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Optimization G6PDH inhibitors towards the development of drugs against Chagas diseases

Grant number: 16/14271-4
Support type:Regular Research Grants
Duration: September 01, 2016 - August 31, 2018
Field of knowledge:Biological Sciences - Biochemistry
Principal Investigator:Artur Torres Cordeiro
Grantee:Artur Torres Cordeiro
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil
Assoc. researchers:Kaliandra de Almeida Gonçalves ; Marjorie Christine Paule Bruder


The enzyme glucose-6-phosphate dehydrogenase catalyzes the first step of the pentoses phosphate pathway through the oxidation of glucose-6-phosphate (G6P) into 6-phosphoglucolactone with the reduction of NADP+ to NADPH. The TcG6PDH has been studied by our group as one of the molecular targets for drug development against Chagas disease. Among the recent finds of our group are: the discovery of new inhibitors by High Throughput Screening (HTS) (Mercali G. et al J. Biomol Screen 2014, 19 (10): 1362-71) and the determination of the crystallographic structure of the ternary complex established by TcG6PDH, G6P and NADPH (Mercaldi G et al. FEBS Letters accepted for publication).Prior to publication of our results, the only options for TcG6PDH inhibitors were steroidal compounds derived from epiandrosterone. This project will proceed with the characterization of these new inhibitors by performing predictive efficiency and cytotoxicity cellular assays. These new inhibitors will be used in soaking experiments on TcG6PDH crystals, in order to identify their binding site by the solving a crystal structure of an enzyme-inhibitor complex.Another point that will be studied is the existence of an adjacent cavity NADP binding site and might have potential for rational drug design. This cavity was observed exclusively in the structure G6PDH T. cruzi and thus may lead to the development and highly selective inhibitors of the parasitic enzyme. The validation of this cavity will be performed by site-directed mutagenesis and synthesis of specific inhibitors. (AU)

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)
MERCALDI, GUSTAVO F.; D'ANTONIO, EDWARD L.; AGUESSI, ANNELIE; RODRIGUEZ, ANA; CORDEIRO, ARTUR T. Discovery of antichagasic inhibitors by high-throughput screening with Trypanosoma cruzi glucokinase. Bioorganic & Medicinal Chemistry Letters, v. 29, n. 15, p. 1948-1953, AUG 1 2019. Web of Science Citations: 0.
MOTA, SABRINA G. R.; MERCALDI, GUSTAVO F.; PEREIRA, JOSE G. C.; OLIVEIRA, PAULO S. L.; RODRIGUEZ, ANA; CORDEIRO, ARTUR T. First Nonphosphorylated Inhibitors of Phosphoglucose Isomerase Identified by Chemical Library Screening. SLAS DISCOVERY, v. 23, n. 10, p. 1051-1059, DEC 2018. Web of Science Citations: 1.

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