title: Heptapeptide ligands against receptor-binding sites of influenza hemagglutinin toward anti-influenza therapy.
abstract: 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.
authors.affiliation: Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Matsubara
authors.affiliation: Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
authors.forename: Ai
authors.initials: A
authors.lastname: Onishi
authors.affiliation: Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Yamaguchi
authors.affiliation: Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama 223-8522, Japan. Electronic address: sato@bio.keio.ac.jp.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Sato
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004285:Dogs; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000378:metabolism*; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects* / Q000502:physiology; D007251:Influenza, Human / Q000378:metabolism / Q000517:prevention & control*; D062105:Molecular Docking Simulation; D016297:Mutagenesis, Site-Directed; D019158:N-Acetylneuraminic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009842:Oligopeptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D009976:Orthomyxoviridae Infections / Q000378:metabolism / Q000517:prevention & control; D019151:Peptide Library
chemical_list: D000998:Antiviral Agents; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D009842:Oligopeptides; D019151:Peptide Library; D019158:N-Acetylneuraminic Acid
keywords: Hemagglutinin; Heptapeptide library; Peptide drug; Phage display; Sialic acid-mimic