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 Netherlands
Citation
Halder, Jayanta, Luis Alvarez de Cienfuegos, Terrence M. Tumpey, Larisa V. Gubareva, Jianzhu Chen, and Alexander M. Klibanov. "Bifunctional polymeric inhibitors of human influenza A viruses." Pharmaceutical Research 27.2 (2009): 259-263.
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 IC[subscript 50] values over three orders of magnitude. While 2 exhibited micromolar IC[subscript 50] 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.
Subjects
drug-resistant mutant
zanamivir
sialic acid
polymeric antiviral agents
Influenza virus
MIT Department
Massachusetts Institute of Technology. Department of Biology
Massachusetts Institute of Technology. Department of Chemistry
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DOI of Published Version
http://dx.doi.org/10.1007/s11095-009-0013-1
https://doi.org/10.1007/s11095-009-0013-1
