Inhibition of Influenza Virus Activity by Multivalent Glycoarchitectures with Matched Sizes

Abstract

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.

Multivalent Peptide–Nanoparticle Conjugates for Influenza‐Virus Inhibition

“…Promisingly, biocompatible polyglycerol (PG)‐based SA‐nanoparticles have been shown to reduce viral infection in vitro by up to 80 % when applied in millimolar ligand, respectively submicromolar nanoparticle concentrations 8. The importance of low receptor density and larger particle size was emphasized in this study similar to the PAMAM study 21…”

“…High molecular‐weight scaffolds displaying a large number of low affinity SA derived ligands were used to achieve high HA avidity. Over the years several carrier systems were employed as scaffolds ranging from polymers,6, 8, 9 dendrimers,10, 11, 12, 13 liposomes,5, 14 proteins,15 to gold nanoparticles 16. The most affine binders reported to date consist of SA tethered to linear polyacrylamide polymers 6.…”

Theory, simulations and the design of functionalized nanoparticles for biomedical applications: A Soft Matter Perspective

“…One is surely that of bio-sensing, especially in those cases where target detection is measured via its ability to drive self-assembly via ligand-receptor bond formation, 144 e.g., functionalised nanoparticles for DNA 145 or enzyme 146 recognition. Another is the fast advancing field of nanoparticles as anti-viral drugs, [147][148][149][150] where multivalent particles are used that mimic, and compete with, cell receptors. Both these applications can benefit from the same approaches and techniques used to understand targeting selectivity, [70][71][72]79 and indeed some initial step in that direction have already been taken.…”

Polyvalent nucleic acid aptamers and modulation of their activity: a focus on the thrombin binding aptamer

“…Such multivalent-nanoparticle-mediated inhibition represents a promising approach for alternative antiviral therapy (Papp et al, 2011;Endsley & Ho, 2012). Particularly, some dendrimers with optimized number of lysine branches and surface groups showed anti-viral activity against HIV-1 and HSV-2, and one of these dendrimers, formulated as the topical microbicide VivaGel™, is in clinical development (Tyssen et al, 2010).…”