Bifunctional Polymeric Inhibitors of Human Influenza A Viruses
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Klibanov_Bifunctional Polymeric.pdf
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Author(s)
Haldar, Jayanta
Alvarez de Cienfuegos, Luis
Tumpey, Terrence M.
Gubareva, Larisa V.
Chen, Jianzhu
Klibanov, Alexander M.
Date Issued
February 2010
Journal
Pharmaceutical Research
Publisher
Springer Science + Business Media B.V.
Citation
Haldar, Jayanta et al. “Bifunctional Polymeric Inhibitors of Human Influenza A Viruses.” Pharmaceutical Research 27.2 (2009): 259–263. Web.
Version
Author's final manuscript
Abstract
Purpose:
New antiviral agents were prepared by attaching derivatives of sialic acid (1) and of the drug zanamivir (2) to poly(isobutylene-alt-maleic anhydride) (poly-(1 + 2)) or by mixing poly-1 and poly-2, followed by assaying them against wild-type and drug-resistant influenza A Wuhan viruses.
Methods:
Individually or together, 1 and 2 were covalently bonded to the polymer. The antiviral potencies of the resultant poly-1, poly-2, poly-(1 + 2), and poly-1 + poly-2, as well as 1 and 2, were assessed using plaque reduction assay.
Results:
Attaching 1 to the polymer improved at best millimolar IC50 values over three orders of magnitude. While 2 exhibited micromolar IC50 values, poly-2 was >100-fold even more potent. The IC50 of poly-(1 + 2) against the wild-type strain was >300-fold and ∼17-fold better than of poly-1 and poly-2, respectively. In contrast, the potency of poly-(1 + 2) vs. poly-2 against the mutant strain merely doubled. The mixture of poly-1 + poly-2 inhibited both viral strains similarly to poly-2.
Conclusions:
The bifunctional poly-(1 + 2) acts synergistically against the wild-type influenza virus, but not against its drug-resistant mutant, as compared to a physical mixture of the monofunctional poly-1 and poly-2.
MIT Department
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
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DOI of Published Version
https://doi.org/10.1007/s11095-009-0013-1
