Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection
Name
Lee-2012-Polymer-Attached Zanamivir Inhibits Synergistically Both Early and Late Stages of Influenza Virus Infection.pdf
Size
1.04 MB
Format
Adobe PDF
Checksum (MD5)
1baec7314fd11e0dc2bd6002a8b1f13e
Author(s)
Lee, Chia Min
Weight, Alisha Kessel
Haldar, Jayanta
Wang, Ling
Klibanov, Alexander M.
Chen, Jianzhu
Date Issued
November 2012
Journal
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences (U.S.)
Citation
Lee, C. M., A. K. Weight, J. Haldar, L. Wang, A. M. Klibanov, and J. Chen. Polymer-attached Zanamivir Inhibits Synergistically Both Early and Late Stages of Influenza Virus Infection. Proceedings of the National Academy of Sciences 109, no. 50 (December 11, 2012): 20385-20390.
Version
Final published version
Abstract
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.
MIT Department
Massachusetts Institute of Technology. Computational and Systems Biology Program
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
Terms of Use
Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.
Persistent DSpace Link
DOI of Published Version
http://dx.doi.org/10.1073/pnas.1219155109
