Abstract
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.
Keywords: Antiprotozoan chemotherapy, crystal structure, enzyme inhibitors, leishmaniasis, sterol 14alpha-demethylase (CYP51), sterol biosynthesis, trypanosomiasis, insect vectors, HIV-coinfections, sleeping sickness, Chagas disease, efficacy, pharmacological properties, American trypanosomiasis
Current Topics in Medicinal Chemistry
Title: Sterol 14alpha-Demethylase (CYP51) as a Therapeutic Target for Human Trypanosomiasis and Leishmaniasis
Volume: 11 Issue: 16
Author(s): Galina I. Lepesheva and Michael R. Waterman
Affiliation:
Keywords: Antiprotozoan chemotherapy, crystal structure, enzyme inhibitors, leishmaniasis, sterol 14alpha-demethylase (CYP51), sterol biosynthesis, trypanosomiasis, insect vectors, HIV-coinfections, sleeping sickness, Chagas disease, efficacy, pharmacological properties, American trypanosomiasis
Abstract: 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.
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Cite this article as:
I. Lepesheva Galina and R. Waterman Michael, Sterol 14alpha-Demethylase (CYP51) as a Therapeutic Target for Human Trypanosomiasis and Leishmaniasis, Current Topics in Medicinal Chemistry 2011; 11 (16) . https://dx.doi.org/10.2174/156802611796575902
DOI https://dx.doi.org/10.2174/156802611796575902 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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