1887

Abstract

The emergence of drug-resistant strains of influenza virus has catalysed a search for new antiviral agents to supplement or replace existing drugs. Following the success of the human immunodeficiency virus entry blocker Enfuvirtide, there has been a resurgence of interest in peptide-based antivirals. In this paper, we report on the discovery of a novel family of peptides (FluPep, FP) that function as inhibitors of influenza A virus infection. The prototype peptide (FP1, also known as Tkip) interacts with haemagglutinin and inhibits the binding of the virus to cell membranes. Using a plaque-reduction assay, we have demonstrated that a variety of influenza A virus subtypes (including H1N1, H3N2 and H5N1) are inhibited by FluPep and its derivatives at nanomolar concentrations. By truncating FluPep we have identified a minimal sequence of 6 aa that binds to haemagglutinin and inhibits infection. Using a mouse model of intranasal influenza virus infection, we observed potent inhibition of virus infection when peptide is given at the time of virus administration. These data indicate that FluPep is a highly effective anti-influenza agent with the potential to translate to the clinic.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.038679-0
2012-05-01
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/93/5/980.html?itemId=/content/journal/jgv/10.1099/vir.0.038679-0&mimeType=html&fmt=ahah

References

  1. Ahmed C. M., Dabelic R., Waiboci L. W., Jager L. D., Heron L. L., Johnson H. M. 2009; SOCS-1 mimetics protect mice against lethal poxvirus infection: identification of a novel endogenous antiviral system. J Virol 83:1402–1415 [View Article][PubMed]
    [Google Scholar]
  2. Altmann S. E., Jones J. C., Schultz-Cherry S., Brandt C. R. 2009; Inhibition of vaccinia virus entry by a broad spectrum antiviral peptide. Virology 388:248–259 [View Article][PubMed]
    [Google Scholar]
  3. Bai F., Town T., Pradhan D., Cox J., Ashish, Ledizet M., Anderson J. F., Flavell R. A., Krueger J. K. other authors 2007; Antiviral peptides targeting the West Nile virus envelope protein. J Virol 81:2047–2055 [View Article][PubMed]
    [Google Scholar]
  4. Budge P. J., Graham B. S. 2004; Inhibition of respiratory syncytial virus by RhoA-derived peptides: implications for the development of improved antiviral agents targeting heparin-binding viruses. J Antimicrob Chemother 54:299–302 [View Article][PubMed]
    [Google Scholar]
  5. Cheng G., Montero A., Gastaminza P., Whitten-Bauer C., Wieland S. F., Isogawa M., Fredericksen B., Selvarajah S., Gallay P. A. other authors 2008; A virocidal amphipathic α-helical peptide that inhibits hepatitis C virus infection in vitro . Proc Natl Acad Sci U S A 105:3088–3093 [View Article][PubMed]
    [Google Scholar]
  6. Cooper D. A., Lange J. M. 2004; Peptide inhibitors of virus-cell fusion: enfuvirtide as a case study in clinical discovery and development. Lancet Infect Dis 4:426–436 [View Article][PubMed]
    [Google Scholar]
  7. Howard W., Hayman A., Lackenby A., Whiteley A., Londt B., Banks J., McCauley J., Barclay W. 2007; Development of a reverse genetics system enabling the rescue of recombinant avian influenza virus A/Turkey/England/50-92/91 (H5N1). Avian Dis 51:Suppl.393–395 [View Article][PubMed]
    [Google Scholar]
  8. Jing X., Ma C., Ohigashi Y., Oliveira F. A., Jardetzky T. S., Pinto L. H., Lamb R. A. 2008; Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel. Proc Natl Acad Sci U S A 105:10967–10972 [View Article][PubMed]
    [Google Scholar]
  9. Jones J. C., Turpin E. A., Bultmann H., Brandt C. R., Schultz-Cherry S. 2006; Inhibition of influenza virus infection by a novel antiviral peptide that targets viral attachment to cells. J Virol 80:11960–11967 [View Article][PubMed]
    [Google Scholar]
  10. Matthews T., Salgo M., Greenberg M., Chung J., DeMasi R., Bolognesi D. 2004; Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. Nat Rev Drug Discov 3:215–225 [View Article][PubMed]
    [Google Scholar]
  11. Mujtaba M. G., Flowers L. O., Patel C. B., Patel R. A., Haider M. I., Johnson H. M. 2005; Treatment of mice with the suppressor of cytokine signaling-1 mimetic peptide, tyrosine kinase inhibitor peptide, prevents development of the acute form of experimental allergic encephalomyelitis and induces stable remission in the chronic relapsing/remitting form. J Immunol 175:5077–5086[PubMed] [CrossRef]
    [Google Scholar]
  12. Sleeman K., Mishin V. P., Deyde V. M., Furuta Y., Klimov A. I., Gubareva L. V. 2010; In vitro antiviral activity of favipiravir (T-705) against drug-resistant influenza and 2009 A(H1N1) viruses. Antimicrob Agents Chemother 54:2517–2524 [View Article][PubMed]
    [Google Scholar]
  13. Thompson W. W., Shay D. K., Weintraub E., Brammer L., Bridges C. B., Cox N. J., Fukuda K. 2004; Influenza-associated hospitalizations in the United States. JAMA 292:1333–1340 [View Article][PubMed]
    [Google Scholar]
  14. Triana-Baltzer G. B., Gubareva L. V., Nicholls J. M., Pearce M. B., Mishin V. P., Belser J. A., Chen L. M., Chan R. W., Chan M. C. other authors 2009; Novel pandemic influenza A(H1N1) viruses are potently inhibited by DAS181, a sialidase fusion protein. PLoS ONE 4:e7788 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.038679-0
Loading
/content/journal/jgv/10.1099/vir.0.038679-0
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error