Zanamivir Conjugated to Poly-L-Glutamine is Much More Active Against Influenza Viruses in Mice and Ferrets Than the Drug Itself
Author(s)
Belser, Jessica A.
Tumpey, Terrence M.
Chen, Jianzhu
Klibanov, Alexander M.
Weight, Alisha Kessel
Date Issued
September 2013
Journal
Pharmaceutical Research
Publisher
Springer-Verlag
Citation
Weight, Alisha K., Jessica A. Belser, Terrence M. Tumpey, Jianzhu Chen, and Alexander M. Klibanov. “Zanamivir Conjugated to Poly-L-Glutamine Is Much More Active Against Influenza Viruses in Mice and Ferrets Than the Drug Itself.” Pharmaceutical Research 31, no. 2 (February 2014): 466–474.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1007/s11095-013-1175-4
