Psoralen derivatives as inhibitors of mycobacterium tuberculosis proteasome

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

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.

• Jezik: Angleški jezik
• Ključne besede: protein degradation, proteasome, Mycobacterium tuberculosis, psoralens, nonpeptidic proteasome inhibitors
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2020
• Št. strani: 14 str.
• Številčenje: Vol. 25, iss. 6, art. 1305
• PID: 20.500.12556/RUL-133422
• UDK: 547.96.057:615.4
• ISSN pri članku: 1420-3049
• DOI: 10.3390/molecules25061305
• COBISS.SI-ID: 4894321
• Datum objave v RUL: 26.11.2021

Gradivo je del revije

• Naslov: Molecules
• Skrajšan naslov: Molecules
• Založnik: MDPI
• ISSN: 1420-3049
• COBISS.SI-ID: 18462981

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 12.03.2020

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: sinteza beljakovin, zaviralci Mycobacterium tuberculosis, imunoproteasom, farmacevtska kemija, beljakovine