Trypanosoma cruzi CYP51 Inhibitor Derived from a Mycobacterium tuberculosis Screen Hit

dc.contributor.authorChen, Chiung-Kuangen
dc.contributor.authorDoyle, Patricia S.en
dc.contributor.authorYermalitskaya, Ludmila V.en
dc.contributor.authorMackey, Zachary B.en
dc.contributor.authorAng, Kenny K. H.en
dc.contributor.authorMcKerrow, James H.en
dc.contributor.authorPodust, L.arissa M.en
dc.contributor.departmentBiochemistryen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessioned2018-06-01T19:05:46Zen
dc.date.available2018-06-01T19:05:46Zen
dc.date.issued2009-02-01en
dc.description.abstractBackground: 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 14a-demethylase (CYP51), a cytochrome P450 enzyme involved in biosynthesis of membrane sterols. Methodology/Principal Finding: In a screening effort targeting Mycobacterium tuberculosis CYP51 (CYP51<sub>Mt</sub>), 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<sub>Mt</sub>. Subsequent assays against the CYP51 orthologue in T. cruzi, CYP51<sub>Tc</sub>, 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<sub>Mt</sub>-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<sub>Tc</sub>.en
dc.description.versionPublished versionen
dc.format.extent? - ? (10) page(s)en
dc.identifier.doihttps://doi.org/10.1371/journal.pntd.0000372en
dc.identifier.issn1935-2735en
dc.identifier.issue2en
dc.identifier.orcidMackey, ZB [0000-0002-4533-0973]en
dc.identifier.urihttp://hdl.handle.net/10919/83439en
dc.identifier.volume3en
dc.language.isoenen
dc.publisherPLOSen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000265536600005&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectInfectious Diseasesen
dc.subjectParasitologyen
dc.subjectTropical Medicineen
dc.subjectX-RAY-STRUCTUREen
dc.subjectCHAGAS-DISEASEen
dc.subjectSTEROL 14-ALPHA-DEMETHYLASEen
dc.subject14-ALPHA-STEROL DEMETHYLASEen
dc.subjectPARASITIC PROTOZOAen
dc.subjectESCHERICHIA-COLIen
dc.subjectSUBSTRATEen
dc.subjectCUREen
dc.subjectINFECTIONen
dc.subjectFUTUREen
dc.titleTrypanosoma cruzi CYP51 Inhibitor Derived from a Mycobacterium tuberculosis Screen Hiten
dc.title.serialPLoS Neglected Tropical Diseasesen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Biochemistryen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/CALS T&R Facultyen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciencesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Life Sciences/Fralin Affiliated Facultyen
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