Discovery of New Uncompetitive Inhibitors of Glucose-6-Phosphate Dehydrogenase

Autor(es)

Mercaldi, Gustavo F. ^{[1, 2]} ; Ranzani, Americo T. ^{[1, 2]} ; Cordeiro, Artur T. ^[2]

Afiliação do(s) autor(es)

^[1] Univ Estadual Campinas, Inst Biol, Campinas, SP - Brazil

^[2] Brazilian Ctr Res Energy & Mat, Brazilian Biosci Natl Lab, BR-13083970 Campinas, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: JOURNAL OF BIOMOLECULAR SCREENING; v. 19, n. 10, p. 1362-1371, DEC 2014.
• Citações Web of Science: 11

Resumo

The enzyme glucose-6-phosphate dehydrogenase (G6PDH) catalyzes the first step of the oxidative branch of the pentose phosphate pathway, which provides cells with NADPH, an essential cofactor for many biosynthetic pathways and antioxidizing enzymes. In Trypanosoma cruzi, the G6PDH has being pursued as a relevant target for the development of new drugs against Chagas disease. At present, the best characterized inhibitors of T. cruzi G6PDH are steroidal halogenated compounds derivatives from the mammalian hormone precursor dehydroepiandrosterone, which indeed are also good inhibitors of the human homologue enzyme. The lack of target selectivity might result in hemolytic side effects due to partial inhibition of human G6PDH in red blood cells. Moreover, the treatment of Chagas patients with steroidal drugs might also cause undesired androgenic side effects. Aiming to identify of new chemical classes of T. cruzi G6PDH inhibitors, we performed a target-based high-throughput screen campaign against a commercial library of diverse compounds. Novel TcG6PDH inhibitors were identified among thienopyrimidine and quinazolinone derivatives. Preliminary structure activity relationships for the identified hits are presented, including structural features that contribute for selectivity toward the parasite enzyme. Our results indicate that quinazolinones are promising hits that should be considered for further optimization. (AU)

• Processo FAPESP: 13/03983-5 - Estudos funcionais e estruturais das enzimas relacionadas a produção de NADPH em trypanosomatídeos
• Beneficiário: Artur Torres Cordeiro
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/17849-0 - Desenvolvimento de um ensaio para triagem molecular de alto desempenho (high throughput screening) de inibidores da enzima glicose-6-fosfato desidrogenase de Trypanosoma cruzi
• Beneficiário: Gustavo Fernando Mercaldi
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 12/23682-7 - Caracterização estrutural da enzima málica de Trypanosoma cruzi e descoberta de inibidores por ensaio de triagem de alto desempenho.
• Beneficiário: Américo Tavares Ranzani
• Modalidade de apoio: Bolsas no Brasil - Doutorado