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

Danielle McShan, Stefan Kathman, Brittiney Lowe, Ziyang Xu, Jennifer Zhan, Alexander Statsyuk, Ifedayo Victor Ogungbe*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4509-4512
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number20
DOIs
StatePublished - Oct 15 2015

Keywords

  • Covalent fragments
  • Cysteine protease
  • Rhodesain
  • Trypanosomes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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