Bifunctional polymeric inhibitors of human influenza A viruses

• Main Authors: Haldar, Jayanta (Contributor), Alvarez de Cienfuegos, Luis (Contributor), Tumpey, Terrence M. (Author), Gubareva, Larisa V. (Author), Chen, Jianzhu (Contributor), Klibanov, Alexander M. (Contributor)
• Other Authors: Massachusetts Institute of Technology. Department of Biology (Contributor), Massachusetts Institute of Technology. Department of Chemistry (Contributor), Klibanov, Alexander M (Contributor)
• Format: Article
• Language: English
• Published: Springer Netherlands, 2009-11-19T20:57:13Z.
• Subjects: Article
• Online Access: Get fulltext

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[subscript 50] values over three orders of magnitude. While 2 exhibited micromolar IC[subscript 50] 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. 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.
National Institutes of Health