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Structural characterization of the interactions between CYP51 from Trypanosoma cruzi and Trypanosoma brucei and the antifungal drugs posaconazole and fluconazole
Author(s) -
Chen ChiungKuang Jack,
Mckerrow James H,
Podust Larissa M
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb198
Subject(s) - trypanosoma cruzi , posaconazole , ergosterol , chagas disease , trypanosoma brucei , fluconazole , leishmania , antifungal drug , pharmacology , biology , microbiology and biotechnology , drug , antiprotozoal , amphotericin b , antifungal , virology , biochemistry , in vitro , parasite hosting , world wide web , computer science , gene
Chagas Disease is the leading cause of heart failure in Latin America. Current drug therapy is limited by issues of both efficacy and severe side effects. Trypansoma cruzi, the protozoan agent of Chagas Disease, is closely related to two other major global pathogens, Leishmania spp., responsible for leishmaniasis, and Trypansoma brucei, the causative agent of African Sleeping Sickness. Both T. cruzi and Leishmania parasites have an essential requirement for ergosterol, and are thus vulnerable to inhibitors of sterol 14‐α‐demethylase (CYP51) which catalyzes the conversion of lanosterol to ergosterol. Clinically employed anti‐fungal azoles inhibit ergosterol biosynthesis in fungi, and specific azoles are also effective against both Trypanosoma and Leishmania parasites. We have now determined the crystal structures for CYP51 from T. cruzi co‐crystallized with the antifungal drugs fluconazole and posaconazole. The structures provide new insights into binding of azoles to CYP51 as well as mechanisms of potential drug resistance. Our studies define in structural detail the CYP51 therapeutic target in T. cruzi, and offer a starting point for rationally designed anti‐Chagasic drugs with improved efficacy and reduced toxicity.