Study of functional relevance NADPH producing enzymes for Trypanosoma cruzi

• Grant number: 19/23995-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: April 01, 2022
• End date: February 28, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Artur Torres Cordeiro
• Grantee: Amanda Gonçalves Eufrásio
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

Chagas Disease (CD) caused by Trypanosoma cruzi is a public health problem in Latin America. Despite killing thousands of people every year and be expanding to other continents, CD treatment boils down to a single drug with inadequate safety profile and efficacy. One of the difficulties in developing new medicines for CD is related to the scarcity of validated targets for the development of trypanocidal drugs. The glucose-6-phosphate dehydrogenase (G6PDH) and cytosolic malic enzyme (MEc) enzymes are described as promising targets for the development of new drugs. G6PDH and MEcparticipate in the energy metabolism f the parasite and are involved in the production of NADPH, an essential cofactor for various biosynthetic processes and maintenance of oxidative balance. Small organic molecules that inhibit the enzymes G6PDH and MEc are also capable of killing the T. cruzi in vitro. Thus, we intend to use chemical-genetic approaches to confirm the mechanism of action of these molecules and validate G6PDH and MEc as molecular targets in DC. To do this, we intend to induce the resistance of T. cruzi to G6PDH and MEc enzymes inhibitors, by expression of isoforms of these enzymes that are not inhibited by the organic molecules studied. If successful this project will contribute to the establishment of molecular targets validated for the development of new medicines for CD. (AU)