Figure 4.

5′END-2 PPMO administered via IT injection markedly limits virus growth in the lungs of K18-hACE2 mice and protects from weight loss

(A–C) K18-hACE2 mice were treated with PBS or the indicated PPMO via IT administration at 24 h before and 18 h after IN administration of 5,000 ffu of SARS-CoV-2 (strain WA-1/2020). MK-4482 (molnupravir), used as a positive control compound, was administered orally twice per day from 1 day before infection until 2 days post-infection. Virus load in the lungs was measured at 3 days post-infection by focus-forming assay, as described in materials and methods, and charted. The experiments represented by the graphs in (A)–(C) were carried out under the same conditions (see materials and methods), but at independent times. The limit of virus detection (LOD) in the focus-forming assay was 100 ffu/g tissue, as represented by a dotted line. n = 5, except the experiment of (C), which tested 5’END-2 at various concentrations, where each group contained 3 mice. (D) Mice were treated with PBS, MK-4482, or PPMO, as indicated, under the same experimental conditions as described above. Body weights were measured daily for 10 days post-infection and represented as a percentage of the animal weight on the day of infection. By 8 days post-infection, all the animals in the NC705 had lost greater than 35% of their original body weight and were considered moribund. n = 5/group. Data shown as mean ± SD and analyzed by one-way ANOVA with Dunnett’s multiple comparisons (∗∗∗p < 0.001; ∗∗∗∗p < 0.0001).