title: Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants.
abstract: By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains, we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker group on the negatively charged poly-l-glutamate resulted in one of the most potent inhibitors for 2's conjugates against drug-resistant influenza strains. Although full recovery of the inhibitory action against drug-resistant strains was not achieved, this study may be a step toward salvaging anti-influenza drugs that are no longer effective.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Alyssa M
authors.initials: AM
authors.lastname: Larson
authors.forename: Jianzhu
authors.initials: J
authors.lastname: Chen
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Klibanov
mesh_terms: D000547:Amantadine / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D004285:Dogs; D004337:Drug Carriers / Q000737:chemistry*; D024882:Drug Resistance, Viral; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D007251:Influenza, Human / Q000188:drug therapy; D009976:Orthomyxoviridae Infections / Q000188:drug therapy; D011099:Polyglutamic Acid / Q000737:chemistry; D011108:Polymers / Q000737:chemistry*; D012299:Rimantadine / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D004337:Drug Carriers; D011108:Polymers; D012299:Rimantadine; D011099:Polyglutamic Acid; D000547:Amantadine
keywords: antiinfectives; biodegradable polymers; conjugation; drug resistance; inhibition; polymeric drug carrier; polymeric drugs; polymers