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

Author(s)

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

Affiliation

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

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

• Document type: Journal article
• Source: JOURNAL OF BIOMOLECULAR SCREENING; v. 19, n. 10, p. 1362-1371, DEC 2014.
• Web of Science Citations: 11

Abstract

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)

• FAPESP's process: 13/03983-5 - Functional and structural studies of the enzymes related to the NADPH production in trypanosomatids
• Grantee: Artur Torres Cordeiro
• Support Opportunities: Regular Research Grants
• FAPESP's process: 10/17849-0 - Development of a High Throughput Screening of inhibitors for the enzyme glucose-6-phosphate dehydrogenase from Trypanosoma cruzi
• Grantee: Gustavo Fernando Mercaldi
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 12/23682-7 - Structural characterization of malic enzyme of Trypanosoma cruzi and inhibitor discovery by a High-Throughput Screening assay.
• Grantee: Américo Tavares Ranzani
• Support Opportunities: Scholarships in Brazil - Doctorate