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Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit.

Abstract：

BACKGROUND:The two front-line drugs for chronic Trypanosoma cruzi infections are limited by adverse side-effects and declining efficacy. One potential new target for Chagas' disease chemotherapy is sterol 14alpha-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane sterols. METHODOLOGY/PRINCIPAL FINDING:In a screening effort targeting Mycobacterium tuberculosis CYP51 (CYP51(Mt)), we previously identified the N-[4-pyridyl]-formamide moiety as a building block capable of delivering a variety of chemotypes into the CYP51 active site. In that work, the binding modes of several second generation compounds carrying this scaffold were determined by high-resolution co-crystal structures with CYP51(Mt). Subsequent assays against the CYP51 orthologue in T. cruzi, CYP51(Tc), demonstrated that two of the compounds tested in the earlier effort bound tightly to this enzyme. Both were tested in vitro for inhibitory effects against T. cruzi and the related protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. One of the compounds had potent, selective anti-T. cruzi activity in infected mouse macrophages. Cure of treated host cells was confirmed by prolonged incubation in the absence of the inhibiting compound. Discrimination between T. cruzi and T. brucei CYP51 by the inhibitor was largely based on the variability (phenylalanine versus isoleucine) of a single residue at a critical position in the active site. CONCLUSIONS/SIGNIFICANCE:CYP51(Mt)-based crystal structure analysis revealed that the functional groups of the two tightly bound compounds are likely to occupy different spaces in the CYP51 active site, suggesting the possibility of combining the beneficial features of both inhibitors in a third generation of compounds to achieve more potent and selective inhibition of CYP51(Tc).

journal_name

PLoS Negl Trop Dis

journal_title

PLoS neglected tropical diseases

authors

Chen CK,Doyle PS,Yermalitskaya LV,Mackey ZB,Ang KK,McKerrow JH,Podust LM

doi

10.1371/journal.pntd.0000372

subject

Has Abstract

pub_date

2009-01-01 00:00:00

pages

e372

issue

eissn

1935-2727

issn

1935-2735

journal_volume

pub_type

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Trypanosoma cruzi CYP51 inhibitor derived from a Mycobacterium tuberculosis screen hit.