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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
Effective date (Start): October 01, 2022
Effective date (End): 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
Research place: 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, theexisting treatment consists of only 2 drugs, benznidazole and nifurtimox, which haveadverse reactions, high toxicity, and limited efficacy in the chronic phase. Furthermore,given the limited interest of the pharmaceutical industry in the search for new therapeuticcandidates, it is urgent to research drugs for this disease. In this context, the search forspecific targets in the parasite offers the possibility of reducing adverse events andtoxicity, 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 ofpyrimidine 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 bepromising. Based on the structure of DHODH, which contains cysteine residues in itsactive binding site, and on the structure of its orotate substrate, with acidic groups that areinvolved in hydrogen bonding interactions, our proposal is to develop compounds thatmimic the interactions that occur between the orotate and the enzyme in order to inhibitit. Thus, we will explore groups known to have potential covalent bonding interactionswith cysteine, the objective is to synthesize analogues derived from orotate, withmaleimides and isothiocyanates as electrophilic substituents, explore bioisostericreplacement of the carboxylic acid and to evaluate their biological activity against theenzyme dihydroorotate dehydrogenase from T. cruzi.

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