Dual-Action Heteromultivalent Glycopolymers Stringently Block and Arrest Influenza A Virus Infection In Vitro and Ex Vivo.

Here, we demonstrate the concerted inhibition of different influenza A virus (IAV) strains using a low-molecular-weight dual-action linear polymer. The 6'-sialyllactose and zanamivir conjugates of linear polyglycerol are optimized for simultaneous targeting of hemagglutinin and neuraminidase on the IAV surface. Independent of IAV subtypes, hemagglutination inhibition data suggest better adsorption of the heteromultivalent polymer than homomultivalent analogs onto the virus surface. Cryo-TEM images imply heteromultivalent compound-mediated virus aggregation. The optimized polymeric nanomaterial inhibits >99.9% propagation of various IAV strains 24 h postinfection in vitro at low nM concentrations and is up to 10000× more effective than the commercial zanamivir drug. In a human lung ex vivo multicyclic infection setup, the heteromultivalent polymer outperforms the commercial drug zanamivir and homomultivalent analogs or their physical mixtures. This study authenticates the translational potential of the dual-action targeting approach using small polymers for broad and high antiviral efficacy.

[1]  Elisabeth Mahase.  H5N1: Has there been human-to-human transmission, and do we have a vaccine? , 2023, British medical journal.

[2]  R. Haag,et al.  Evaluation of Multivalent Sialylated Polyglycerols for Resistance Induction in and Broad Antiviral Activity against Influenza A Viruses. , 2021, Journal of medicinal chemistry.

[3]  J. Huskens,et al.  A Dynamic, Supramolecular View on the Multivalent Interaction between Influenza Virus and Host Cell. , 2021, Small.

[4]  Yu Chen,et al.  Coinfection with influenza A virus enhances SARS-CoV-2 infectivity , 2021, Cell Research.

[5]  L. Fruk,et al.  Polyglycerol-based hydrogels and nanogels: from synthesis to applications. , 2021, Future medicinal chemistry.

[6]  B. Muller-Pebody,et al.  Interactions between SARS-CoV-2 and influenza, and the impact of coinfection on disease severity: a test-negative design , 2020, medRxiv.

[7]  R. Haag,et al.  Adaptive Flexible Sialylated Nanogels as Highly Potent Influenza A Virus Inhibitors , 2020, Angewandte Chemie.

[8]  S. De Carlo,et al.  Phage capsid nanoparticles with defined ligand arrangement block influenza virus entry , 2020, Nature Nanotechnology.

[9]  C. D. de Haan,et al.  Influenza A Virus Hemagglutinin–Neuraminidase–Receptor Balance: Preserving Virus Motility , 2019, Trends in Microbiology.

[10]  L. Brown,et al.  Influenza Virus Neuraminidase Structure and Functions , 2019, Front. Microbiol..

[11]  D. Fletcher,et al.  Low-Fidelity Assembly of Influenza A Virus Promotes Escape from Host Cells , 2018, Cell.

[12]  J. Yewdell,et al.  Neuraminidase inhibition contributes to influenza A virus neutralization by anti-hemagglutinin stem antibodies , 2018, bioRxiv.

[13]  R. Haag,et al.  Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo. , 2017, Biomaterials.

[14]  N. D. da Silveira,et al.  Self-assembled carbohydrate-based vesicles for lectin targeting. , 2016, Colloids and surfaces. B, Biointerfaces.

[15]  K. Qu,et al.  Glycosylated Conductive Polymer: A Multimodal Biointerface for Studying Carbohydrate-Protein Interactions. , 2016, Accounts of chemical research.

[16]  Kai Ludwig,et al.  Size dependence of steric shielding and multivalency effects for globular binding inhibitors. , 2015, Journal of the American Chemical Society.

[17]  Holger Frey,et al.  Beyond poly(ethylene glycol): linear polyglycerol as a multifunctional polyether for biomedical and pharmaceutical applications. , 2014, Biomacromolecules.

[18]  R. Fouchier,et al.  Role of receptor binding specificity in influenza A virus transmission and pathogenesis , 2014, The EMBO journal.

[19]  G. Nienhaus,et al.  Carbohydrate-lectin recognition of sequence-defined heteromultivalent glycooligomers. , 2014, Journal of the American Chemical Society.

[20]  Lai-Xi Wang,et al.  Design and synthesis of glycoprotein-based multivalent glyco-ligands for influenza hemagglutinin and human galectin-3. , 2013, Bioorganic & medicinal chemistry.

[21]  D. Frenkel,et al.  Communication: a simple analytical formula for the free energy of ligand-receptor-mediated interactions. , 2012, The Journal of chemical physics.

[22]  D. Frenkel,et al.  A general theory of DNA-mediated and other valence-limited colloidal interactions. , 2012, The Journal of chemical physics.

[23]  Kai Ludwig,et al.  Inhibition of influenza virus infection by multivalent sialic-acid-functionalized gold nanoparticles. , 2010, Small.

[24]  R. Haag,et al.  Dendritic polyglycerol sulfates as multivalent inhibitors of inflammation , 2010, Proceedings of the National Academy of Sciences.

[25]  Christoph J. Burckhardt,et al.  Virus Movements on the Plasma Membrane Support Infection and Transmission between Cells , 2009, PLoS pathogens.

[26]  Giovanni Cardone,et al.  Influenza virus pleiomorphy characterized by cryoelectron tomography , 2006, Proceedings of the National Academy of Sciences.

[27]  M. Yamashita,et al.  Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives. , 2003, Chemical & pharmaceutical bulletin.

[28]  J. C. Dyason,et al.  A study of the active site of influenza virus sialidase: an approach to the rational design of novel anti-influenza drugs. , 1996, Journal of medicinal chemistry.

[29]  G M Whitesides,et al.  Effective inhibitors of hemagglutination by influenza virus synthesized from polymers having active ester groups. Insight into mechanism of inhibition. , 1995, Journal of medicinal chemistry.

[30]  G M Whitesides,et al.  Polyacrylamides bearing pendant alpha-sialoside groups strongly inhibit agglutination of erythrocytes by influenza A virus: multivalency and steric stabilization of particulate biological systems. , 1994, Journal of medicinal chemistry.

[31]  G M Whitesides,et al.  Hemagglutinins from two influenza virus variants bind to sialic acid derivatives with millimolar dissociation constants: a 500-MHz proton nuclear magnetic resonance study. , 1989, Biochemistry.

[32]  R. Kane,et al.  Nanostructured glycan architecture is important in the inhibition of influenza A virus infection. , 2017, Nature nanotechnology.