Zanamivir Conjugated to Poly-L-Glutamine is Much More Active Against Influenza Viruses in Mice and Ferrets Than the Drug Itself

• Published in: Pharmaceutical research 2014-02, Vol.31 (2), p.466-474
• Main Authors: Weight, Alisha K., Belser, Jessica A., Tumpey, Terrence M., Chen, Jianzhu, Klibanov, Alexander M.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Antiviral drugs; Biochemistry; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Ferrets - virology; Glutamine - chemistry; Influenza; Influenza A virus - drug effects; Influenza virus; Male; Medical Law; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections - drug therapy; Orthomyxoviridae Infections - virology; Pharmacology; Pharmacology/Toxicology; Pharmacy; Research Paper; Structure-Activity Relationship; Zanamivir - chemistry; Zanamivir - pharmacology
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-1175-4

ABSTRACT Purpose Previously, polymer-attached zanamivir had been found to inhibit influenza A viruses in vitro far better than did small-molecule zanamivir ( 1 ) itself. The aim of this study was to identify in vitro —using the plaque reduction assay—a highly potent 1 -polymer conjugate, and subsequently test its antiviral efficacy in vivo . Methods By examining the structure-activity relationship of 1 -polymer conjugates in the plaque assay, we have determined that the most potent inhibitor against several representative influenza virus strains has a neutral high-molecular-weight backbone and a short alkyl linker. We have examined this optimal polymeric inhibitor for efficacy and immunogenicity in the mouse and ferret models of infection. Results 1 attached to poly- L -glutamine is an effective therapeutic for established influenza infection in ferrets, reducing viral titers up to 30-fold for 6 days. There is also up to a 190-fold reduction in viral load when the drug is used as a combined prophylactic/therapeutic in mice. Additionally, we see no evidence that the drug conjugate stimulates an immune response in mice upon repeat administration. Conclusions 1 attached to a neutral high-molecular-weight backbone through a short alkyl linker drastically reduced both in vitro and in vivo titers compared to those observed with 1 itself. Thus, further development of this polymeric zanamivir for the mitigation of influenza infection seems warranted.