On the development of SARS-CoV-2 3CL Mpro Coronavirus main protease inhibitors as antiviral agents

• Grant number: 22/01393-5
• Support Opportunities: Regular Research Grants
• Duration: July 01, 2022 - June 30, 2025
• Field of knowledge: Physical Sciences and Mathematics - Chemistry
• Principal Investigator: Carlos Alberto Montanari
• Grantee: Carlos Alberto Montanari
• Host Institution: Instituto de Química de São Carlos (IQSC). Universidade de São Paulo (USP). São Carlos , SP, Brazil
• Associated researchers: Andrei Leitão ; Carolina Borsoi Moraes ; Fernanda Canduri ; João Santana da Silva ; Luiz Juliano Neto ; Maria Aparecida Juliano

Abstract

Despite the FDA approval of Paxlovid and Molnupiravir and the hope that they will act on the omicron strain - both are effective on the delta strain; there is still room for nirmatrelvir optimization. Considering the excellent results obtained through the FAPESP project #2020/04653-2, we will continue the in vitro and in vivo assays of the best-identified antivirals (Neq1119, Neq1167, Neq1184) for the establishment of in vivo proof of concept (PoC) with desire for better efficacy and tolerability. While there is clear evidence of antiviral action in the new variants of SARS-CoV-2, its main protease Mpro continues to experiment with mutations that need to be constantly challenged. Of particular interest are positions P3 and P4 of the peptide-like inhibitors, for improvement to get higher affinity Mpro inhibitors can be envisaged. In addition, P2 is also amenable to optimization, and we will investigate new unnatural prolines and new six-membered rings. Too, we will endeavor to evaluate new warheads with differing electrophilicity character. Thus, this project will apply hypothesis-driven molecular design to synthesize and structurally characterize new chemical entities as inhibitors of SARS-CoV-2 Mpro with antiviral action in vitro and in vivo. (AU)