Inhibition of Trypanosoma brucei glucose-6-phosphate dehydrogenase by human steroids and their effects on the viability of cultured parasites

Autor(es)

Cordeiro, Artur T. ^[1] ; Thiemann, Otavio H. ^[1] ; Michels, Paul A. M. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Ctr Biol Mol Estrutural, Inst Fis Sao Carlos, Sao Carlos, SP - Brazil

^[2] Univ Catholique Louvain, Trop Dis Res Unit, Duve Inst & Lab Biochem, B-1200 Brussels - Belgium

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry; v. 17, n. 6, p. 2483-2489, MAR 15 2009.
• Citações Web of Science: 35

Resumo

Dehydroepiandrosterone ( DHEA) is known as an intermediate in the synthesis of mammalian steroids and a potent uncompetitive inhibitor of mammalian glucose-6-phosphate dehydrogenase (G6PDH), but not the enzyme from plants and lower eukaryotes. G6PDH catalyzes the first step of the pentose-phosphate pathway supplying cells with ribose 5-phosphate, a precursor of nucleic acid synthesis, and NADPH for biosynthetic processes and protection against oxidative stress. In this paper we demonstrate that also G6PDH of the protozoan parasite Trypanosoma brucei is uncompetitively inhibited by DHEA and epiandrosterone (EA), with K(i) values in the lower micromolar range. A viability assay confirmed the toxic effect of both steroids on cultured T. brucei bloodstream form cells. Additionally, RNAi mediated reduction of the G6PDH level in T. brucei bloodstream forms validated this enzyme as a drug target against Human African Trypanosomiasis. Together these findings show that inhibition of G6PDH by DHEA derivatives may lead to the development of a new class of anti-trypanosomatid compounds. Crown Copyright (C) 2009 Published by Elsevier Ltd. All rights reserved. (AU)

• Processo FAPESP: 05/51966-6 - Emprego de ensaios de HTS na identificação de compostos guia de produtos naturais e abordagens de planejamento racional de fármacos a alvos selecionados de doenças parasitárias
• Beneficiário: Otavio Henrique Thiemann
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Regular
• Processo FAPESP: 98/14138-2 - Center for Structural Molecular Biotechnology
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 07/02663-6 - Caracterizacao estrutural das enzimas de trypanosomatideos que atuam sobre a primeira etapa da via glicolitica e da via de pentoses.
• Beneficiário: Artur Torres Cordeiro
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado