Abstract
Resistance to nirmatrelvir (Paxlovid) has been shown by multiple groups and may already exist in clinical SARS-CoV-2 isolates. Here a robust cell-based assay is used to determine the relative potencies of nirmatrelvir, ensitrelvir, and FB2001 against a panel of SARS-CoV-2 main protease (Mpro) variants. The results reveal that these three drugs have at least partly distinct resistance mutation profiles and raise the possibility that the latter compounds may be effective in some instances of Paxlovid resistance and vice versa.