Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection

Proc Natl Acad Sci U S A. 2012 Dec 11;109(50):20385-90. doi: 10.1073/pnas.1219155109. Epub 2012 Nov 26.

Abstract

Covalently conjugating multiple copies of the drug zanamivir (ZA; the active ingredient in Relenza) via a flexible linker to poly-l-glutamine (PGN) enhances the anti-influenza virus activity by orders of magnitude. In this study, we investigated the mechanisms of this phenomenon. Like ZA itself, the PGN-attached drug (PGN-ZA) binds specifically to viral neuraminidase and inhibits both its enzymatic activity and the release of newly synthesized virions from infected cells. Unlike monomeric ZA, however, PGN-ZA also synergistically inhibits early stages of influenza virus infection, thus contributing to the markedly increased antiviral potency. This inhibition is not caused by a direct virucidal effect, aggregation of viruses, or inhibition of viral attachment to target cells and the subsequent endocytosis; rather, it is a result of interference with intracellular trafficking of the endocytosed viruses and the subsequent virus-endosome fusion. These findings both rationalize the great anti-influenza potency of PGN-ZA and reveal that attaching ZA to a polymeric chain confers a unique mechanism of antiviral action potentially useful for minimizing drug resistance.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiviral Agents / administration & dosage*
  • Antiviral Agents / chemistry
  • Dogs
  • Drug Synergism
  • Endocytosis / drug effects
  • Hemagglutinin Glycoproteins, Influenza Virus / drug effects
  • Humans
  • Influenza A Virus, H1N1 Subtype / drug effects*
  • Influenza A Virus, H1N1 Subtype / pathogenicity
  • Influenza A Virus, H1N1 Subtype / physiology
  • Influenza A Virus, H1N1 Subtype / ultrastructure
  • Influenza, Human / drug therapy*
  • Influenza, Human / virology*
  • Madin Darby Canine Kidney Cells
  • Microscopy, Electron, Transmission
  • Neuraminidase / antagonists & inhibitors
  • Orthomyxoviridae Infections / drug therapy*
  • Orthomyxoviridae Infections / virology*
  • Peptides / chemistry
  • Zanamivir / administration & dosage
  • Zanamivir / analogs & derivatives*
  • Zanamivir / chemistry

Substances

  • Antiviral Agents
  • H1N1 virus hemagglutinin
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Peptides
  • polyglutamine
  • Neuraminidase
  • Zanamivir