Nirmatrelvir exerts distinct antiviral potency against different human coronaviruses

Nirmatrelvir is the main component of Paxlovid, an oral antiviral drug approved for the treatment of COVID-19 caused by SARS-COV-2 infection. Nirmatrelvir targets the main protease (M(pro)), which is substantially conserved among different coronaviruses. Here, our molecular docking analysis indicates comparable affinity of nirmatrelvir binding to the M(pro) enzymes of SARS-CoV-2 and three seasonal coronaviruses (OC43, 229E and NL63). However, in cell culture models, we found that nirmatrelvir potently inhibited SARS-CoV-2, OC43 and 229E, but not NL63. The insensitivity of NL63 to nirmatrelvir treatment was demonstrated at both viral replication and infectious titer levels. The antiviral activity of nirmatrelvir against OC43 and 229E was further confirmed in human airway organoids. The combination of nirmatrelvir and molnupiravir exerted differential patterns of antiviral response against OC43 and 229E. These results revealed disparities in the ability of nirmatrelvir to inhibit different coronaviruses, and caution against repurposing of nirmatrelvir as a pan-coronavirus treatment.