Michael Waterman
Faculty Member
Last active: 2/12/2015

Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis.

Lepesheva GI, Waterman MR
Curr Top Med Chem. 2011 11 (16): 2060-71

PMID: 21619513 · PMCID: PMC3391166 · DOI:10.2174/156802611796575902

Pathogenic protozoa threaten lives of several hundred million people throughout the world and are responsible for large numbers of deaths globally. The parasites are transmitted to humans by insect vectors, more than a hundred of infected mammalian species forming reservoir. With human migrations, HIV-coinfections, and blood bank contamination the diseases are now spreading beyond the endemic tropical countries, being found in all parts of the world including the USA, Canada and Europe. In spite of the widely appreciated magnitude of this health problem, current treatment for sleeping sickness (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi) and leishmaniasis (Leishmania spp.) remains unsatisfactory. The drugs are decades old, their efficacy and safety profiles are unacceptable. This review describes sterol 14α-demethylase, an essential enzyme in sterol biosynthesis in eukaryotes and clinical target for antifungal azoles, as a promising target for antiprotozoan chemotherapy. While several antifungal azoles have been proven active against Trypanosomatidae and are under consideration as antiprotozoan agents, crystal structures of sterol 14α-demethylases from three protozoan pathogens, Trypanosoma brucei, Trypanosoma cruzi and Leishmania infantum provide the basis for the development of new, highly potent and pathogen-specific drugs with rationally optimized pharmacological properties.

MeSH Terms (23)

Amino Acid Sequence Animals Antiprotozoal Agents Binding Sites Chagas Disease Crystallography, X-Ray Enzyme Inhibitors Humans Insect Vectors Leishmania infantum Leishmaniasis Models, Molecular Molecular Sequence Data Protein Binding Protein Structure, Tertiary Protozoan Proteins Sequence Alignment Sterol 14-Demethylase Sterols Substrate Specificity Trypanosoma brucei brucei Trypanosoma cruzi Trypanosomiasis, African

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