Evaluating the malic enzyme as a target in the treatment of Chagas Disease

• Grant number: 15/03336-5
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• Start date: July 06, 2015
• End date: July 05, 2016
• Field of knowledge: Biological Sciences - Genetics - Molecular Genetics and Genetics of Microorganisms
• Principal Investigator: Artur Torres Cordeiro
• Grantee: Américo Tavares Ranzani
• Supervisor: Shane Wilkinson
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil
• Institution abroad: Queen Mary University of London, England
• Associated to the scholarship: 12/23682-7 - Structural characterization of malic enzyme of Trypanosoma cruzi and inhibitor discovery by a High-Throughput Screening assay., BP.DR

Abstract

Chagas disease is an illness caused by the protozoan parasite Trypanosoma cruzi. The acute phase of this condition is the only stage amenable to drug treatment although these therapies can be highly toxic. Research into novel metabolic targets might lead to the development of new more effective drugs that target all stages of this infection. Dehydrogenase enzymes such as glucose-6-phosphate dehydrogenase, malic enzyme (ME) and isocitrate dehydrogenase that catalyze the conversion of NADP+ to NADPH are considered promising targets, as reduction in these activities leads to lowered intracellular NADPH levels that direct effects on a range of anabolic process and on pathways T. cruzi employs to defend itself from oxidative stress. As part of my PhD I am determining the structural characterization of ME and identifying new inhibitors targeting such activities using high-throughput biochemical screens. This work has generated 10 chemical classes several of which display trypanocidal activity against T. cruzi. In this proposal our primary aims are to evaluate the role played by the ME complement in T. cruzi and determine where in the parasites life cycle these activities are important, if not essential, for parasite viability. The cell lines generated from this work, in conjunction with the inhibitory compounds, will extend our chemical validation studies targeting ME activity and genetically confirm that these enzymes are bona fide drug targets within the parasite itself. (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.; 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 T.; NOWICKI, CRISTINA; WILKINSON, SHANE R.; CORDEIRO, ARTUR T.. Identification of Specific Inhibitors of Trypanosoma cruzi Malic Enzyme Isoforms by Target-Based HTS. SLAS DISCOVERY, v. 22, n. 9, p. 1150-1161, OCT 2017. (15/03336-5, 13/03983-5)