Identification of non-peptidic cysteine reactive fragments as inhibitors of cysteine protease rhodesain.

Abstract

Rhodesain, the major cathepsin L-like cysteine protease in the protozoan Trypanosoma brucei rhodesiense, the causative agent of African sleeping sickness, is a well-validated drug target. In this work, we used a fragment-based approach to identify inhibitors of this cysteine protease, and identified inhibitors of T. brucei. To discover inhibitors active against rhodesain and T. brucei, we screened a library of covalent fragments against rhodesain and conducted preliminary SAR studies. We envision that in vitro enzymatic assays will further expand the use of the covalent tethering method, a simple fragment-based drug discovery technique to discover covalent drug leads.

• Authors: Danielle McShan, Stefan Kathman, Brittiney Lowe, Ziyang Xu, Jennifer Zhan, Alexander Statsyuk, Ifedayo Victor Ogungbe
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 25 Issue 20 Pg. 4509-12 (Oct 15 2015) ISSN: 1464-3405 [Electronic] England
• PMID: 26342866 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Cysteine Proteinase Inhibitors
• Trypanocidal Agents
• Cysteine Endopeptidases
• rhodesain
• Cysteine

Topics

• Cysteine (analogs & derivatives, chemistry, pharmacology)
• Cysteine Endopeptidases (metabolism)
• Cysteine Proteinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Molecular Structure
• Parasitic Sensitivity Tests
• Structure-Activity Relationship
• Trypanocidal Agents (chemical synthesis, chemistry, pharmacology)
• Trypanosoma brucei brucei (drug effects, enzymology)
• Trypanosoma brucei rhodesiense (metabolism)