Pharmaceutical Research

, Volume 27, Issue 2, pp 259–263

Bifunctional Polymeric Inhibitors of Human Influenza A Viruses

  • Jayanta Haldar
  • Luis Álvarez de Cienfuegos
  • Terrence M. Tumpey
  • Larisa V. Gubareva
  • Jianzhu Chen
  • Alexander M. Klibanov
Research Paper

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 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.

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.

KEY WORDS

drug-resistant mutant influenza virus polymeric antiviral agents sialic acid zanamivir 

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jayanta Haldar
    • 1
  • Luis Álvarez de Cienfuegos
    • 1
  • Terrence M. Tumpey
    • 2
  • Larisa V. Gubareva
    • 2
  • Jianzhu Chen
    • 3
  • Alexander M. Klibanov
    • 1
    • 4
  1. 1.Department of ChemistryMassachusetts Institute of TechnologyCambridgeUSA
  2. 2.Centers for Disease Control and PreventionAtlantaUSA
  3. 3.Department of Biology and the David H. Koch Institute for Integrative Cancer ResearchMassachusetts Institute of TechnologyCambridgeUSA
  4. 4.Department of Biological EngineeringMassachusetts Institute of TechnologyCambridgeUSA

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