Nirmatrelvir acting on SARS-CoV-2 Main Protease

In order to replicate, SARS-CoV-2 uses its main protease (3C like protease, or 3CLpro) to cleave its pp1a and pp1ab polyproteases into 16 mature non-structural proteins. These nsps are then integrated into the host’s replication-transcription complex to reproduce the virus. Nirmatrelvir (PF-07321332) is a reversible covalent inhibitor capable of complexing with the SARS-CoV-2 Mpro active site to disable it. This is because PF-07321332 contains a highly nucleophilic nitrile carbon that binds to the cysteine 145 protease, forming a standard 1.8-Å C-S covalent bond. A series of hydrogen bonds and hydrophobic interactions then stabilise the complex. (Yao Zhao et al, 2021)