A new SARS-CoV-2 main protease (M^pro) inhibitor, RAY1216, has been developed and shown to have improved pharmacokinetic properties compared to nirmatrelvir (PF-07321332). RAY1216 is an α-ketoamide-based peptidomimetic inhibitor that covalently binds to the catalytic Cys145 of M^pro. It exhibits similar antiviral activity against SARS-CoV-2 variants as nirmatrelvir, but with a longer drug-target residence time and better pharmacokinetic properties. RAY1216 has been approved as a single-component drug named 'leritrelvir' for the treatment of COVID-19 in China. The crystal structure of the RAY1216-M^pro complex shows that RAY1216 forms a stable covalent bond with M^pro through its α-ketoamide group. RAY1216 has a higher dissociation rate constant than nirmatrelvir, indicating a longer residence time on the target enzyme. In vitro and in vivo studies show that RAY1216 has good antiviral activity and can protect against SARS-CoV-2 infection in human ACE2 transgenic mice. RAY1216 has better pharmacokinetic properties than nirmatrelvir, allowing it to be used without ritonavir, which is typically co-administered with nirmatrelvir. RAY1216 has been shown to have improved pharmacokinetic properties in mice and rats, with a longer elimination half-life and higher area under the curve (AUC) values. RAY1216 has also been shown to have good antiviral activity against SARS-CoV-2 variants, including Omicron. RAY1216 has completed phase III clinical trials and is approved for use in China. Despite its success, RAY1216, like other antiviral drugs, faces challenges from drug resistance mutations. Further research is needed to develop more effective M^pro inhibitors.A new SARS-CoV-2 main protease (M^pro) inhibitor, RAY1216, has been developed and shown to have improved pharmacokinetic properties compared to nirmatrelvir (PF-07321332). RAY1216 is an α-ketoamide-based peptidomimetic inhibitor that covalently binds to the catalytic Cys145 of M^pro. It exhibits similar antiviral activity against SARS-CoV-2 variants as nirmatrelvir, but with a longer drug-target residence time and better pharmacokinetic properties. RAY1216 has been approved as a single-component drug named 'leritrelvir' for the treatment of COVID-19 in China. The crystal structure of the RAY1216-M^pro complex shows that RAY1216 forms a stable covalent bond with M^pro through its α-ketoamide group. RAY1216 has a higher dissociation rate constant than nirmatrelvir, indicating a longer residence time on the target enzyme. In vitro and in vivo studies show that RAY1216 has good antiviral activity and can protect against SARS-CoV-2 infection in human ACE2 transgenic mice. RAY1216 has better pharmacokinetic properties than nirmatrelvir, allowing it to be used without ritonavir, which is typically co-administered with nirmatrelvir. RAY1216 has been shown to have improved pharmacokinetic properties in mice and rats, with a longer elimination half-life and higher area under the curve (AUC) values. RAY1216 has also been shown to have good antiviral activity against SARS-CoV-2 variants, including Omicron. RAY1216 has completed phase III clinical trials and is approved for use in China. Despite its success, RAY1216, like other antiviral drugs, faces challenges from drug resistance mutations. Further research is needed to develop more effective M^pro inhibitors.