N-acetyl-alpha-neuraminyl-(2--3)-beta-D-galactosyl-(1--4)-beta-D-glucose and Orthomyxoviridae-Infections

The initial attachment of influenza virus to cells is the binding of hemagglutinin (HA) to the sialyloligosaccharide receptor; therefore, the small molecules that inhibit the sugar-protein interaction are promising as HA inhibitors to prevent the infection. We herein demonstrate that sialic acid-mimic heptapeptides are identified through a selection from a primary library against influenza virus HA. In order to obtain lead peptides, an affinity selection from a phage-displayed random heptapeptide library was performed with the HAs of the H1 and H3 strains, and two kinds of the HA-binding peptides were identified. The binding of the peptides to HAs was inhibited in the presence of sialic acid, and plaque assays indicated that the corresponding N-stearoyl peptide strongly inhibited infections by the A/Aichi/2/68 (H3N2) strain of the virus. Alanine scanning of the peptides indicated that arginine and proline were responsible for binding. The affinities of several mutant peptides with single-amino-acid substitutions against H3 HA were determined, and corresponding docking studies were performed. A Spearman analysis revealed a correlation between the affinity of the peptides and the docking study. These results provide a practicable method to design of peptide-based HA inhibitors that are promising as anti-influenza drugs.

Topics: Animals; Antiviral Agents; Cell Line; Dogs; Hemagglutinin Glycoproteins, Influenza Virus; Humans; Influenza A virus; Influenza, Human; Molecular Docking Simulation; Mutagenesis, Site-Directed; N-Acetylneuraminic Acid; Oligopeptides; Orthomyxoviridae Infections; Peptide Library