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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.

SUBMITTER: McShan D

PROVIDER: S-EPMC4592840 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

McShan Danielle D Kathman Stefan S Lowe Brittiney B Xu Ziyang Z Zhan Jennifer J Statsyuk Alexander A Ogungbe Ifedayo Victor IV

Bioorganic & medicinal chemistry letters 20150902 20

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 envisio ...[more]

PMID: 26342866

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New Cysteine Protease Inhibitors: Electrophilic (Het)arenes and Unexpected Prodrug Identification for the Trypanosoma Protease Rhodesain.

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