The SARS-CoV-2 main protease (Mpro) is an attractive antiviral target due to its indispensable role in viral replication, high degree of conservation across coronaviruses, and low homology with human proteases. Indeed, first generation oral Mpro inhibitors, such as nirmatrelvir, have demonstrated clinical efficacy. However, as co-dosing with a cytochrome P450 3A4 inhibitor (such as ritonavir) is required to achieve adequate exposure, this may limit use in some patients due to drug–drug interactions. There is therefore a need for novel, chemically different, oral antiviral protease inhibitors.

doi: https://doi.org/10.1038/d41573-023-00195-6