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In vivo anti-influenza virus activity of a zinc finger peptide
A K Judd1, A Sanchez, D J Bucher
1SynVax, Belmont, California 94002, USA.
Abstract:
Matrix protein (M1) is a major structural protein of influenza virus, and it inhibits its own polymerase. A 19-amino-acid peptide, corresponding to a zinc finger region of the M1 sequence of influenza virus strain A/PR/8/34 (H1N1), centered around amino acids 148 to 166, was synthesized. This peptide, designated peptide 6, represents a zinc finger which includes a 7-amino-acid loop or finger and a 4-amino-acid tail at the carboxyl terminus, in addition to the 8 amino acids involved in the coordination of Zn. Three experiments were run to evaluate the activity of peptide 6 on infections induced in mice by influenza A/PR/8/34 and A/Victoria/3/75 (H3N2) viruses. Intranasal (i.n.) treatment of the H1N1 virus infection with 30 or 60 mg/kg of body weight/day, three times daily for 5 days, beginning 4 h pre-or 8 h post-virus exposure, was effective in preventing death, reducing the arterial oxygen decline, and inhibiting lung consolidation. Virus titers in the lungs determined on day 5 were reduced by up to 1.5 log10 in treated groups, but considerable variation in the titers of the recovered virus was seen. The H3N2 virus infection was treated i.n. with 30, 60, or 120 mg of peptide 6/kg/day by using the above-mentioned delayed initiation treatment schedule, and similar protection was seen, although lung virus titers were not reduced in the day-5 assay. Peptide 6 was well tolerated at doses up to 60 mg/kg/day. This zinc finger peptide may provide a new class of antivirals effective against influenza virus.
Insights
A novel zinc finger peptide, peptide 6, effectively protected mice against influenza virus infections by reducing mortality and lung consolidation. This peptide shows promise as a new class of influenza antivirals.
Area of Science:
- Virology
- Biochemistry
- Drug Discovery
Background:
- Influenza virus matrix protein (M1) plays a role in viral replication and can inhibit its own polymerase.
- Zinc finger motifs are crucial for protein structure and function, including in viral proteins.
Purpose of the Study:
- To synthesize and evaluate a novel peptide derived from the M1 protein's zinc finger region for antiviral activity against influenza.
- To assess the efficacy and safety of this peptide in mouse models of influenza A virus infection.
Main Methods:
- A 19-amino acid peptide (peptide 6) representing the zinc finger region of influenza A/PR/8/34 (H1N1) M1 protein was synthesized.
- Peptide 6 was administered intranasally to mice infected with H1N1 or H3N2 influenza strains.
- Efficacy was measured by survival rates, arterial oxygen levels, lung consolidation, and viral titers.
Main Results:
- Intranasal peptide 6 treatment significantly reduced mortality and lung consolidation in mice infected with H1N1 and H3N2 influenza viruses.
- Viral titers in the lungs of H1N1-infected mice were reduced by up to 1.5 log10.
- Peptide 6 was well-tolerated at doses up to 60 mg/kg/day.
Conclusions:
- The synthesized zinc finger peptide (peptide 6) demonstrates significant antiviral activity against influenza A virus in a mouse model.
- Peptide 6 represents a potential new class of antiviral agents for treating influenza infections.
- Further research is warranted to explore the therapeutic potential of this peptide.