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Psoralen derivatives as inhibitors of mycobacterium tuberculosis proteasome [Elektronski vir]Rožman, Kaja, farmacevtka ...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.Source: Molecules [Elektronski vir]. - ISSN 1420-3049 (Vol. 25, no. 6, 2020, str. 1-14)Type of material - e-article ; adult, seriousPublish date - 2020Language - englishCOBISS.SI-ID - 4894321
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https://www.mdpi.com/1420-3049/25/6/1305Odprt dostop
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DOI
Author
Rožman, Kaja, farmacevtka |
Alexander, Evan M. |
Ogorevc, Eva, 1982- |
Bozovičar, Krištof |
Sosič, Izidor |
Aldrich, Courtney C., 1970- |
Gobec, Stanislav, 1970-
Topics
Farmacevtska kemija |
Beljakovine |
sinteza beljakovin |
zaviralci Mycobacterium tuberculosis |
imunoproteasom |
protein degradation |
proteasome |
Mycobacterium tuberculosis |
psoralens |
nonpeptidic proteasome inhibitors
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Database name | Field | Year |
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Links to authors' personal bibliographies | Links to information on researchers in the SICRIS system |
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Rožman, Kaja, farmacevtka | 37050 |
Alexander, Evan M. | |
Ogorevc, Eva, 1982- | 33169 |
Bozovičar, Krištof | 53738 |
Sosič, Izidor | 30816 |
Aldrich, Courtney C., 1970- | |
Gobec, Stanislav, 1970- | 15284 |
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