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

Abstract

Rapid change1 and zoonotic transmission to humans2 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.

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Figure 1: Design and synthesis of multivalent 6SL–PAMAM dendrimer conjugates.
Figure 2: The ligand number calculated for the S3–G4 6SL dendrimer conjugates provides for the detailed structure shown.
Figure 3: In vitro inhibitory activity of 6SL–PAMAM dendrimer conjugates against H1N1 virus infection.
Figure 4: In vivo inhibitory efficacy of S3–G4 against H1N1 and HA binding models.

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Acknowledgements

This work was supported by the National Research Foundation of Korea grant funded by the Korea government (MSIP) (NRF-2013R1A2A2A01068858), Marine Biotechnology Program (PJT200620) funded by Ministry of Oceans and Fisheries, and Basic Science Research Program funded by the Ministry of Education (2015R1D1A1A01060512).

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S.-J.K, D.H.N., and J.H.K. performed all of the experiments and analysed all data. M.D. performed the microneutralization assays. F.Z. performed the SPR analyses. E.J.P. synthesized the 6SL–PAMAM dendrimer conjugates. J.-H.P., H.Y. and C.-S.S. conducted the murine experiments. R.S.K. and J.S.D. provided critical feedback on the manuscript. S.-J.K and K.B.L. planned the experiments, interpreted the results, and wrote the manuscript with R.J.L. and J.S.D.

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Correspondence to Kyung Bok Lee or Robert J. Linhardt.

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The authors declare no competing financial interests.

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Kwon, S., Na, D., Kwak, J. et al. Nanostructured glycan architecture is important in the inhibition of influenza A virus infection. Nature Nanotech 12, 48–54 (2017). https://doi.org/10.1038/nnano.2016.181

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