Search and characterization of inhibitors of the enzyme papain-like protease (PL-Pro) of SarS-Cov-2

• Grant number: 22/15854-4
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2023
• End date: December 31, 2025
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Maria Cristina Nonato
• Grantee: Diogo Fernandes Boerin
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Even after almost three years since the first case of COVID-19, the development of vaccines, and even the identification of some drugs that help reducing the severity of the disease, COVID-19 still represents a serious public health problem in the world. The search for effective ways to combat the symptoms of the disease is still necessary and urgent. In this project, we intend to contribute to the search for inhibitors for the PLPro enzyme of SarS-CoV-2, the virus responsible for COVID-19. This is a project developed by our laboratory in collaboration with national and international researchers and with financial support in the BRICS-CNPQ modality. Through the use of in silico techniques, several inhibitors were proposed by Professor Carolina Horta Andrade's group from the Faculty of Pharmacy at the Federal University of Goiás (UFG) and synthesized by the South African partner group, H3D, from the University of Cape Town , coordinated by Professor Kelly Chibale. Our project consists of exploring the Differential Fluorimetry (DSF) screening technique for the identification of PLPro protein ligands and the X-ray diffraction technique for the characterization of the molecular bases of interaction of the identified ligands with the target protein. The results obtained through our studies will be used by the team for the planning and synthesis of more potent and selective inhibitors for PLPro, as well as with optimized pharmacokinetic, pharmacodynamic and toxicological properties. This project aims to introduce the student to the area of structural biology applied to medicinal chemistry.

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)

SOUSA, BRUNA K. P.; MOTTIN, MELINA; SEANEGO, DONALD; JURISCH, CHRISTOPHER D.; RODRIGUES, BEATRIZ S. A.; DA SILVA, VERONICA L. S.; ANDRADE, MILENE APARECIDA; MORAIS JR, GILBERTO S.; BOERIN, DIOGO F.; FROES, THAMIRES Q.; et al. Discovery of Non-Covalent Inhibitors for SARS-CoV-2 PLpro: Integrating Virtual Screening, Synthesis, and Experimental Validation. ACS Medicinal Chemistry Letters, v. N/A, p. 10-pg., 2024-12-02. (21/13237-5, 20/06190-0, 22/15854-4, 20/05369-6, 21/10084-3)