Fig. 3: Amino acid substitution P132S in the M protein is selected by CIM-834 and is associated with antiviral resistance.
From: A coronavirus assembly inhibitor that targets the viral membrane protein
a, In vitro resistance selection was done by passaging SARS-CoV-2 B.1.1.7 in the presence of increasing concentrations of CIM-834 in A549ACE2+TMPRSS2 cells. b, The P132S substitution is located in the carboxy-terminal intravirion domain of the M protein. c, Introduction of M(P132S) in the background of SARS-CoV-2 (Wuhan and Omicron BF.7) through reverse genetics. d, Replication kinetics of rWuhan-WT and the M(P132S) mutant in human nasal epithelial airway cultures grown at the air–liquid interface. Infectious virus titres from apical washes collected at different time points were determined (mean ± s.e.m.; n = 6 biologically independent experiments). e, Susceptibility of rWuhan-WT and M(P132S) for CIM-834 and the reference inhibitors GS-441524 and nirmatrelvir, in A549ACE2+TMPRSS2 cells (individual and median values are shown; n = 6 biologically independent experiments). Two-way analysis of variance (ANOVA) with Sidak’s multiple comparisons test was used to compare EC50 values. f, Level of compound resistance associated with other M substitutions reported in ref. 32. Mutations were reverse-engineered in the omicron BF.7 background (individual and median values are shown; n = 3 or n = 4 (P132S) biologically independent experiments with two technical repeats). Two-way ANOVA with Dunnett’s multiple comparisons test was used to compare EC50 values. g, Fold changes in EC50 values of M mutants versus wild-type virus (same data as in f; individual and mean values are shown; n = 3 or n = 4 (P132S) biologically independent experiments). Credit: b,c, created in BioRender, M. Laporte (2025). https://BioRender.com/t04g029.
