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

Povzetek

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.

Ključne besede

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

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 547.96.057:615.4
COBISS: 4894321 Povezava se bo odprla v novem oknu
ISSN: 1420-3049
Št. ogledov: 188
Št. prenosov: 80
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: Farmacevtska kemija;Beljakovine;
Vrsta dela (COBISS): Članek v reviji
Strani: str. 1-14
Letnik: ǂVol. ǂ25
Zvezek: ǂno. ǂ6
Čas izdaje: 2020
DOI: 10.3390/molecules25061305
ID: 14031700