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Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome

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 st...

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Autores principales: Rožman, Kaja, Alexander, Evan M., Ogorevc, Eva, Bozovičar, Krištof, Sosič, Izidor, Aldrich, Courtney C., Gobec, Stanislav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144120/
https://www.ncbi.nlm.nih.gov/pubmed/32178473
http://dx.doi.org/10.3390/molecules25061305
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author Rožman, Kaja
Alexander, Evan M.
Ogorevc, Eva
Bozovičar, Krištof
Sosič, Izidor
Aldrich, Courtney C.
Gobec, Stanislav
author_facet Rožman, Kaja
Alexander, Evan M.
Ogorevc, Eva
Bozovičar, Krištof
Sosič, Izidor
Aldrich, Courtney C.
Gobec, Stanislav
author_sort Rožman, Kaja
collection PubMed
description 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.
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spelling pubmed-71441202020-04-13 Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome Rožman, Kaja Alexander, Evan M. Ogorevc, Eva Bozovičar, Krištof Sosič, Izidor Aldrich, Courtney C. Gobec, Stanislav Molecules Article 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. MDPI 2020-03-12 /pmc/articles/PMC7144120/ /pubmed/32178473 http://dx.doi.org/10.3390/molecules25061305 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Rožman, Kaja
Alexander, Evan M.
Ogorevc, Eva
Bozovičar, Krištof
Sosič, Izidor
Aldrich, Courtney C.
Gobec, Stanislav
Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome
title Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome
title_full Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome
title_fullStr Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome
title_full_unstemmed Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome
title_short Psoralen Derivatives as Inhibitors of Mycobacterium tuberculosis Proteasome
title_sort psoralen derivatives as inhibitors of mycobacterium tuberculosis proteasome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144120/
https://www.ncbi.nlm.nih.gov/pubmed/32178473
http://dx.doi.org/10.3390/molecules25061305
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