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Novel Carbohydrate-Based Inhibitors That Target Influenza A Virus Sialidase

  • Mark von Itzstein
Conference paper

Abstract

Influenza virus continues to cause significant morbidity and mortality despite the fact that both anti-influenza viral drugs and vaccines to the current circulating strains are available [1, 2]. In terms of anti-influenza drug development, the surface-oriented viral enzyme sialidase (neuraminidase, NA), which plays a major role in the virus life cycle by facilitating release of virus progeny from the infected cell [3], has proven a successful target for the development of clinically useful drugs [4, 5]. Potent and selective inhibitors of the viral sialidase, such as zanamivir (1, Relenza) and oseltamivir carboxylate (OC, 2; the active form of oseltamivir 3, Tamiflu), the two widely used anti-influenza drugs, efficiently block viral sialidase activity resulting in virus progeny remaining clumped at the infected cell’s surface [6] and, consequently, limitation of the spread of infection. The phenomenon of resistance development to drugs-in-use, however, is a continuing issue [7], and applies to both zanamivir and oseltamivir. Oseltamivir, the most used anti-influenza drug, has suffered significant loss of efficacy as a result of drug resistance during the past 4 years [7].

Keywords

Virus Progeny Virus Life Cycle Virus Group Oseltamivir Carboxylate Sialidase Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Moscona A (2005) Neuraminidase inhibitors for influenza. N Engl J Med 353:1363–1373CrossRefPubMedGoogle Scholar
  2. 2.
    Hayden F (2009) Developing new antiviral agents for influenza treatment: what does the future hold? Clin Infect Dis 48:S3–S13CrossRefPubMedGoogle Scholar
  3. 3.
    Wagner R, Matrosovich M, Klenk H-D (2002) Functional balance between haemagglutinin and neuraminidase in influenza virus infections. Rev Med Virol 12:159–166CrossRefPubMedGoogle Scholar
  4. 4.
    De Clercq E (2006) Antiviral agents active against influenza A viruses. Nat Rev Drug Discov 5:1015–1025CrossRefPubMedGoogle Scholar
  5. 5.
    von Itzstein M (2007) The war against influenza: discovery and development of sialidase inhibitors. Nat Rev Drug Discov 6:967–974CrossRefGoogle Scholar
  6. 6.
    Gubareva LV, Kaiser L, Hayden FG (2000) Influenza virus neuraminidase inhibitors. Lancet 355:827–835CrossRefPubMedGoogle Scholar
  7. 7.
    Okomo-Adhiambo M, Nguyen HT, Sleeman K, Sheu TG, Deyde VM et al (2010) Host cell selection of influenza neuraminidase variants: implications for drug resistance monitoring in A(H1N1) viruses. Antiviral Res 85:381–388CrossRefPubMedGoogle Scholar
  8. 8.
    Russell RJ, Haire LF, Stevens DJ, Collins PJ, Lin YP, Blackburn GM, Hay AJ, Gamblin SJ, Skehel JJ (2006) The structure of H5N1 avian influenza neuraminidase suggests new opportunities for drug design. Nature (Lond) 443:45–49CrossRefGoogle Scholar
  9. 9.
    Amaro RE, Minh DDL, Cheng LS, Lindstrom WM Jr, Olson AJ, Lin J-H, Li WW, McCammon JA (2007) Remarkable loop flexibility in avian influenza N1 and its implications for antiviral drug design. J Am Chem Soc 129:7764–7765CrossRefPubMedGoogle Scholar
  10. 10.
    Dyason JC, von Itzstein M (2012) Influenza virus sialidase and structure-based drug design. In: von Itzstein M (ed) Influenza virus sialidase: a drug discovery target. Springer, Basel, pp 67–75CrossRefGoogle Scholar
  11. 11.
    Wen W-H, Wang S-Y, Tsai K-C, Cheng Y-SE, Yang A-S, Fang J-M, Wong C-H (2010) Analogs of zanamivir with modified C4-substituents as the inhibitors against the group-1 neuraminidases of influenza viruses. Bioorg Med Chem 18:4074–4084CrossRefPubMedGoogle Scholar
  12. 12.
    Rudrawar S, Dyason JC, Rameix-Welti MA, Rose FJ, Kerry PS et al (2010) Novel sialic acid derivatives lock open the 150-loop of an influenza A virus group-1 sialidase. Nat Commun 1:113CrossRefPubMedGoogle Scholar
  13. 13.
    Mohan S, McAtamney S, Haselhorst T, von Itzstein M, Pinto BM (2010) Carbocycles related to oseltamivir as influenza virus group-1-specific neuraminidase inhibitors. Binding to N1 enzymes in the context of virus-like particles. J Med Chem 53:7377–7391CrossRefPubMedGoogle Scholar
  14. 14.
    Holzer CT, von Itzstein M, Jin B, Pegg MS, Stewart WP, Wu WY (1993) Inhibition of sialidases from viral, bacterial and mammalian sources by analogues of 2-deoxy-2,3-didehydro-N-acetylneuraminic acid modified at the C-4 position. Glycoconj J 10:40–44CrossRefPubMedGoogle Scholar
  15. 15.
    Okamoto K, Kondo T, Goto T (1987) Synthetic studies on gangliosides. 2. Functionalization of 2-deoxy-2,3-dehydro-N-acetylneuraminic acid methyl ester. Bull Chem Soc Jpn 60:631–636CrossRefGoogle Scholar
  16. 16.
    Paulsen H, Matschulat P (1991) Synthese von C-Glycosiden der N-Acetylneuraminsäure und weiteren Derivaten. Liebigs Ann Chem 5:487–495CrossRefGoogle Scholar
  17. 17.
    Nolan SP, Clavier H (2010) Chemoselective olefin metathesis transformations mediated by ruthenium complexes. Chem Soc Rev 39:3305–3316CrossRefPubMedGoogle Scholar
  18. 18.
    Scholl M, Ding S, Lee CW, Grubbs RH (1999) Synthesis and activity of a new generation of ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ligands. Org Lett 1:953–956CrossRefPubMedGoogle Scholar
  19. 19.
    Rameix-Welti MA, Agou F, Buchy P, Mardy S, Aubin JT, Véron M, van der Werf S, Naffakh N (2006) Natural variation can significantly alter the sensitivity of influenza A (H5N1) viruses to oseltamivir. Antimicrob Agents Chemother 50:3809–3815CrossRefPubMedGoogle Scholar
  20. 20.
    Hartshorn MJ (2002) AstexViewer: a visualisation aid for structure-based drug design. J Comput Aided Mol Des 16:871–881CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2012

Authors and Affiliations

  1. 1.Institute for GlycomicsGriffith UniversitySouthportAustralia

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