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-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.
Highlights
The kinetoplastid protozoan Trypanosoma cruzi is the causative agent of Chagas’ disease, a leading cause of heart failure in endemic regions of Latin America [1]
Among a number of drug targets being investigated are cruzain [7,8,9,10], the major cysteine protease active in the parasite, and T. cruzi CYP51 (TcCYP51), a 14-α-demethylase enzyme of the cytochrome P450 family required for ergosterol biosynthesis [11,12,13,14]
TcCYP51 is analogous to the fungal enzyme targeted by the azole class of antifungals, and the observation that some of these drugs inhibit TcCYP51 has led to their preclinical and clinical investigation as potential new treatments for Chagas’ disease [2,15,16]
Summary
The kinetoplastid protozoan Trypanosoma cruzi is the causative agent of Chagas’ disease, a leading cause of heart failure in endemic regions of Latin America [1]. 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. Among a number of drug targets being investigated are cruzain [7,8,9,10], the major cysteine protease active in the parasite, and T. cruzi CYP51 (TcCYP51), a 14-α-demethylase enzyme of the cytochrome P450 family required for ergosterol biosynthesis [11,12,13,14].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
