molecules25061305
ID: 14031700