Structural characterization of malic enzyme of Trypanosoma cruzi and inhibitor discovery by a High-Throughput Screening assay.

• Grant number: 12/23682-7
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2013
• End date: August 31, 2017
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Artur Torres Cordeiro
• Grantee: Américo Tavares Ranzani
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Associated scholarship(s): 15/03336-5 - Evaluating the malic enzyme as a target in the treatment of Chagas Disease, BE.EP.DR

Abstract

American trypanosomiasis is an infectious disease caused by the protozoan Trypanosoma cruzi. The acute phase is the only stage with treatment, which is made with highly toxic drugs . The research of novel metabolic targets might lead to the development of new effective drugs to the chronic phase of the disease. Enzymes that produce NADPH are considered promising targets, since the reduction of NADPH levels of the parasites affects as much their growth as their defense against oxidative attack caused by the mammalian host immune system. This way, dehydrogenases which reduce NADP+ can be interesting drug targets, being the enzymes of the pentose phosphate pathway, like glucose-6-phosphate dehydrogenase (G6PD), the main producers when the parasite uses glucose as the carbon source, what takes place when the parasite is at the bloodstream of the mammalian host. However, inside the cell, the parasite changes its metabolism to degradation of aminoacids, becoming other enzymes important too, like malic enzyme and isocitrate dehydrogenase. This project is focused on structural characterization of the malic enzyme of T. cruzi and on discovery of new inhibitors that can be used as chemical probes to study the inhibition effect of this target in the parasite. Furthermore, we will take advantage of the crystallization system of G6PD developed during the Master's project, using it to study new inhibitors identified by the group.

Scientific publications

(4)

(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)

RANZANI, AMERICO TAVARES; CORDEIRO, ARTUR TORRES. Mutations in the tetramer interface of human glucose-6-phosphate dehydrogenase reveals kinetic differences between oligomeric states. FEBS Letters, v. 591, n. 9, p. 1278-1284, MAY 2017. (12/23682-7)

MERCALDI, GUSTAVO F.; RANZANI, AMERICO T.; CORDEIRO, ARTUR T.. Discovery of New Uncompetitive Inhibitors of Glucose-6-Phosphate Dehydrogenase. JOURNAL OF BIOMOLECULAR SCREENING, v. 19, n. 10, p. 1362-1371, DEC 2014. (13/03983-5, 10/17849-0, 12/23682-7)

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, AUG 13 2021. (15/03336-5, 13/03983-5, 14/15590-0, 18/22202-8, 16/19141-1, 12/23682-7)

RANZANI, AMERICO TAVARES; CORDEIRO, ARTUR TORRES. Mutations in the tetramer interface of human glucose-6-phosphate dehydrogenase reveals kinetic differences between oligomeric states. FEBS LETTERS, v. 591, n. 9, p. 7-pg., 2017-05-01. (12/23682-7)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

RANZANI, Américo Tavares. Discovery of inhibitors and structural studies of the malic enzyme from Trypanosoma cruzi. 2017. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia Campinas, SP.