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: Teruhiko Matsubara, Ai Onishi, Daisuke Yamaguchi, Toshinori Sato
• Journal: Bioorganic & medicinal chemistry (Bioorg Med Chem) Vol. 24 Issue 5 Pg. 1106-14 (Mar 01 2016) ISSN: 1464-3391 [Electronic] England
• PMID: 26833245 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Antiviral Agents
• Hemagglutinin Glycoproteins, Influenza Virus
• Oligopeptides
• Peptide Library
• N-Acetylneuraminic Acid

Topics

• Animals
• Antiviral Agents (chemistry, metabolism, pharmacology)
• Cell Line
• Dogs
• Hemagglutinin Glycoproteins, Influenza Virus (metabolism)
• Humans
• Influenza A virus (drug effects, physiology)
• Influenza, Human (metabolism, prevention & control)
• Molecular Docking Simulation
• Mutagenesis, Site-Directed
• N-Acetylneuraminic Acid (analogs & derivatives, pharmacology)
• Oligopeptides (chemistry, genetics, pharmacology)
• Orthomyxoviridae Infections (metabolism, prevention & control)
• Peptide Library