Search for Human Dihydroorotate Dehydrogenase inhibitors as a new strategy against COVID-19 disease

• Grant number: 21/13237-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: September 01, 2022
• End date: March 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Maria Cristina Nonato
• Grantee: Aline Dias da Purificação
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

The Dihydroorate Dehydrogenase (DHODH) is present in bacteria, fungi, animals, and plants, being an important target of study. It is an essential enzyme for the maintenance of cellular homeostasis, and responsible for the conversion of dihydroorate into orotate, in the fourth enzymatic step of the de novo pyrimidine nucleotide synthesis pathway. This project aims to develop potent inhibitors for the human enzyme DHODH, as a strategy for the development of drugs for the treatment of COVID-19. Considering the dependence of the virus on the supply of nucleotides by the host cell for its viral replication cycle, the enzyme hsDHODH has been exploited as an innovative target in the fight against COVID-19. COVID-19 is an infectious disease caused by the SARS-CoV-2 virus, which has infected more than 250 million people and has been responsible for more than 5 million deaths to date around the world. The studies will involve enzymatic and biophysical assays, determination of the crystallographic structure of protein-fragment complexes for the identification and characterization of the mechanism of action of the fragment-size ligands and their subsequent optimization through computational studies. The best inhibitors will be submitted to cytotoxicity and antiviral activity tests. The project brings together leading national researchers in their respective areas of research, which significantly contributes not only to the successful execution of the project, but also to the student's learning about this complex and multidisciplinary pipeline that involves drug discovery.