Exploring diverse reactive warheads for the design of SARS-CoV-2 main protease inhibitors
- Eur J Med Chem. 2023 Nov 5:259:115667. doi: 10.1016/j.ejmech.2023.115667.
- 1. Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, United States.
- 2. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, 33612, United States.
- 3. Department of Medicinal Chemistry, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, United States. Electronic address: [email protected].
SARS-CoV-2 main protease (Mpro) is a validated Antiviral drug target of nirmatrelvir, the active ingredient in Pfizer's oral drug Paxlovid. Drug-drug interactions limit the use of Paxlovid. In addition, drug-resistant Mpro mutants against nirmatrelvir have been identified from Cell Culture viral passage and naturally occurring variants. As such, there is a need for a second generation of Mpro inhibitors. In this study, we explored several reactive warheads in the design of Mpro inhibitors. We identified Jun11119R (vinyl sulfonamide warhead), Jun10221R (propiolamide warhead), Jun1112R (4-chlorobut-2-ynamide warhead), Jun10541R (nitrile warhead), and Jun10963R (dually activated nitrile warhead) as potent Mpro inhibitors. Jun10541R and Jun10963R also had potent Antiviral activity against SARS-CoV-2 in Calu-3 cells with EC50 values of 2.92 and 6.47 μM, respectively. X-ray crystal structures of Mpro with Jun10541R and Jun10221 revealed covalent modification of Cys145. These Mpro inhibitors with diverse reactive warheads collectively represent promising candidates for further development.