Schistosomiasis: Therapeutic Innovation for a Neglected Disease with a Focus on Inhibiting the Dihydroorotate Dehydrogenase Enzyme of Schistosoma mansoni

• Grant number: 24/19469-3
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2026
• End date: February 28, 2029
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Maria Cristina Nonato
• Grantee: Maria Cristina Nonato
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• City of the host institution: Ribeirão Preto
• Associated researchers: Carolina Horta Andrade ; Flavio da Silva Emery ; Josué de Moraes ; Marília Cristina Oliveira Souza

Abstract

Schistosomiasis, a parasitic disease caused by worms of the Schistosoma genus, poses a significant public health challenge, especially in tropical and subtropical regions. The diversity of life stages of these parasites and the different species involved, such as Schistosoma mansoni, responsible for intestinal schistosomiasis in Brazil, and S. haematobium, which causes the urogenital form prevalent in Africa, illustrate the complexity of this disease. Although classified as a neglected tropical disease by the World Health Organization, research on schistosomiasis remains insufficient to address its various manifestations. The increasing threat of resistance to the only available treatment, praziquantel, and its ineffectiveness against the young stages of the worm, underscore the urgency of investing in new therapeutic approaches. The biological complexity of the disease, along with limited research funding, makes schistosomiasis a public health issue requiring renewed attention and resources to mitigate its impact on affected populations.This project, led by CRAFT (Center for Research and Advancement on Fragments and Molecular Targets), aims to develop a platform for discovering innovative therapeutic candidates against schistosomiasis, integrating strategies for drug repurposing and identifying new chemical entities, with a focus on selective inhibition of the S. mansoni enzyme dihydroorotate dehydrogenase (SmDHODH). SmDHODH, essential for pyrimidine nucleotide biosynthesis, is a validated pharmacological target for several proliferative and parasitic diseases, showing promise for schistosomiasis treatment. The project will include computational screening, enzymatic and biophysical assays with a compound library, cytotoxicity tests on mammalian cells, and antiparasitic assays against S. mansoni.Within the drug development pipeline, this initiative aims to progress robustly and systematically from hit-to-lead optimization, incorporating the evaluation of the compounds' physicochemical and pharmacokinetic properties, including absorption, bioavailability, metabolism, excretion, and toxicity. Synthesis and optimization of the most promising compounds will follow, leading to preclinical testing in animal models. CRAFT, dedicated to driving innovation in drug discovery in Brazil, aims to shape the future of pharmaceutical research by promoting collaboration and generating a positive impact on public health in Brazil, especially for the most vulnerable populations. This project reflects the commitment of a team of renowned national and international researchers in the search for effective strategies to combat schistosomiasis. This partnership not only advances scientific knowledge but also strengthens a multidisciplinary and innovative drug discovery pipeline in Brazil. (AU)