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

Autor(es)

Naciuk, Fabricio Fredo ^[1] ; Faria, Jessica do Nascimento ^[1] ; Eufrasio, Amanda Goncalves ^[1] ; Cordeiro, Artur Torres ^[1] ; Bruder, Marjorie ^[1]

Afiliação do(s) autor(es)

^[1] Brazilian Ctr Res Energy & Mat, Brazilian Biosci Natl Lab, BR-13083100 Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: ACS Medicinal Chemistry Letters; v. 11, n. 6, p. 1250-1256, JUN 11 2020.
• Citações Web of Science: 0

Resumo

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)

• Processo FAPESP: 13/16534-4 - Desenho e síntese de inibidores irreversíveis da glicose-6-fosfato desidrogenase baseados em esteróides para mapear o sítio de ligação
• Beneficiário: Marjorie Christine Paule Bruder
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/14271-4 - Aperfeiçoamento dos inibidores da enzima G6PDH para desenvolvimento de fármacos contra Chagas
• Beneficiário: Artur Torres Cordeiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 18/22202-8 - Caracterização de alvos metabólicos em T. cruzi para a pesquisa de fármacos contra a Doença de Chagas
• Beneficiário: Artur Torres Cordeiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular