Bifunctional Polymeric Inhibitors of Human Influenza A Viruses
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.
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.
Attaching 1 to the polymer improved at best millimolar IC50 values over three orders of magnitude. While 2 exhibited micromolar IC50 values, poly-2 was >100-fold even more potent. The IC50 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.
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.
KEY WORDSdrug-resistant mutant influenza virus polymeric antiviral agents sialic acid zanamivir
This work was financially supported by NIH grant U01-AI074443. L.A.d.C. is grateful to Fundacion Ramon Areces of Spain for a postdoctoral fellowship.
- 10.Lees WJ, Spaltenstein A, Kingery-Wood JE, Whitesides GM. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza A virus: multivalency and steric stabilization of particulate biological systems. J Med Chem. 1994;37:3419–33.CrossRefPubMedGoogle Scholar
- 15.Chandler M, Bamford MJ, Conroy R, Lamont B, Patel B, Patel VK, et al. Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino-Neu5Ac2en. X-ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-erythro-L-guco-nononic acid. J Chem Soc Perkin Trans. 1995;1:1173–80.CrossRefGoogle Scholar