Structural characterization of the enzyme dihydroorotate dehydrogenase of Schistosoma mansoni

• Grant number: 19/08376-6
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: September 01, 2019
• End date: May 31, 2022
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Maria Cristina Nonato
• Grantee: Luana Carlos Campisano Zapata
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

According to the World Health Organization (WHO), schistosomiasis is considered a neglected parasitic disease, in other words, there is a lack of investments for the development of new and effective therapies. It is a devastating disease, affecting almost 240 million people, mostly located in the poorest portion of the world. In Brazil, schistosomiasis is caused only by the parasite Schistosoma mansoni, and its intermediate host is the snail of the genus Biomphalaria. The only treatment available for schistosomiasis against all parasites that causes schistosomiasis is Praziquantel, and with its continuously use since the early 1980s, drug-resistant strains have been reported, stressing the urgent need to develop new therapies. The flavoenzyme dihydroorotate dehydrogenase (DHODH) has been considered a promising target in the development of drugs, including antiparasitics. DHODH catalyzes the oxidation of the dihydroorotate in orotate according to a ping-pong type enzymatic mechanism, acting on the de novo biosynthesis of uridylate, the precursor of all pyrimidine nucleotides. It is known that Schistosoma mansoni presents all pathways of pyrimidine metabolism as functional, suggesting the parasite's dependence on supplying its own demand for pyrimidine nucleotides. Thus, central enzymes for nucleotide biosynthesis become interesting targets to be explored for the development of new therapeutic strategies against schistosomiasis. As an important step in the validation of targets, the present project aims to contribute through the structural characterization of the DHODH enzyme of Schistosoma mansoni by determining the crystallographic structure in holo form and in complex with potent binders previously identified in our laboratory.

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)

FROES, THAMIRES QUADROS; CAMPISANO ZAPATA, LUANA CARLOS; AKAMINE, JULIANA SAYURI; CASTILHO, MARCELO SANTOS; NONATO, MARIA CRISTINA. DHODH Hot Spots: An Underexplored Source to Guide Drug Development Efforts. CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. 21, n. 23, p. 2134-2154, 2021. (19/08376-6, 20/06190-0)

DE MORI, RENAN M.; ALEIXO, MARIANA A. A.; ZAPATA, LUANA C. C.; CALIL, FELIPE A.; EMERY, FLAVIO S.; NONATO, M. CRISTINA. Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni. FEBS Journal, v. 288, n. 3, JUN 2020. (19/08376-6, 15/25099-5, 19/04395-6)