Chemical genetic validation of drug targets for Chagas disease

• Grant number: 21/14741-9
• Support Opportunities: Regular Research Grants
• Start date: August 01, 2022
• End date: January 31, 2025
• Field of knowledge: Biological Sciences - Biochemistry - Biochemistry of Microorganisms
• Principal Investigator: Artur Torres Cordeiro
• Grantee: Artur Torres Cordeiro
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Campinas , SP, Brazil
• City of the host institution: Campinas
• Associated researchers: Gustavo Fernando Mercaldi

Abstract

The validation of a molecular target is a fundamental step in the drug research and development process. This project aims to advance the characterization and validation of four "potential" targets of the protozoan Trypanosoma cruzi, which causes Chagas disease. These targets are the enzymes L-threonine dehydrogenase (TcTDH), inosine-5-monophosphate dehydrogenase (TcIMPDH), NADPH-dependent Malic Enzyme (TcME) and glucose-6-phosphate dehydrogenase (TcG6PDH). The TcTDH and TcIMPDH enzymes were partially characterized in the previous project (FAPESP Regular Aid, n. 2018/22202-8). In this project, we intend to complete the characterization of the allosteric regulation of these enzymes and expand the high-throughput screening experiments to select more potent and selective inhibitors for in vitro assays against the parasite. Concomitant to the studies with TcTDH and TcIMPDH, we will continue the chemical-genetic validation of the enzymes TcME and TcG6PDH, for which resistant variants were already established towards specific inhibitors of each target (preliminary results). These inhibitors were identified by HTS trials performed previously (Mercaldi, G.F., 2014 and Ranzani, A. T, 2017) and the resistant variants were selected by the PhD student Amanda G. Eufrásio. If successful, this project will complete the requirements to move drug candidates, with defined mode of action, to the pre-clinical stages of the development of new drugs against Chagas disease. (AU)

Scientific publications

(The scientific publications listed on this page originate from the Web of Science or SciELO databases. Their authors have cited FAPESP grant or fellowship project numbers awarded to Principal Investigators or Fellowship Recipients, whether or not they are among the authors. This information is collected automatically and retrieved directly from those bibliometric databases.)

FARIA, JESSICA DO NASCIMENTO; EUFRASIO, AMANDA G.; FAGUNDES, MICHELLE; LOBO-ROJAS, ANGEL; MARCHESE, LETICIA; SILVA, CAIO CESAR DE LIMA; BEZERRA, EDUARDO H. S.; MERCALDI, GUSTAVO F.; ALBORGHETTI, MARCOS R.; SFORCA, MAURICIO L.; et al. Inhibition of L-threonine dehydrogenase from Trypanosoma cruzi reduces glycine and acetate production and interferes with parasite growth and viability. Journal of Biological Chemistry, v. 301, n. 2, p. 14-pg., 2025-02-01. (18/22202-8, 21/14741-9, 19/23995-4)

DOS SANTOS, THAIS CRISTINA FERREIRA; DE SILVA, RAMON BORGES; DE SOUSA, IRENE LAYANE; NACIUK, FABRICIO FREDO; MARCHESE, LETICIA; EUFRASIO, AMANDA GONCALVES; LOBO-ROJAS, ANGEL EDUARDO; GIAMPAULI, RENAN MARCEL; DE SOUZA, VALERIA BARBOSA; SCHENKA, ANDRE ALMEIDA; et al. Efficacy of sulfonamides targeting malic enzyme in an animal model of Chagas disease. FRONTIERS IN PHARMACOLOGY, v. 16, p. 15-pg., 2025-11-28. (21/14741-9)