Identification of non-peptidic cysteine reactive fragments as inhibitors of cysteine protease rhodesain.
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.
Department of Chemistry and Biochemistry, Jackson State University, Jackson, MS 39217, United States.
Danielle
D
McShan
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, United States.
Stefan
S
Kathman
Department of Chemistry and Biochemistry, Jackson State University, Jackson, MS 39217, United States.
Brittiney
B
Lowe
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, United States.
Ziyang
Z
Xu
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, United States.
Jennifer
J
Zhan
Department of Chemistry, Center for Molecular Innovation and Drug Discovery, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, United States.
Alexander
A
Statsyuk
Department of Chemistry and Biochemistry, Jackson State University, Jackson, MS 39217, United States.
Ifedayo Victor
IV
Ogungbe
D003545:Cysteine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D016833:Trypanosoma brucei rhodesiense / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C446033:rhodesain; D003545:Cysteine
Covalent fragments; Cysteine protease; Rhodesain; Trypanosomes