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: Alyssa M Larson, Jianzhu Chen, Alexander M Klibanov
• Journal: Journal of pharmaceutical sciences (J Pharm Sci) Vol. 102 Issue 8 Pg. 2450-9 (Aug 2013) ISSN: 1520-6017 [Electronic] United States
• PMID: 23832466 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Wiley Periodicals, Inc.

Chemical References

• Antiviral Agents
• Drug Carriers
• Polymers
• Rimantadine
• Polyglutamic Acid
• Amantadine

Topics

• Amantadine (administration & dosage, chemistry, pharmacology)
• Animals
• Antiviral Agents (administration & dosage, chemistry, pharmacology)
• Cell Line
• Dogs
• Drug Carriers (chemistry)
• Drug Resistance, Viral
• Humans
• Influenza A virus (drug effects)
• Influenza, Human (drug therapy)
• Orthomyxoviridae Infections (drug therapy)
• Polyglutamic Acid (chemistry)
• Polymers (chemistry)
• Rimantadine (administration & dosage, chemistry, pharmacology)