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.
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REFERENCES
De Clercq E. Antiviral agents active against influenza A viruses. Nature Rev Drug Discov. 2006;5:1015–25.
Von Itzstein M. The war against influenza: discovery and development of sialidase inhibitors. Nature Rev Drug Discov. 2007;6:967–74.
Haldar J, An D, Álvarez de Cienfuegos L, Chen J, Klibanov AM. Polymeric coatings that inactivate both influenza virus and pathogenic bacteria. Proc Natl Acad Sci USA. 2006;103:17667–71.
Klibanov AM. Permanently microbiocidal materials coatings. J Mater Chem. 2007;17:2479–82.
Haldar J, Chen J, Tumpey TM, Gubareva LV, Klibanov AM. Hydrophobic polycationic coatings inactivate wild-type and zanamivir- and/or oseltamivir-resistant human and avian influenza viruses. Biotechnol Lett. 2008;30:475–9.
Mammen M, Choi S-K, Whitesides GM. Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors. Angew Chem Int Ed. 1998;37:2754–94.
Matrosovich MN, Mochalova LV, Marinina VP, Byramova NE, Bovin NV. Synthetic polymeric sialoside inhibitors of influenza virus receptor-binding activity. FEBS Lett. 1990;272:209–12.
Spaltenstein A, Whitesides GM. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza virus. J Am Chem Soc. 1991;113:686–7.
Nagy JO, Wang P, Gilbert JH, Schaefer ME, Hill TG, Callstro MR, et al. Carbohydrate materials bearing neuraminidase-resistant C-glycosides of sialic acid strongly inhibit the in vitro infectivity of influenza virus. J Med Chem. 1992;35:4501–2.
Lees WJ, Spaltenstein A, Kingery-Wood JE, Whitesides GM. Polyacrylamides bearing pendant α-sialoside groups strongly inhibit agglutination of erythrocytes by influenza A virus: multivalency and steric stabilization of particulate biological systems. J Med Chem. 1994;37:3419–33.
Mammen M, Dahmann G, Whitesides GM. Effective inhibitors of hemagglutination by influenza virus synthesized from polymers having active ester groups. Insight into mechanism of inhibition. J Med Chem. 1995;38:4179–90.
Honda T, Yoshida S, Arai M, Masuda T, Yamashita M. Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-NeuAc2en derivatives. Bioorg Med Chem Lett. 2002;12:1929–32.
Masuda T, Yoshida S, Ara M, Kaneko S, Yamashita M, Honda T. Synthesis and anti-influenza evaluation of polyvalent sialidase inhibitors bearing 4-guanidino-Neu5Ac2en derivatives. Chem Pharm Bull. 2003;51:1386–98.
Byramova NE, Mochalova LV, Belyanchikov IM, Matrosovich MN, Bovin NV. Synthesis of sialic acid pseudopolysaccharides by coupling of spacer-connected Neu5Ac with activated polymer. J Carbohydr Chem. 1991;10:691–700.
Chandler M, Bamford MJ, Conroy R, Lamont B, Patel B, Patel VK, et al. Synthesis of the potent influenza neuraminidase inhibitor 4-guanidino-Neu5Ac2en. X-ray molecular structure of 5-acetamido-4-amino-2,6-anhydro-3,4,5-trideoxy-D-erythro-L-guco-nononic acid. J Chem Soc Perkin Trans. 1995;1:1173–80.
Andrews DM, Cherry PC, Humber DC, Jones PS, Keeling SP, Martin PF, et al. Synthesis and influenza virus sialidase inhibitory activity of analogues of 4-guanidino-NeuAc2en (Zanamivir) modified in the glycerol side-chain. Eur J Med Chem. 1999;34:563–74.
Herlocher ML, Truscon R, Elias S, Yen H-L, Roberts NA, Ohmit SE, et al. Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets. J Infect Dis. 2004;190:1627–30.
Yen H-L, Herlocher LM, Hoffmann E, Matrosovich MN, Monto AS, Webster RG, et al. Neuraminidase inhibitor-resistant influenza viruses may differ substantially in fitness and transmissibility. Antimicrob Agents Chemother. 2005;49:4075–84.
Hayden FG, Vote KM, Gordon DR Jr. Plaque inhibition assay for drug susceptibility testing of influenza viruses. Antimicrob Agents Chemother. 1980;17:865–70.
Dowdle WR. Influenza pandemic periodicity, virus recycling, and the art of risk assessment. Emerg Infect Dis. 2006;12:34–9.
ACKNOWLEDGMENTS
This work was financially supported by NIH grant U01-AI074443. L.A.d.C. is grateful to Fundacion Ramon Areces of Spain for a postdoctoral fellowship.
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Haldar, J., Álvarez de Cienfuegos, L., Tumpey, T.M. et al. Bifunctional Polymeric Inhibitors of Human Influenza A Viruses. Pharm Res 27, 259–263 (2010). https://doi.org/10.1007/s11095-009-0013-1
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DOI: https://doi.org/10.1007/s11095-009-0013-1