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|a Lee, Chia Min
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|a Massachusetts Institute of Technology. Computational and Systems Biology Program
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|a Massachusetts Institute of Technology. Department of Biological Engineering
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|a Massachusetts Institute of Technology. Department of Biology
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|a Massachusetts Institute of Technology. Department of Chemistry
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|a Koch Institute for Integrative Cancer Research at MIT
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|a Weight, Alisha Kessel
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|a Haldar, Jayanta
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|a Wang, Ling
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|a Klibanov, Alexander M.
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|a Chen, Jianzhu
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|a Lee, Chia Min
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|a Weight, Alisha Kessel
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|a Haldar, Jayanta
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|a Wang, Ling
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|a Klibanov, Alexander M.
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|a Chen, Jianzhu
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|a Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection
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|b National Academy of Sciences (U.S.),
|c 2013-09-26T16:50:50Z.
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|z Get fulltext
|u http://hdl.handle.net/1721.1/81198
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|a Covalently conjugating multiple copies of the drug zanamivir (ZA; the active ingredient in Relenza) via a flexible linker to poly-l-glutamine (PGN) enhances the anti-influenza virus activity by orders of magnitude. In this study, we investigated the mechanisms of this phenomenon. Like ZA itself, the PGN-attached drug (PGN-ZA) binds specifically to viral neuraminidase and inhibits both its enzymatic activity and the release of newly synthesized virions from infected cells. Unlike monomeric ZA, however, PGN-ZA also synergistically inhibits early stages of influenza virus infection, thus contributing to the markedly increased antiviral potency. This inhibition is not caused by a direct virucidal effect, aggregation of viruses, or inhibition of viral attachment to target cells and the subsequent endocytosis; rather, it is a result of interference with intracellular trafficking of the endocytosed viruses and the subsequent virus-endosome fusion. These findings both rationalize the great anti-influenza potency of PGN-ZA and reveal that attaching ZA to a polymeric chain confers a unique mechanism of antiviral action potentially useful for minimizing drug resistance.
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|a National Institutes of Health (U.S.) (Grant U01-AI074443)
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|a en_US
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|a Article
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|t Proceedings of the National Academy of Sciences
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