title: Structure-guided development of selective TbcatB inhibitors.
abstract: The trypanosomal cathepsin TbcatB is essential for parasite survival and is an attractive therapeutic target. Herein we report the structure-guided development of TbcatB inhibitors with specificity relative to rhodesain and human cathepsins B and L. Inhibitors were tested for enzymatic activity, trypanocidal activity, and general cytotoxicity. These data chemically validate TbcatB as a drug target and demonstrate that it is possible to potently and selectively inhibit TbcatB relative to trypanosomal and human homologues.
authors.affiliation: Graduate Program in Chemistry and Chemical Biology, University of California, San Francisco, California 94143-2280, USA.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Mallari
authors.forename: Anang A
authors.initials: AA
authors.lastname: Shelat
authors.forename: Aaron
authors.initials: A
authors.lastname: Kosinski
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.forename: Michele
authors.initials: M
authors.lastname: Connelly
authors.forename: Fangyi
authors.initials: F
authors.lastname: Zhu
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: R Kiplin
authors.initials: RK
authors.lastname: Guy
mesh_terms: D000818:Animals; D002401:Cathepsin B / Q000037:antagonists & inhibitors / Q000378:metabolism; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011487:Protein Conformation; D011687:Purines / Q000737:chemistry; D013379:Substrate Specificity; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000201:enzymology
chemical_list: D011480:Protease Inhibitors; D011687:Purines; D014344:Trypanocidal Agents; D003546:Cysteine Endopeptidases; C533458:TbcatB protein, Trypanosoma brucei; C446033:rhodesain; D002401:Cathepsin B; D056668:Cathepsin L