title: Attaching zanamivir to a polymer markedly enhances its activity against drug-resistant strains of influenza a virus.
abstract: Effects of the commercial drug zanamivir (Relenza) covalently attached to poly-l-glutamine on the infectivity of influenza A viruses are examined using the plaque reduction assay and binding affinity to viral neuraminidase (NA). These multivalent drug conjugates exhibit (i) up to a 20,000-fold improvement in anti-influenza potency compared with the zanamivir parent against human and avian viral strains, including both wild-type and drug-resistant mutants, and (ii) superior neuraminidase (NA) inhibition constants, especially for the mutants. These findings provide a basis for exploring polymer-attached inhibitors as more efficacious therapeutics, particularly against drug-resistant influenza strains.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Alisha K
authors.initials: AK
authors.lastname: Weight
authors.forename: Jayanta
authors.initials: J
authors.lastname: Haldar
authors.forename: Luis
authors.initials: L
authors.lastname: Alvarez de Cienfuegos
authors.forename: Larisa V
authors.initials: LV
authors.lastname: Gubareva
authors.forename: Terrence M
authors.initials: TM
authors.lastname: Tumpey
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Chen
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Klibanov
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005079:Excipients; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053139:Oseltamivir / Q000494:pharmacology; D010455:Peptides; D011108:Polymers; D010948:Viral Plaque Assay; D053243:Zanamivir / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D005079:Excipients; D010455:Peptides; D011108:Polymers; D053139:Oseltamivir; C097188:polyglutamine; D009439:Neuraminidase; D053243:Zanamivir