EFFECT of ASTODRIMER SODIUM AGAINST SARS-CoV-2 VARIANTS (Α, Β, Γ, Δ, Κ) in VITRO

ABSTRACT

Background: The dominance of SARS-CoV-2 Variants of Concern (VOC) and Interest (VOI) has challenged the efficacy of public health strategies to control the current pandemic. Astodrimer sodium is a broad-spectrum antiviral dendrimer that has been formulated as a topical nasal spray to help reduce exposure to infectious viral load in the nasal cavity. Astodrimer sodium showed antiviral and virucidal activity against early pandemic isolates of SARS-CoV-2 in vitro and after nasal administration in vivo. The current studies assessed the spectrum of activity of astodrimer sodium against emerging variants of SARS-CoV-2 and other pandemic viruses. Methods: Assays utilized hACE2+ and hTMPRSS2+ HEK-293T cells, Calu-3 and Vero E6 cells. Time of addition studies involved adding astodrimer sodium 1 hour prior to, at the time of, or 1-hour post-infection. Coronavirus spike receptor binding domain (RBD) or S1 binding studies were analysed by ELISA or confocal microscopy. Virucidal studies involved exposing 105 SARS-CoV-2 PFU to 10mg/mL astodrimer sodium for 0.5, 1, 5, 15 and 30 mins. Results: Astodrimer sodium demonstrated potent antiviral and virucidal activity against SARS-CoV-2 VOC α, β, δ and γ, and VOI κ in Vero E6 and Calu-3 cells. Astodrimer sodium reduced infectious viral load of all variants by >99.9% vs virus control. The pan-SARS-CoV-2 activity of astodrimer sodium occurred despite multiple mutations and deletions in the viral spike protein of each variant. The attachment of SARS-CoV-2 early pandemic virus isolates, Wuhan-Hu-1 and USA-WA-1/2020, and SARS-CoV-1 Spike binding to ACE2, as well as attachment of Middle Eastern respiratory syndrome (MERS) coronavirus spike protein to its cellular receptor, was inhibited by astodrimer sodium. Astodrimer sodium did not prevent attachment of the SARS-CoV-2 VOC α and β spike S1, or γ RBD spike protein, to the ACE2 receptor in vitro. Conclusion: Astodrimer sodium mimics negatively charged glycosaminoglycans and provides a potent antiviral and virucidal barrier to viral attachment and entry. The potent broad-spectrum anti-pandemic coronavirus and virucidal efficacy of astodrimer sodium against whole virus is likely due to blocking multiple electrostatic interactions of the spike protein that are not negated by minor or major changes to the isolated RBD of SARS-CoV-2 VOC α, β and γ alone. Astodrimer sodium has the potential to block the binding of pan-SARS-CoV-2, thus reducing the potential for the development of COVID-19.