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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). 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.

News published in Agência FAPESP Newsletter about the scholarship:
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Scientific publications
(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.)
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, . (15/03336-5, 13/03983-5)
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)