COMMUNICATIONAttaching Zanamivir to a Polymer Markedly Enhances Its Activity Against Drug-resistant Strains of Influenza a Virus
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INTRODUCTION
In addition to yearly outbreaks affecting hundreds of millions of people worldwide,1 influenza pandemics of animal–human reassortment strains are increasingly common. Influenza infection is somewhat mitigated by prompt treatment with the neuraminidase (NA) inhibitors, oseltamivir (Tamiflu™), and zanamivir (Relenza™).1 Sialic acid cleavage from glycoproteins and glycolipids catalyzed by NA promotes both initiation of infection and multicycle infection by preventing viral aggregation, cleaving
MATERIALS AND METHODS
Poly-l-glutamic acid (molecular weight = 50,000–100,000 Da) and all other chemicals, biochemicals, and solvents were purchased from Sigma-Aldrich Chemical Co (St. Louis, Missouri, USA). Influenza viruses [A/Wuhan/359/95 (H3N2) and A/turkey/MN/833/80 (H4N2), as well as their drug-resistant mutants] were obtained from the Centers for Disease Control and Prevention (Atlanta, Georgia, USA). Madin-Darby canine kidney (MDCK) cells were purchased from the ATCC. Zanamivir (1, Fig. 1) was obtained from
RESULTS AND DISCUSSION
To explore the benefits of multivalency10 (i.e., in the present case, covalent attachment of multiple copies of zanamivir to the same polymeric chain) with respect to drug-resistant strains, herein we have selected three influenza A viruses carrying NA mutations at position 119: two in vitro selected zanamivir-resistant16 avian A/turkey/MN/833/80 (turkey/MN; H4N2) E119D and E119G mutants and a clinically isolated oseltamivir-resistant A/Wuhan/359/95 (Wuhan; H3N2) E119V mutant, which is
ACKNOWLEDGEMENTS
This work was partly supported by National Institutes of Health grant U01-AI074443. L.A.d.C. was supported by a postdoctoral fellowship from Fundación Ramón Areces of Spain.
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