Drug repurposing and search of selective inhibitors for human dihydroorotate dehydrogenase as a strategy in fighting against COVID-19

• Grant number: 20/06190-0
• Support Opportunities: Regular Research Grants
• Duration: April 01, 2021 - March 31, 2023
• 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
• Associated researchers: Carolina Horta Andrade ; Fabio Trindade Maranhão Costa ; Flavio da Silva Emery
• Associated grant(s): 23/03641-9 - Twenty-Sixth Congress and General Assembly of the International Union of Crystallography, AR.EXT

Abstract

No longer than four months ago, the world was not aware of the existence of the virus SARS-CoV-2. Today, this virus, responsible for COVID-19, has already spread around the all planet, infecting more than 2 million people and killing more than 150 thousand. The pandemic caused by COVID-19 has led to the collapse of both economic and the health systems around the world. So far, social distance is the only weapon available to minimize the impact of the virus proliferation. There is no vaccine available to prevent the infection caused by SARS-CoV-2, neither an effective treatment for COVID-19. In this context, this proposal aims at contributing to the development of an innovative therapy against COVID-19, either through drug repurposing or by identifying new chemical identities, all based on the selective inhibition of the human enzyme dihydroorotate dehydrogenase (HsDHODH). HsDHODH, which, takes part of the de novo pyrimidine biosynthetic pathway, is the pharmacological validated target for proliferative and parasitic diseases, and have been considered an attractive target for the development of antivirais. The fact that the virus relies on the host cell biochemical machinery to provide nucleosides for its viral replication cycle makes enzymes involved in the biosynthesis of nucleosides, such as HsDHODH, potential targets for the development of broad spectrum antivirals. Our studies include enzymatic and biophysical assays, citotoxicity tests using different mammal cells, antiviral assays in cell culture using a biosafety level 3 laboratory and synthesis of drugs and analogues based on virtual screening studies. Our project put together research leaders in complementary areas, contributing not only to accomplish our goals, but also to consolidate a complex and multidisciplinary pipeline in drug discovery. (AU)

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)