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Published online before print November 26, 2012, doi: 10.1073/pnas.1219155109 PNAS November 26, 2012
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Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection
Chia Min Leea,b,
Alisha K. Weightc,
Jayanta Haldarc,
Ling Wangb,
Alexander M. Klibanovc,d,1, and
Jianzhu Chenb,e,1
+ Author Affiliations
aComputational and Systems Biology Initiative,
bKoch Institute for Integrative Cancer Research,
cDepartment of Chemistry,
dDepartment of Biological Engineering, and
eDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
Contributed by Alexander M. Klibanov, November 5, 2012 (sent for review July 11, 2012)
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.
http://www.pnas.org/content/early/2012/11/21/1219155109.abstract
PNAS
Proceedings of the National Academy of Sciences of the United States of America
Guidance for the Description of Animal Research in Scientific Publications (2011)
Sign up for PNAS eTOCs
Science Sessions: The PNAS Podcast Program
Polymer-attached zanamivir inhibits synergistically both early and late stages of influenza virus infection
Chia Min Leea,b,
Alisha K. Weightc,
Jayanta Haldarc,
Ling Wangb,
Alexander M. Klibanovc,d,1, and
Jianzhu Chenb,e,1
+ Author Affiliations
aComputational and Systems Biology Initiative,
bKoch Institute for Integrative Cancer Research,
cDepartment of Chemistry,
dDepartment of Biological Engineering, and
eDepartment of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139
Contributed by Alexander M. Klibanov, November 5, 2012 (sent for review July 11, 2012)
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.
http://www.pnas.org/content/early/2012/11/21/1219155109.abstract