title: Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection.
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.
authors.affiliation: Computational and Systems Biology Initiative, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Chia Min
authors.initials: CM
authors.lastname: Lee
authors.forename: Alisha K
authors.initials: AK
authors.lastname: Weight
authors.forename: Jayanta
authors.initials: J
authors.lastname: Haldar
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Klibanov
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry; D004285:Dogs; D004357:Drug Synergism; D004705:Endocytosis / Q000187:drug effects; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000187:drug effects; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology / Q000648:ultrastructure; D007251:Influenza, Human / Q000188:drug therapy* / Q000821:virology*; D061985:Madin Darby Canine Kidney Cells; D046529:Microscopy, Electron, Transmission; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology*; D010455:Peptides / Q000737:chemistry; D053243:Zanamivir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000998:Antiviral Agents; C543345:H1N1 virus hemagglutinin; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D010455:Peptides; C097188:polyglutamine; D009439:Neuraminidase; D053243:Zanamivir