Fig. 3: WEHI-P8 improves disease outcome in an acute mouse model of severe disease.
From: A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID
a WEHI-P8 was selected for mouse in vivo efficacy due to its favourable ADME properties. b Calculated unbound plasma concentration of WEHI-P8 in male C57BL/6 (WT) mice following oral administration at 100 mg/kg. c Schematic showing treatment regime used in d-g. Mice were treated at 6 h, 24 h and 48 h with euthanasia performed at 72 h post-infection. WT 7-9 week-old mice were infected with SARS-CoV-2 P21 (see Supplementary Fig. 7a) and treated with either vehicle, PLT (Paxlovid-like treatment: 56 mg/kg nirmatrelvir, 19 mg/kg ritonavir), or WEHI-P8 (100 mg/kg or 150 mg/kg) (see schematic and Methods d,e At 3 days port-infection (dpi), mice were monitored for d viral burden and e percent weight change compared to initial weight; nvehicle = 7, nPLT = 7, nP8-100 = 8, nP8-150 = 8 mice per group. Mean ± SD. f Haematoxylin and eosin (H&E) and immunohistochemistry (IHC) stained lungs are shown. Markers used for each cell type are indicated in brackets and images are representative of 4 animals per condition. Scale bars = 100 µm. g Levels of cytokines and chemokines measured by ELISA of lung homogenates from mice infected with SARS-CoV-2 P21; nvehicle = 7, nPLT = 7, nP8-100 = 8, nP8-150 = 8 mice per group; boxplots depict the median and interquartile range (IQR). Whiskers extend to the furthest data point within 1.5 times the IQR from each box end. P-values are indicated above each group and were determined by e one-way ANOVA with Tukey’s multiple comparisons tests d after log10 transformation and g Two-sided wilcoxon rank-sum test, with Bonferroni adjustment for multiple comparisons; **p < 0.01, ***p < 0.001. Exact P-values for Fig. 3g are provided in the Source Data file. Source data are provided as a Source Data file. Figure 3c Partially created in BioRender93.
