{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T13:57:35Z","timestamp":1791295055416,"version":"4.1.0"},"reference-count":48,"publisher":"American Society for Microbiology","issue":"6","license":[{"start":{"date-parts":[[2010,6,1]],"date-time":"2010-06-01T00:00:00Z","timestamp":1275350400000},"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":[[2010,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Chagas\u2019 disease, the leading cause of heart failure in Latin America, is caused by the kinetoplastid protozoan\n            <jats:italic>Trypanosoma cruzi.<\/jats:italic>\n            The sterols of\n            <jats:italic>T. cruzi<\/jats:italic>\n            resemble those of fungi, both in composition and in biosynthesis. Azole inhibitors of sterol 14\u03b1-demethylase (CYP51) successfully treat fungal infections in humans, and efforts to adapt the success of antifungal azoles posaconazole and ravuconazole as second-use agents for Chagas\u2019 disease are under way. However, to address concerns about the use of azoles for Chagas\u2019 disease, including drug resistance and cost, the rational design of nonazole CYP51 inhibitors can provide promising alternative drug chemotypes. We report the curative effect of the nonazole CYP51 inhibitor LP10 in an acute mouse model of\n            <jats:italic>T. cruzi<\/jats:italic>\n            infection. Mice treated with an oral dose of 40 mg LP10\/kg of body weight twice a day (BID) for 30 days, initiated 24 h postinfection, showed no signs of acute disease and had histologically normal tissues after 6 months. A very stringent test of cure showed that 4\/5 mice had negative PCR results for\n            <jats:italic>T. cruzi<\/jats:italic>\n            , and parasites were amplified by hemoculture in only two treated mice. These results compare favorably with those reported for posaconazole. Electron microscopy and gas chromatography-mass spectrometry (GC-MS) analysis of sterol composition confirmed that treatment with LP10 blocked the 14\u03b1-demethylation step and induced breakdown of parasite cell membranes, culminating in severe ultrastructural and morphological alterations and death of the clinically relevant amastigote stage of the parasite.\n          <\/jats:p>","DOI":"10.1128\/aac.00281-10","type":"journal-article","created":{"date-parts":[[2010,4,13]],"date-time":"2010-04-13T03:45:08Z","timestamp":1271130308000},"page":"2480-2488","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":63,"title":["A Nonazole CYP51 Inhibitor Cures Chagas\u2019 Disease in a Mouse Model of Acute Infection"],"prefix":"10.1128","volume":"54","author":[{"given":"Patricia S.","family":"Doyle","sequence":"first","affiliation":[{"name":"Sandler Center for Basic Research in Parasitic Diseases"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiung-Kuang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan B.","family":"Johnston","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94158"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie D.","family":"Hopkins","sequence":"additional","affiliation":[{"name":"Sandler Center for Basic Research in Parasitic Diseases"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siegfried S. 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