Inhibition of Viral Adhesion and Infection by Sialic-Acid-Conjugated Dendritic Polymers

Abstract

Multiple sialic acid (SA) residues conjugated to a linear polyacrylamide backbone are more effective than monomeric SA at inhibiting influenza-induced agglutination of red blood cells. However, "polymeric inhibitors" based on polyacrylamide backbones are cytotoxic. Dendritic polymers offer a nontoxic alternative to polyacrylamide and may provide a variety of potential synthetic inhibitors of influenza virus adhesion due to the wide range of available polymer structures. We evaluated several dendritic polymeric inhibitors, including spheroidal, linear, linear-dendron copolymers, comb-branched, and dendrigraft polymers, for the ability to inhibit virus hemagglutination (HA) and to block infection of mammalian cells in vitro. Four viruses were tested: influenza A H2N2 (selectively propagated two ways), X-31 influenza A H3N2, and sendai. The most potent of the linear and spheroidal inhibitors were 32-256-fold more effective than monomeric SA at inhibiting HA by the H2N2 influenza virus. Linear-dendron copolymers were 1025-8200-fold more effective against H2N2 influenza, X-31 influenza, and sendai viruses. The most effective were the comb-branched and dendrigraft inhibitors, which showed up to 50000-fold increased activity against these viruses. We were able to demonstrate significant (p < 0.001) dose-dependent reduction of influenza infection in mammalian cells by polymeric inhibitors, the first such demonstration for multivalent SA inhibitors. Effective dendrimer polymers were not cytotoxic to mammalian cells at therapeutic levels. Of additional interest, variation in the inhibitory effect was observed with different viruses, suggesting possible differences due to specific growth conditions of virus. SA-conjugated dendritic polymers may provide a new therapeutic modality for viruses that employ SA as their target receptor.

Development of photocrosslinked sialic acid containing polymers for use in Aβ toxicity attenuation

“…Others have developed multivalent sialic acid polymers by conjugating sialic acid to a dendrimer backbone for prevention of viral adhesion and infection that were effective both in vitro and in vivo [34,35]. However, when we have previously used sialic acid modified dendrimers to attenuate Aβ toxicity in cell culture models using neuroblastoma cells, dendrimer backbone toxicity was evident at concentrations between 3 and 80 µM dendrimer, depending upon the dendrimer concentration [1,36].…”

Synthetic Multivalent Ligands as Probes of Signal Transduction

“…Polymers are generally assembled in a single step by methods such as radical, ionic, or ring-opening metathesis polymerization of RE-bearing monomers. [101,[143][144][145][146][147][148][149] Alternatively, REs can be appended to a pre-formed polymeric scaffold. [101,147] Certain polymerization reactions are more tolerant of biologically active functionality than others; thus, the type of epitopes to be incorporated will determine the most effective synthetic strategy.…”

Multivalent Peptide–Nanoparticle Conjugates for Influenza‐Virus Inhibition

“…The most affine binders reported to date consist of SA tethered to linear polyacrylamide polymers 6. Although they have a high inhibitory potential, polyacrylamide‐based inhibitors and their degradation products often show high cytotoxicity 6, 17, 18, 19, 20. Polyamidoamine (PAMAM) dendrimers have also been used for multivalent display, for example, of siallyllactose21 showing in vitro inhibition at micromolar ligand concentrations as well as protection of mice from infection.…”

“…Polyamidoamine (PAMAM) dendrimers have also been used for multivalent display, for example, of siallyllactose21 showing in vitro inhibition at micromolar ligand concentrations as well as protection of mice from infection. However, depending on their structure multivalent PAMAM scaffolds may also be cytotoxic 17, 22, 23…”