Format

Send to

Choose Destination
See comment in PubMed Commons below
Beilstein J Org Chem. 2013;9:15-25. doi: 10.3762/bjoc.9.3. Epub 2013 Jan 4.

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

Author information

1
Small Molecule Discovery Center, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA ; Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA ; Department of Cellular and Molecular Pharmacology, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA.

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.

KEYWORDS:

14-α-demethylase; CYP51; Chagas’ disease; Trypanosoma cruzi; activity-based probes; cruzain; hybrid drugs

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for PubMed Central
    Loading ...
    Support Center