Psoralen derivatives as inhibitors of mycobacterium tuberculosis proteasome

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

Research output: Contribution to journalArticlepeer-review

Abstract

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 µM) and carboxaldehyde-based derivative 15 (Ki = 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 Ki 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 (Ki = 5.2 ± 1.9 µM, 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.

Original languageEnglish (US)
Article number25061305
JournalMolecules
Volume25
Issue number6
DOIs
StatePublished - Mar 12 2020

Bibliographical note

Funding Information:
Acknowledgments: This research was financially supported by the Slovenian Research Agency (research core funding No. P1-0208) and Ministry of Education, Science and Sports of Republic of Slovenia (grant number C3330-17-529028 Raziskovalci-2.0-UL-FFA-529028). A special thank you to Gang Lin from Weill Medical College of Cornell University for providing the Mtb plasmid and sharing his knowledge about the protein expression.

Funding Information:
This research was funded by the Slovenian Research Agency (research core funding No. P1-0208) and Ministry of Education, Science and Sports of Republic of Slovenia (grant number C3330-17-529028 Raziskovalci-2.0-UL-FFA-529028). This research was financially supported by the Slovenian Research Agency (research core funding No. P1-0208) and Ministry of Education, Science and Sports of Republic of Slovenia (grant number C3330-17-529028 Raziskovalci-2.0-UL-FFA-529028). A special thank you to Gang Lin from Weill Medical College of Cornell University for providing the Mtb plasmid and sharing his knowledge about the protein expression.

Funding Information:
Funding: This research was funded by the Slovenian Research Agency (research core funding No. P1-0208) and Ministry of Education, Science and Sports of Republic of Slovenia (grant number C3330-17-529028 Raziskovalci-2.0-UL-FFA-529028).

Publisher Copyright:
© 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/).

Keywords

  • Mycobacterium tuberculosis
  • Nonpeptidic proteasome inhibitors
  • Proteasome
  • Protein degradation
  • Psoralens

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