Optimization G6PDH inhibitors towards the development of drugs against Chagas Diseases.

• Grant number: 16/14271-4
• Support Opportunities: Regular Research Grants
• Start date: September 01, 2016
• End date: August 31, 2018
• Field of knowledge: Biological Sciences - Biochemistry - Enzymology
• 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: Kaliandra de Almeida Gonçalves ; Marjorie Christine Paule Bruder

Abstract

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

(4)

(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.)

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, JUN 11 2020. (13/16534-4, 16/14271-4, 18/22202-8)

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. (16/14271-4, 16/03151-8)

CORDEIRO, ARTUR T.. NADPH Producing Enzymes as Promising Drug Targets for Chagas Disease. Current Medicinal Chemistry, v. 26, n. 36, p. 6564-6571, 2019. (16/14271-4)

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. (14/15590-0, 16/14271-4, 16/19141-1, 16/03151-8)