{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T06:40:53Z","timestamp":1770446453410,"version":"3.49.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"2","license":[{"start":{"date-parts":[[2016,2,1]],"date-time":"2016-02-01T00:00:00Z","timestamp":1454284800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,2]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>A novel antifungal drug candidate, the 1-tetrazole-based agent VT-1161 [(<jats:italic>R<\/jats:italic>)-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1<jats:italic>H<\/jats:italic>-tetrazol-1-yl)-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol], which is currently in two phase 2b antifungal clinical trials, was found to be a tight-binding ligand (apparent dissociation constant [<jats:italic>K<jats:sub>d<\/jats:sub><\/jats:italic>], 24 nM) and a potent inhibitor of cytochrome P450 sterol 14\u03b1-demethylase (CYP51) from the protozoan pathogen<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Trypanosoma cruzi<\/jats:named-content>. Moreover, VT-1161 revealed a high level of antiparasitic activity against amastigotes of the Tulahuen strain of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. cruzi<\/jats:named-content>in cellular experiments (50% effective concentration, 2.5 nM) and was active<jats:italic>in vivo<\/jats:italic>, causing &gt;99.8% suppression of peak parasitemia in a mouse model of infection with the naturally drug-resistant Y strain of the parasite. The data strongly support the potential utility of VT-1161 in the treatment of Chagas disease. The structural characterization of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">T. cruzi<\/jats:named-content>CYP51 in complex with VT-1161 provides insights into the molecular basis for the compound's inhibitory potency and paves the way for the further rational development of this novel, tetrazole-based inhibitory chemotype both for antiprotozoan chemotherapy and for antifungal chemotherapy.<\/jats:p>","DOI":"10.1128\/aac.02287-15","type":"journal-article","created":{"date-parts":[[2015,12,8]],"date-time":"2015-12-08T15:05:43Z","timestamp":1449587143000},"page":"1058-1066","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":35,"title":["Clinical Candidate VT-1161's Antiparasitic Effect<i>In Vitro<\/i>, Activity in a Murine Model of Chagas Disease, and Structural Characterization in Complex with the Target Enzyme CYP51 from Trypanosoma cruzi"],"prefix":"10.1128","volume":"60","author":[{"given":"William J.","family":"Hoekstra","sequence":"first","affiliation":[{"name":"Viamet Pharmaceuticals, Inc., Durham, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tatiana Y.","family":"Hargrove","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zdzislaw","family":"Wawrzak","sequence":"additional","affiliation":[{"name":"Synchrotron Research Center, Life Science Collaborative Access Team, Northwestern University, Argonne, Illinois, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"da Gama Jaen Batista","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Celular, Instituto Oswaldo Cruz, Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristiane F.","family":"da Silva","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Celular, Instituto Oswaldo Cruz, Funda\u00e7\u00e3o Oswaldo Cruz, Rio de Janeiro, RJ, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aline S. 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