Influenza viruses, a class of single-stranded RNA virus, continue to cause serious respiratory disease throughout the world. Type A influenza virus causes pneumonia and deaths, especially in the elderly. Type B influenza viruses tend to infect a younger population than does Type A and are associated with Reye's syndrome. With antigenic drift, Type B influenza viruses are capable of producing disease in people of all ages. The only effective antiviral drugs for influenza are amantadine and its close relative rimantadine. Although these drugs can be quite effective against influenza, they are useful only against disease caused by Type A influenza virus and are not well-tolerated in the elderly group at highest risk of morbidity and mortality. Considerable morbidity and mortality also occur with Type B influenza. Recently, virus strains resistant to amantadine have been identified. Use of other reagents (e.g., ribavirin and interferon) is limited by dose-related side effects. Hence, there is a great need of new antiviral drugs for influenza. The long-term goal of the proposed project is to develop a broad-spectrum antiviral agent against influenza that can inhibit the replication of both influenza A and B viruses. The approach is based on the virus transcription inhibitory properties of influenza matrix protein (M1).A synthetic 19- residue peptide fragment (Peptide 6) of M1 has been identified which inhibits influenza RNA polymerase leading to inhibition of viral transcription (IC50=0.5nM). Recently, the applicant demonstrated that Peptide 6 inhibits cytopathic effect (CPE) of influenza virus on MDCK cell monolayers. This peptide has a great potential as an antiviral agent for influenza. A patent application entitled """"""""M-Protein Peptides of Influenza Virus As Antiviral Agents"""""""" was filed on June 19, 1991. The goal during Phase I is to conduct feasibility studies on Peptide 6 for its in vivo influenza virus inhibitory effect. Additionally, a determination will be made whether it is feasible to shorten the length of Peptide 6 and to determine the minimum sequence required for in vitro CPE inhibitory effect. Phase II studies will involve the synthesis of a metabolically stable peptide. The candidate peptide will be tested against different strains of type A and type B influenza viruses. Tests will also be done to test the effect of the peptide on normal cellular functions. Pharmacokinetics, cell penetration, and toxicological studies will be conducted. An inhalation delivery device will be developed.
