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

Jonathan W. Choy; Clifford Bryant; Claudia M. Calvet; Patricia S. Doyle; Shamila S. Gunatilleke; Siegfried S. F. Leung; Kenny K. H. Ang; Steven Chen; Jiri Gut; Juan A. Oses-Prieto; Jonathan B. Johnston; Michelle R. Arkin; Alma L. Burlingame; Jack Taunton; Matthew P. Jacobson; James M. McKerrow; Larissa M. Podust; Adam R. Renslo

doi:10.3762/bjoc.9.3

Beilstein Journal of Organic Chemistry (Jan 2013)

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

Jonathan W. Choy,
Clifford Bryant,
Claudia M. Calvet,
Patricia S. Doyle,
Shamila S. Gunatilleke,
Siegfried S. F. Leung,
Kenny K. H. Ang,
Steven Chen,
Jiri Gut,
Juan A. Oses-Prieto,
Jonathan B. Johnston,
Michelle R. Arkin,
Alma L. Burlingame,
Jack Taunton,
Matthew P. Jacobson,
James M. McKerrow,
Larissa M. Podust,
Adam R. Renslo

Affiliations

Jonathan W. Choy: Small Molecule Discovery Center, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Clifford Bryant: Small Molecule Discovery Center, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Claudia M. Calvet: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Patricia S. Doyle: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Shamila S. Gunatilleke: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Siegfried S. F. Leung: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Kenny K. H. Ang: Small Molecule Discovery Center, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Steven Chen: Small Molecule Discovery Center, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Jiri Gut: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Juan A. Oses-Prieto: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Jonathan B. Johnston: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Michelle R. Arkin: Small Molecule Discovery Center, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Alma L. Burlingame: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Jack Taunton: Department of Cellular and Molecular Pharmacology, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Matthew P. Jacobson: Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
James M. McKerrow: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Larissa M. Podust: Center for Discovery and Innovation in Parasitic Diseases, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA
Adam R. Renslo: Small Molecule Discovery Center, University of California San Francisco, 1700 4th Street, San Francisco, CA, 94158, USA

DOI: https://doi.org/10.3762/bjoc.9.3
Journal volume & issue: Vol. 9, no. 1
pp. 15 – 25

Abstract

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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.

Published in Beilstein Journal of Organic Chemistry

ISSN: 1860-5397 (Online)
Publisher: Beilstein-Institut
Country of publisher: Germany
LCC subjects: Science: Chemistry: Organic chemistry
Website: http://www.beilstein-journals.org/bjoc

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