Development of covalent inhibitors of the enzyme dihydroorotate dehydrogenase for the discovery of therapeutic candidates for Chagas Disease

• Grant number: 22/06007-6
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• Start date: October 01, 2022
• End date: January 31, 2023
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Flavio da Silva Emery
• Grantee: Bruna Fleck Godoi
• Supervisor: Lori Ferrins
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: Northeastern University, United States
• Associated to the scholarship: 21/10084-3 - Development of covalent inhibitors of the enzyme dihydroorotate dehydrogenase for the discovery of therapeutic candidates for Chagas disease, BP.MS

Abstract

Chagas disease is a neglected tropical disease, caused by the parasite Trypanosoma cruzi, which affects about 8 million people worldwide. However, despite alarming rates, the existing treatment consists of only 2 drugs, benznidazole and nifurtimox, which have adverse reactions, high toxicity, and limited efficacy in the chronic phase. Furthermore, given the limited interest of the pharmaceutical industry in the search for new therapeutic candidates, it is urgent to research drugs for this disease. In this context, the search for specific targets in the parasite offers the possibility of reducing adverse events and toxicity, and for this reason it has been used in the rational planning of new compounds. Thus, the enzyme dihydroorotate dehydrogenase (DHODH), essential in the synthesis of pyrimidine nucleotides via the de novo pathway, is a target to be investigated in this work, since it is a specific protein for T. cruzi, the development of inhibitors for it tends to be promising. Based on the structure of DHODH, which contains cysteine residues in its active binding site, and on the structure of its orotate substrate, with acidic groups that are involved in hydrogen bonding interactions, our proposal is to develop compounds that mimic the interactions that occur between the orotate and the enzyme in order to inhibit it. Thus, we will explore groups known to have potential covalent bonding interactions with cysteine, the objective is to synthesize analogues derived from orotate, with maleimides and isothiocyanates as electrophilic substituents, explore bioisosteric replacement of the carboxylic acid and to evaluate their biological activity against the enzyme dihydroorotate dehydrogenase from T. cruzi. (AU)