Zanamivir conjugated to poly-L-glutamine is much more active against influenza viruses in mice and ferrets than the drug itself.
OBJECTIVE
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.
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, 02139, USA.
Alisha K
AK
Weight
Jessica A
JA
Belser
Terrence M
TM
Tumpey
Jianzhu
J
Chen
Alexander M
AM
Klibanov
D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D005289:Ferrets / Q000821:virology; D005973:Glutamine / Q000737:chemistry*; D009980:Influenza A virus / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology; D013329:Structure-Activity Relationship; D053243:Zanamivir / Q000737:chemistry* / Q000494:pharmacology*
D000998:Antiviral Agents; D005973:Glutamine; D053243:Zanamivir