Inhibition of Influenza Virus Activity by Multivalent Glycoarchitectures with Matched Sizes

• Published in: Chembiochem : a European journal of chemical biology Vol. 12; no. 6; pp. 887 - 895
• Main Authors: Papp, Ilona, Sieben, Christian, Sisson, Adam L., Kostka, Johanna, Böttcher, Christoph, Ludwig, Kai, Herrmann, Andreas, Haag, Rainer
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 11.04.2011; WILEY‐VCH Verlag
• Subjects: Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Line; Dogs; Erythrocytes - immunology; Erythrocytes - metabolism; Glycerol - chemistry; influenza; Influenza A virus - drug effects; Influenza A virus - metabolism; Kinetics; multivalent inhibition; nanogels; Nanoparticles - chemistry; Particle Size; polyglycerol; Polymers - chemistry; sialic acids; Sialic Acids - chemistry; Viral Fusion Proteins - antagonists & inhibitors; Viral Fusion Proteins - metabolism; Virus Internalization - drug effects; viruses
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201000776

We describe the synthesis of a series of sialic acid‐conjugated, polyglycerol‐based nanoparticles with diameters in the range of 1–100 nm. Particle sizes were varied along with the degree of functionalization to match the corresponding virus size and receptor multiplicity in order to achieve maximum efficiency. To build up these architectures, we used biocompatible, hyperbranched polyglycerols as scaffolds and recently developed polyglycerol‐based nanogels, the sizes of which can be varied between 2–4 nm and 40–100 nm, respectively. We demonstrate here that such multivalent nanoparticles inhibit influenza A virus cell binding and fusion and consequently infectivity. The potential of multivalency is evident from larger particles showing very efficient inhibition of viral infection up to 80 %. Indeed, both the size of the nanoparticle and the amount of ligand density are important determinants of inhibition efficiency. The inhibitory activity of the tested polymeric nanoparticles drastically increased with size. Particles with similar dimensions to the virus (50–100 nm) are exceedingly effective. We also observed a saturation point in degree of surface functionalization (i.e. ligand density), above which inhibition was not significantly improved. Our study emphasizes the importance of matching particle sizes and ligand densities to mimic biological surfaces and improve interactions; this is a vital concept underlying multivalent interactions. Polyglycerol nanoparticles of diameter 50–70 nm were coated with sialic acid residues to afford excellent inhibitors of influenza virus binding and fusion, and hence infectivity of erythrocytes. This approach highlights the versatility and potential of a growing class of biocompatible, branched, polyether nanogels that benefit from a highly functionalizable, hydrophilic surface.