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

Bioorganic & Medicinal Chemistry Letters
Danielle McShanIfedayo Victor Ogungbe

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.

References

Aug 3, 2004·Nature Reviews. Drug Discovery·David C ReesRobin Carr
Sep 24, 2009·Memórias do Instituto Oswaldo Cruz·J H McKerrowC S Craik
Feb 13, 2013·Beilstein Journal of Organic Chemistry·Jonathan W ChoyAdam R Renslo
Nov 19, 2013·ChemMedChem·Roberta EttariPaola Conti

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Citations

Jul 12, 2016·MedChemComm·Stefan G Kathman, Alexander V Statsyuk
May 27, 2017·Chemical Biology & Drug Design·Juliana da Fonseca Rezende E MelloGustavo Henrique Goulart Trossini
Nov 18, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Roberta EttariMaria Zappalà
Nov 21, 2020·ACS Medicinal Chemistry Letters·Huaisheng ZhangIfedayo Victor Ogungbe

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African trypanosomiasis, also known as sleeping sickness, is an insect-borne parasitic disease of humans and other animals. It is caused by protozoa of the species Trypanosoma brucei and almost invariably progresses to death unless treated. Discover the latest research on African trypanosomiasis here.