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

Abstract

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-a-demethylase (TcCYP51), a cytochrome P450 © 2013 Santra et al; licensee Beilstein-Institut.