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Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

Inhibition of the Trypanosoma cruzi cysteine protease cruzain has been proposed as a therapeutic approach for the treatment of Chagas’ disease. Among the best-studied cruzain inhibitors to date is the vinylsulfone K777 (1), which has proven effective in animal models of Chagas’ disease. Recent struc...

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Detalles Bibliográficos
Autores principales: Choy, Jonathan W, Bryant, Clifford, Calvet, Claudia M, Doyle, Patricia S, Gunatilleke, Shamila S, Leung, Siegfried S F, Ang, Kenny K H, Chen, Steven, Gut, Jiri, Oses-Prieto, Juan A, Johnston, Jonathan B, Arkin, Michelle R, Burlingame, Alma L, Taunton, Jack, Jacobson, Matthew P, McKerrow, James M, Podust, Larissa M, Renslo, Adam R
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Beilstein-Institut 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566858/
https://www.ncbi.nlm.nih.gov/pubmed/23400640
http://dx.doi.org/10.3762/bjoc.9.3
Descripción
Sumario:Inhibition of the Trypanosoma cruzi cysteine protease cruzain has been proposed as a therapeutic approach for the treatment of Chagas’ disease. Among the best-studied cruzain inhibitors to date is the vinylsulfone K777 (1), which has proven effective in animal models of Chagas’ disease. Recent structure–activity studies aimed at addressing potential liabilities of 1 have now produced analogues such as N-[(2S)-1-[[(E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-3-(4-methylphenyl)-1-oxopropan-2-yl]pyridine-4-carboxamide (4), which is trypanocidal at ten-fold lower concentrations than for 1. We now find that the trypanocidal activity of 4 derives primarily from the inhibition of T. cruzi 14-α-demethylase (TcCYP51), a cytochrome P450 enzyme involved in the biosynthesis of ergosterol in the parasite. Compound 4 also inhibits mammalian CYP isoforms but is trypanocidal at concentrations below those required to significantly inhibit mammalian CYPs in vitro. A chemical-proteomics approach employing an activity-based probe derived from 1 was used to identify mammalian cathepsin B as a potentially important off-target of 1 and 4. Computational docking studies and the evaluation of truncated analogues of 4 reveal structural determinants for TcCYP51 binding, information that will be useful in further optimization of this new class of inhibitors.