Bifunctional Polymeric Inhibitors of Human Influenza A Viruses

Abstract

Purpose-New antiviral agents were prepared by attaching derivatives of sialic acid (1) and of the drug zanamivir (2) to poly(isobutylene-alt-maleic anhydride) (poly-(1+2)) or by mixing poly-1 and poly-2, followed by assaying them against wild-type and drug-resistant influenza A Wuhan viruses.Methods-Individually or together, 1 and 2 were covalently bonded to the polymer. The antiviral potencies of the resultant poly-1, poly-2, poly-(1+2), and poly-1 + poly-2, as well as 1 and 2, were assessed using plaque reduction assay.Results-Attaching 1 to the polymer improved at best millimolar IC 50 values over three orders of magnitude. While 2 exhibited micromolar IC 50 values, poly-2 was >100-fold even more potent. The IC 50 of poly-(1+2) against the wild-type strain was >300-fold and ~17-fold better than of poly-1 and poly-2, respectively. In contrast, the potency of poly-(1+2) vs. poly-2 against the mutant strain merely doubled. The mixture of poly-1 + poly-2 inhibited both viral strains similarly to poly-2.Conclusions-The bifunctional poly-(1+2) acts synergistically against the wild-type influenza virus, but not against its drug-resistant mutant, as compared to a physical mixture of the monofunctional poly-1 and poly-2.

Multivalent Peptide–Nanoparticle Conjugates for Influenza‐Virus Inhibition

“…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.…”

Conjugating drug candidates to polymeric chains does not necessarily enhance anti‐influenza activity

“…In the United States alone, some 20% of the population contracts the virus annually leading to countless missed days of work and school and tens of billions of dollars in associated costs. 1,2 The two FDA-approved drugs for the treatment of influenza infections, Oseltamivir (Tamiflu™) and Zanamivir (Relenza™), have fallen short of expectations due to their mediocre activity in reducing the symptoms and duration of the infection, as well as emerging resistance in clinical isolates. 3,4,5 Thus new, more effective anti-influenza therapeutic agents are greatly needed.…”

“…2,4,[6][7][8][9][10][11] Conjugating multiple copies of influenza inhibitors to a flexible polymeric chain has been shown to result in multivalent interactions between the polymerattached inhibitors and the viral surface receptor proteins. 2,4,[6][7][8][9][10][11] These enhanced interactions, in turn, lead to a much stronger binding compared to that of the small-molecule parents stemming from favorable entropic factors; additionally, water-swollen polymeric chains may sterically hinder physical contacts between the virus and the target cell. 6 The foregoing benefits of multivalency for binding to influenza virus have been demonstrated for viral surface proteins with the natural ligand of hemagglutinin, Nacetylneuraminic (sialic) acid, and with the neuraminidase inhibitor Zanamivir.…”

“…6 The foregoing benefits of multivalency for binding to influenza virus have been demonstrated for viral surface proteins with the natural ligand of hemagglutinin, Nacetylneuraminic (sialic) acid, and with the neuraminidase inhibitor Zanamivir. 2,4,[6][7][8][9][10][11] However, both of these compounds are structurally complex requiring many-step syntheses to become amenable to attachment to polymeric chains in order to investigate the effect of multivalency. 2,4 They are also difficult to modify selectively and thus not optimal for structure-activity relationship (SAR) studies.…”

“…2,4,[6][7][8][9][10][11] However, both of these compounds are structurally complex requiring many-step syntheses to become amenable to attachment to polymeric chains in order to investigate the effect of multivalency. 2,4 They are also difficult to modify selectively and thus not optimal for structure-activity relationship (SAR) studies. In the present work, we instead have employed simple organic molecules 12 with anti-influenza properties to investigate the SAR of multivalency.…”