Therapeutic efficacy of an oral nucleoside analog of remdesivir against SARS-CoV-2 pathogenesis in mice

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  Figure 1.. Chemical Structure and in vitro potency of GS-621763 in comparison to RDV (GS-5734) and GS-441524. (A) Chemical structure of the parental adenosine nucleoside analog GS-441524. (B) Chemical structure of the monophosphoramidate prodrug RDV. (C) Chemical structure of GS-621763, the tri-isobutyryl ester of GS-441524. (D) Mean percent inhibition of SARS-CoV-2 replication by GS-621763, in comparison to the prodrug RDV - and the parental nucleoside GS-441524 in A459-hACE2 cells (done in triplicates). (E) Cytotoxicity in A459-hACE2 cells treated with GS-621763, RDV, and GS-441524 in A459-hACE2 cells (done in triplicates, CellTiter-Glo – CTG). (F) Inhibition of SARS-CoV-2 replication by GS-621763, in comparison to the prodrug RDV and the parental nucleoside GS-441524 in human primary airway epithelial cells (HAE, done in duplicates). (G) Inhibition of SARS-CoV-2-Fluc replication by GS-621763, RDV -, and the parental nucleoside GS-441524 in normal human bronchial epithelial (NHBE) cultures (done in duplicates). (H) In vitro EC50 values for inhibition of viral replication by GS-621763, RDV, and the parental nucleoside GS-441524 in A459-hACE2 and NHBE cells.

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  Figure 2.. Dose-dependent therapeutic protection against COVID-19 disease by GS-621763 in mice. (A) Plasma Pharmacokinetics of GS-441524 in uninfected Balb/c mice following a single oral administration of GS-621763 at either 5 or 20 mg/kg. Plasma concentrations of GS-621763 were below the limit of quantification at all time points. (B) Depicted is the % starting weight in therapeutically treated mice with vehicle (n=19) or 3 mg/kg (n=9), 10 mg/kg (n=10), and 30 mg/kg (n=10) GS-621763 at 8 hr. All mice were infected with 1×104 PFU SARS-CoV-2 MA10. (C) Lung viral titers in therapeutically treated mice with vehicle (n=19) or 3 mg/kg (n=9), 10 mg/kg (n=10), and 30 mg/kg (n=10) GS-621763 at 8 hr. All mice were infected with 1×104 PFU SARS-CoV-2 MA10. Limit of detection (LoD) (D) Pulmonary function in therapeutically treated mice with vehicle (n=4) or 3 mg/kg (n=4), 10 mg/kg (n=4), and 30 mg/kg (n=4) GS-621763 at 8 hr. All mice were infected with 1×104 PFU SARS-CoV-2 MA10. (E) Lung congestion score in therapeutically treated mice with vehicle (n=19) or 3 mg/kg (n=9), 10 mg/kg (n=10), and 30 mg/kg (n=10) GS-621763 at 8 hr. All mice were infected with 1×104 PFU SARS-CoV-2 MA10. (F and G) Lung…

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  Figure 3.. Extended therapeutic protection of mice against COVID-19 disease by oral GS-621763 in mice. (A) Depicted is the % starting weight in therapeutically treated mice with either 30 mg/kg or 60 mg/kg BID or QD GS-621763 at 12 and 24 hrs (n=10 for all treatment groups, except n=8 for 60 mg/kg, 12 hr QD treatment group). All mice were infected with 1×104 PFU SARS-CoV-2 MA10. (B) Lung viral titers in therapeutically treated mice with either 30 mg/kg or 60 mg/kg BID or QD GS-621763 at 12 and 24hrs (n=10 for all treatment groups, except n=8 for 60 mg/kg, 12 hr QD treatment group). All mice were infected with 1×104 PFU SARS-CoV-2 MA10. Limit of detection (LoD). (C) Viral N RNA in therapeutically treated mice with either 30 mg/kg or 60 mg/kg BID or QD GS-621763 at 12 and 24 hrs (n=10 for all treatment groups, except n=8 for 60 mg/kg, 12 hr QD treatment group). All mice were infected with 1×104 PFU SARS-CoV-2 MA10. (D) Pulmonary function in therapeutically treated mice with either 30 mg/kg or 60 mg/kg BID or QD GS-621763 at 12 and 24 hrs (n=4 for all treatment groups). All mice were infected with 1×104 PFU SARS-CoV-2 MA10. (n=4 for all treatment groups). (F and G) Lung pathology in the…

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  Figure 4.. Evaluation of therapeutic intervention of GS-621763 in comparison to molnupiravir (MPV). (A) Depicted is the % starting weight in therapeutically treated mice with either 30 mg/kg or 60 mg/kg GS-621763 or MPV at 12 or 24 hrs (n=10 for all treatment groups). All mice were infected with 1×104 PFU SARS-CoV-2 MA10. (B) Lung viral titers in therapeutically treated mice with either 30 mg/kg or 60 mg/kg GS-621763 or MPV at 12 or 24 hrs (n=10 for all treatment groups). All mice were infected with 1×104 PFU SARS-CoV-2 MA10. Limit of detection (LoD). (C) Viral N RNA in therapeutically treated mice with either 30 mg/kg or 60 mg/kg GS-621763 or MPV at 12 or 24 hrs (n=10 for all treatment groups). All mice were infected with 1×104 PFU SARS-CoV-2 MA10. (D) Pulmonary function in therapeutically treated mice with either 30 mg/kg or 60mg/kg GS-621763 or MPV at 12 or 24 hrs (n=4 for all treatment groups). All mice were infected with 1×104 PFU SARS-CoV-2 MA10. (F and G) Lung pathology in the therapeutically treated mice with either 30 mg/kg or 60 mg/kg GS-621763 or MPV at 12or 24 hrs (n=10 for all treatment groups). All mice were infected with 1×104 PFU SARS-CoV-2 MA10. Data were analyzed using…