Nanostructured glycan architecture is important in the inhibition of influenza A virus infection
Kwon, Seok Joon; Na, Dong Hee; Kwak, Jong Hwan; Douaisi, Marc; Zhang, Fuming; Park, Eun Ji; Park, Jong Hwan; Youn, Hana; Song, Chang Seon; Kane, Ravi S.; Dordick, Jonathan S.; Lee, Kyung Bok; Linhardt, Robert J.
Biology; Chemistry and chemical biology; Chemical and biological engineering; Biomedical engineering
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Nanostructured glycan architecture is important in the inhibition of influenza A virus infection, S.-J. Kwon, D. H. Na, J. H. Kwak, M. Douaisi, F. Zhang, E. J. Park, J.-H. Park, H. Youn, C.-S. Song, R. S. Kane, J. S. Dordick, K. B. Lee, R. J. Linhardt, Nature Nanotechnology, 12, 48-56, 2017.
Rapid change and zoonotic transmission to humans have enhanced the virulence of the influenza A virus (IAV)3. Neutralizing antibodies fail to provide lasting protection from seasonal epidemics1,4. Furthermore, the effectiveness of anti-influenza neuraminidase inhibitors has declined because of drug resistance5. Drugs that can block viral attachment and cell entry independent of antigenic evolution or drug resistance might address these problems. We show that multivalent 6′-sialyllactose-polyamidoamine (6SL–PAMAM) conjugates, when designed to have well-defined ligand valencies and spacings, can effectively inhibit IAV infection. Generation 4 (G4) 6SL–PAMAM conjugates with a spacing of around 3 nm between 6SL ligands (S3–G4) showed the strongest binding to a hemagglutinin trimer (dissociation constant of 1.6 × 10−7 M) and afforded the best inhibition of H1N1 infection. S3–G4 conjugates were resistant to hydrolysis by H1N1 neuraminidase. These conjugates protected 75% of mice from a lethal challenge with H1N1 and prevented weight loss in infected animals. 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.;
Nature Nanotechnology, 12, 48-56; Note : if this item contains full text it may be a preprint, author manuscript, or a Gold OA copy that permits redistribution with a license such as CC BY. The final version is available through the publisher’s platform.
The Linhardt Research Labs.; The Shirley Ann Jackson, Ph.D. Center for Biotechnology and Interdisciplinary Studies (CBIS);
The Linhardt Research Labs Online Collection; Rensselaer Polytechnic Institute, Troy, NY; Nature Nanotechnology; https://harc.rpi.edu/;