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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.)

Development of Selective Steroid Inhibitors for the Glucose-6-phosphate Dehydrogenase from Trypanosoma cruzi

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Author(s):
Naciuk, Fabricio Fredo [1] ; Faria, Jessica do Nascimento [1] ; Eufrasio, Amanda Goncalves [1] ; Cordeiro, Artur Torres [1] ; Bruder, Marjorie [1]
Total Authors: 5
Affiliation:
[1] Brazilian Ctr Res Energy & Mat, Brazilian Biosci Natl Lab, BR-13083100 Campinas, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: ACS Medicinal Chemistry Letters; v. 11, n. 6, p. 1250-1256, JUN 11 2020.
Web of Science Citations: 0
Abstract

Chagas disease is a parasitic infection affecting millions of people across Latin America, imposing a dramatic socioeconomic burden. Despite the availability of drugs, nifurtimox and benznidazole, lack of efficacy and incidence of side-effects prompt the identification of novel, efficient, and affordable drug candidates. To address this issue, one strategy could be probing the susceptibility of Trypanosoma parasites toward NADP-dependent enzyme inhibitors. Recently, steroids of the androstane group have been described as highly potent but nonselective inhibitors of parasitic glucose-6-phosphate dehydrogenase (G6PDH). In order to promote selectivity, we have synthesized and evaluated 26 steroid derivatives of epiandrosterone in enzymatic assays, whereby 17 compounds were shown to display moderate to high selectivity for T. cruzi over the human G6PDH. In addition, three compounds were effective in killing intracellular T. cruzi forms infecting rat cardiomyocytes. Altogether, this study provides new SAR data around G6PDH and further supports this target for treating Chagas disease. (AU)

FAPESP's process: 13/16534-4 - Design and synthesis of Steroid-based irreversible inhibitors of glucose-6-phosphate dehydrogenase: mapping of the binding site
Grantee:Marjorie Christine Paule Bruder
Support Opportunities: Regular Research Grants
FAPESP's process: 16/14271-4 - Optimization G6PDH inhibitors towards the development of drugs against Chagas Diseases.
Grantee:Artur Torres Cordeiro
Support Opportunities: Regular Research Grants
FAPESP's process: 18/22202-8 - Characterization of T. cruzi metabolic targets for the research of drug for Chagas Disease
Grantee:Artur Torres Cordeiro
Support Opportunities: Regular Research Grants