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. 2023 Mar 29;9(13):eade8778. doi: 10.1126/sciadv.ade8778

Fig. 3. ∆P168/A173V double mutant elicits synergistic selective resistance to nirmatrelvir.

Fig. 3.

(A) Dose response of ∆P168/A173V mutant versus WT using the live-cell Src-Mpro-Tat-fLuc assay with fourfold serial dilution of inhibitor beginning at 10 μM. (B) Relative luminescence of cells expressing respective Src-Mpro-Tat-fLuc variants in the absence of inhibitor. (C) Kinetic parameters of purified Mpro variants in vitro using the Dabcyl-KTSAVLQSGFRKM-E(Edans)-NH2 FRET peptide (FP) as a substrate. (D) Ki of nirmatrelvir and ensitrelvir for purified Mpro variants derived using the Morrison equation with kinetic parameters calculated from data in (C). (E and F) Antiviral activity of nirmatrelvir, ensitrelvir, and remdesivir with the indicated recombinant SARS2 viruses in A549-hACE2 cells (twofold dilution series beginning at 25 μM; data are means ± SD of biologically independent quadruplicate experiments). (G) Representative fluorescence microscopy images of mCherry-expressing WT and ∆P168/A173V SARS2 infections following dosage with the indicated concentrations of nirmatrelvir.