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Characterization of T. cruzi metabolic targets for the research of drug for Chagas Disease

Abstract

The discovery of drugs against Chagas' disease lacks the identification and characterization of new molecular targets. In recent years, my research group has been dedicated to studying the structure and function of key enzymes of T. cruzi metabolism, with an emphasis on NADP-dependent dehydrogenases. The enzymes glucose-6-phosphate dehydrogenase (TcG6PDH), isocitrate dehydrogenase (TcIDH) and the two isoforms (cytosolic and mitochondrial) of the malic enzyme (TcMEc and TcMEm) have already been studied. Among the most significant results are the identification of new inhibitors of TcG6PDH (Mercaldi, 2014), determination of its crystallographic structure in complex with substrate (G6P) and cofactor (NADPH) (Mercaldi, 2016), the identification of inhibitors with low nanomolar affinity for TcMEc (Ranzani, 2017) and the determination of crystallographic structures of TcMEm and TcMEc complexes with its most potent inhibitors. In addition, we have recently established an assay to quantify the intracellular amastigote form of T. cruzi during the infection of rat cardiomyocytes. This assay allowed us to evaluate the efficacy and safety of TcG6PDH and TcMEc inhibitors identified by HTS. The present project intends to proceed with the cellular studies of the inhibitors of TcMEc and TcG6PDH and to apply the acquired know-how in bioassays (enzymatic, HTS and cellular assays) in order to evaluate the potential of other enzymes of the metabolism of T. cruzi for the development of drugs against Chagas' disease. The new targets that we intend to study appear as putative dehydrogenases in the TriTryps database, i.e., the function of these enzymes still needs to be demonstrated experimentally. Other criteria used in the selection of the targets were: to present evidence of transcription in the amastigote stage of T. cruzi, to have no transmembrane domains and to have all substrates and cofactors commercially available. Thus, the present project aims to contribute both to the basic knowledge about T. cruzi metabolism and eventually reveal new molecular targets and compounds with potential to proceed in the development of drugs for Chagas' disease. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
NACIUK, FABRICIO FREDO; FARIA, JESSICA DO NASCIMENTO; EUFRASIO, AMANDA GONCALVES; CORDEIRO, ARTUR TORRES; BRUDER, MARJORIE. Development of Selective Steroid Inhibitors for the Glucose-6-phosphate Dehydrogenase from Trypanosoma cruzi. ACS Medicinal Chemistry Letters, v. 11, n. 6, p. 1250-1256, . (13/16534-4, 16/14271-4, 18/22202-8)
MERCALDI, GUSTAVO F.; EUFRASIO, AMANDA G.; RANZANI, AMERICO T.; FARIA, JESSICA DO NASCIMENTO; MOTA, SABRINA G. R.; FAGUNDES, MICHELLE; BRUDER, MARJORIE; CORDEIRO, ARTUR T.. Trypanosoma cruzi Malic Enzyme Is the Target for Sulfonamide Hits from the GSK Chagas Box. ACS INFECTIOUS DISEASES, v. 7, n. 8, p. 2455-2471, . (15/03336-5, 13/03983-5, 14/15590-0, 18/22202-8, 16/19141-1, 12/23682-7)

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