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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Cordeiro, Artur T. [1] ; Thiemann, Otavio H. [1] ; Michels, Paul A. M. [2]
Total Authors: 3
[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
Total Affiliations: 2
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry; v. 17, n. 6, p. 2483-2489, MAR 15 2009.
Web of Science Citations: 35

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)

FAPESP's process: 05/51966-6 - Use of HTS tests in the identification of leading compounds of natural products and approaches to rational planning of medicines for selected targets of parasitic diseases
Grantee:Otavio Henrique Thiemann
Support Opportunities: BIOTA-FAPESP Program - Regular Research Grants
FAPESP's process: 98/14138-2 - Center for Structural Molecular Biotechnology
Grantee:Glaucius Oliva
Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC