Rapid change and zoonotic transmission to humans have enhanced virulence of influenza A virus (IAV). Neutralizing antibodies fail to provide lasting protection from seasonal epidemics. Furthermore, the effectiveness of anti-influenza neuraminidase inhibitors has declined because of drug resistance. Drugs that can block viral attachment and cell entry independent of antigenic evolution or drug resistance might address these problems. Multivalent 6'-sialyllactose-polyamidoamine (6SL-PAMAM) conjugates, designed to have well-defined ligand valency and spacing, can effectively inhibit IAV infection. Generation 4 (G4) 6SL-PAMAM conjugates with ~3 nm spacing between 6SL ligands (S3-G4) showed the strongest binding to a hemagglutinin (HA) trimer (KD = 1.6 X 10-7 M) and afforded the best inhibition of H1N1 infection. These conjugates were resistant to hydrolysis by H1N1 neuraminidase and protected 75% of mice from a lethal challenge with H1N1. The structure-based design of multivalent nanomaterials, involving modulation of nanoscale backbone structures and number and spacing between ligands, resulted in optimal inhibition of IAV infection. This approach may be broadly applicable for designing effective and enduring therapeutic protection against human or avian influenza viruses.

Nanostructured glycan architecture is important in the inhibition of influenza A virus infection

253rd National Meeting (2017)

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