A novel family of peptides with potent activity against influenza A viruses.

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.

[1]  L. Flowers,et al.  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 Form1 , 2005, The Journal of Immunology.

[2]  D. Cooper,et al.  Peptide inhibitors of virus-cell fusion: enfuvirtide as a case study in clinical discovery and development. , 2004, The Lancet. Infectious diseases.

[3]  F. Chisari,et al.  A virocidal amphipathic α-helical peptide that inhibits hepatitis C virus infection in vitro , 2008, Proceedings of the National Academy of Sciences.

[4]  J. C. Jones,et al.  Inhibition of Vaccinia virus entry by a broad spectrum antiviral peptide. , 2009, Virology.

[5]  E. Turpin,et al.  Inhibition of Influenza Virus Infection by a Novel Antiviral Peptide That Targets Viral Attachment to Cells , 2006, Journal of Virology.

[6]  Xianghong Jing,et al.  Functional studies indicate amantadine binds to the pore of the influenza A virus M2 proton-selective ion channel , 2008, Proceedings of the National Academy of Sciences.

[7]  Ashish,et al.  Antiviral Peptides Targeting the West Nile Virus Envelope Protein , 2006, Journal of Virology.

[8]  B. Graham,et al.  Inhibition of respiratory syncytial virus by RhoA-derived peptides: implications for the development of improved antiviral agents targeting heparin-binding viruses. , 2004, The Journal of antimicrobial chemotherapy.

[9]  Vasiliy P. Mishin,et al.  In Vitro Antiviral Activity of Favipiravir (T-705) against Drug-Resistant Influenza and 2009 A(H1N1) Viruses , 2010, Antimicrobial Agents and Chemotherapy.

[10]  Fang Fang,et al.  Novel Pandemic Influenza A(H1N1) Viruses Are Potently Inhibited by DAS181, a Sialidase Fusion Protein , 2009, PloS one.

[11]  J. McCauley,et al.  Development of a Reverse Genetics System Enabling theRescue of Recombinant Avian Influenza Virus A/Turkey/England/50-92/91 (H5N1) , 2007, Avian diseases.

[12]  Michael Greenberg,et al.  Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes , 2004, Nature Reviews Drug Discovery.

[13]  Lilian W. Waiboci,et al.  SOCS-1 Mimetics Protect Mice against Lethal Poxvirus Infection: Identification of a Novel Endogenous Antiviral System , 2008, Journal of Virology.

[14]  Keiji Fukuda,et al.  Influenza-associated hospitalizations in the United States. , 2004, JAMA.