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

University of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. Department of Cellular and Molecular Pharmacology. San Francisco, CA, USA.
University of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. San Francisco, CA, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.
University of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.
University of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. San Francisco, CA, USA.
University of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. San Francisco, CA, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.
University of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.
University of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.
University of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, USA.
University of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.
University of California San Francisco. Department of Cellular and Molecular Pharmacology. San Francisco, CA, USA.
University of California San Francisco. Department of Pharmaceutical Chemistry. San Francisco, CA. USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.
University of California San Francisco. Center for Discovery and Innovation in Parasitic Diseases. Department of Pathology. San Francisco, CA, USA.
University of California San Francisco. Small Molecule Discovery Center. Department of Pharmaceutical Chemistry. Center for Discovery and Innovation in Parasitic Diseases. San Francisco, CA, 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

Activity-based probes
Chagas disease
Cruzain
CYP51
Hybrid drugs
Trypanosoma cruzi

DeCS

Trypanosoma cruzi
Doença de Chagas

Publisher

Beilstein-Institut

Citation

CHOY, Jonathan W. et al. Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target. Beilstein Journal of Organic Chemistry, v. 9, p. 15–25, 2013.

DOI

10.3762/bjoc.9.3

ISSN

1860-5397

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/11786

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Open access

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