Psoralen derivatives as inhibitors of mycobacterium tuberculosis proteasome

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

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.

• Language: English
• Keywords: protein degradation, proteasome, Mycobacterium tuberculosis, psoralens, nonpeptidic proteasome inhibitors
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FFA - Faculty of Pharmacy
• Publication status: Published
• Publication version: Version of Record
• Year: 2020
• Number of pages: 14 str.
• Numbering: Vol. 25, iss. 6, art. 1305
• PID: 20.500.12556/RUL-133422
• UDC: 547.96.057:615.4
• ISSN on article: 1420-3049
• DOI: 10.3390/molecules25061305
• COBISS.SI-ID: 4894321
• Publication date in RUL: 26.11.2021

Record is a part of a journal

• Title: Molecules
• Shortened title: Molecules
• Publisher: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.
• Licensing start date: 12.03.2020

Secondary language

• Language: Slovenian
• Keywords: sinteza beljakovin, zaviralci Mycobacterium tuberculosis, imunoproteasom, farmacevtska kemija, beljakovine