Sialic acid-mimic peptides as hemagglutinin inhibitors for anti-influenza therapy

Teruhiko Matsubara; Ai Onishi; Tomomi Saito; Aki Shimada; Hiroki Inoue; Takao Taki; Kyosuke Nagata; Yoshio Okahata; Toshinori Sato

doi:10.1021/jm1002183

Sialic acid-mimic peptides as hemagglutinin inhibitors for anti-influenza therapy

J Med Chem. 2010 Jun 10;53(11):4441-9. doi: 10.1021/jm1002183.

Authors

Teruhiko Matsubara¹, Ai Onishi, Tomomi Saito, Aki Shimada, Hiroki Inoue, Takao Taki, Kyosuke Nagata, Yoshio Okahata, Toshinori Sato

Affiliation

¹ Department of Biosciences and Informatics, Keio University, Yokohama 223-8522, Japan.

PMID: 20476787
DOI: 10.1021/jm1002183

Abstract

Influenza is an infectious disease caused by the influenza virus, and each year many people suffer from this disease. Hemagglutinin (HA) in the membrane of type A influenza viruses recognizes sialylglycoconjugate receptors on the host cell surface at an initial step in the infection process; consequently, HA inhibitors are considered potential candidates for antiviral drugs. We identified peptides that bind to receptor-binding sites through a multiple serial selection from phage-displayed random peptide libraries. Using the HA of the H1 and H3 strains as target proteins, we obtained peptides that bind to both HAs. The binding affinities of peptides for these HAs were improved by secondary and tertiary selections from the corresponding sublibraries. A docking simulation suggested that, similar to sialic acid, the peptides are recognized by the receptor-binding site in HA, which indicates that these peptides mimic the sialic acid structure. N-stearoyl peptides inhibited infections by the A/Puerto Rico/8/34 (H1N1) and A/Aichi/2/68 (H3N2) strains of influenza virus. Such HA-inhibitors are promising candidates for novel antiviral drugs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Motifs
Amino Acid Sequence
Animals
Antiviral Agents / chemistry*
Antiviral Agents / metabolism
Antiviral Agents / pharmacology
Cell Line
Conserved Sequence
Dogs
Drug Evaluation, Preclinical
Hemagglutinin Glycoproteins, Influenza Virus / chemistry
Hemagglutinin Glycoproteins, Influenza Virus / metabolism*
Influenza A Virus, H1N1 Subtype / drug effects*
Influenza A Virus, H1N1 Subtype / metabolism
Influenza A Virus, H1N1 Subtype / physiology
Influenza A Virus, H3N2 Subtype / drug effects*
Influenza A Virus, H3N2 Subtype / metabolism
Influenza A Virus, H3N2 Subtype / physiology
Models, Molecular
Molecular Sequence Data
Mutagenesis
N-Acetylneuraminic Acid / chemistry*
Peptides / chemistry*
Peptides / genetics
Peptides / metabolism
Peptides / pharmacology*
Small Molecule Libraries / chemistry
Small Molecule Libraries / metabolism
Small Molecule Libraries / pharmacology
Virus Internalization / drug effects

Substances

Antiviral Agents
Hemagglutinin Glycoproteins, Influenza Virus
Peptides
Small Molecule Libraries
hemagglutinin, human influenza A virus
N-Acetylneuraminic Acid