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Crystallographic studies of Dihydroorotate dehydrogenase from schistosoma mansoni

Grant number: 11/14269-6
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): October 01, 2011
Effective date (End): September 30, 2013
Field of knowledge:Biological Sciences - Biophysics - Molecular Biophysics
Principal researcher:Maria Cristina Nonato
Grantee:Giovani Pinton Tomaleri
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Schistosomiasis is considered a serious burden in public health worldwide. Caused by several species of platyhelmynth parasite of the genus schistosoma infects around 240 million people, distributed in 74 countries, preferencially in tropical and sub-tropical areas.From the six species of Schistosoma already identified, Schistosoma mansoni is the form found in the american continent and is responsible for the intestinal schistosomiasis , characterized by abdominal pain, diarrhea, retal blood and enlargement of liver and spleen.Schistosomiasis is treated using a single oral dose of the drug praziquantel (Merck). Neverthless, problems such difficulties in patient adherence due to side effects and the possibilty of re-infection limited the use of this therapeutic strategy. There is a urgent and real need of the development of new drugs against schistosomiasis.We are interested in starting the investigation of the role of the enzyme Dihydroorotate Dehydrogenase in Schistosoma mansoni (SmDHODH) and evaluate its potential as a therapeutic target against schistosomiasis The enzyme takes places in the fourth step of the de novo pyrimidine biosynthesis pathway through the catalysis of dihydroorotate into orotate,Due to the need for nucleotides for accomplishing a diverse range of cell function, for example, cell metabolism, acting as transporte of chemical energy as well as subunity of nucleic acids (DNA and RNA), DHODH has been considered an interesting target for the development of anti-proliferative, anti-inflamatory and anty-parasitic diseases.As a first step, we intend to establish a protocol for heterologous expresiion of SmDHODH, as well as the crystallographic characterization of SmDHODH. Our results will provide important tools not only for allowing the development of functional studies, but also the structural basis for the development of specific ligands.

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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)
NONATO, M. CRISTINA; DE PADUA, RICARDO A. P.; DAVID, JULIANA S.; REIS, RENATA A. G.; TOMALERI, GIOVANI P.; PEREIRA, HUMBERTO D'MUNIZ; CALIL, FELIPE A. Structural basis for the design of selective inhibitors for Schistosoma mansoni dihydroorotate dehydrogenase. Biochimie, v. 158, p. 180-190, MAR 2019. Web of Science Citations: 3.
PADUA, RICARDO A. P.; TOMALERI, GIOVANI P.; REIS, RENATA A. G.; DAVID, JULIANA S.; SILVA, VALERIA C.; PINHEIRO, MATHEUS P.; NONATO, MARIA CRISTINA. ThermoFMN - A Thermofluor Assay Developed for Ligand-Screening as an Alternative Strategy for Drug Discovery. Journal of the Brazilian Chemical Society, v. 25, n. 10, p. 1864+, OCT 2014. Web of Science Citations: 7.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.