title: Chemoenzymatic synthesis, characterization, and application of glycopolymers carrying lactosamine repeats as entry inhibitors against influenza virus infection.
abstract: To control interspecies transmission of influenza viruses, it is essential to elucidate the molecular mechanisms of the interaction of influenza viruses with sialo-glycoconjugate receptors expressed on different host cells. Competitive inhibitors containing mimetic receptor carbohydrates that prevent virus entry may be useful tools to address such issues. We chemoenzymatically synthesized and characterized the glycopolymers that were carrying terminal 2,6-sialic acid on lactosamine repeats as influenza virus inhibitors. In vitro and in vivo infection experiments using these glycopolymers demonstrated marked differences in inhibitory activity against different species of viruses. Human viruses, including clinically isolated strains, were consistently inhibited by glycopolymers carrying lactosamine repeats with higher activity than those containing a single lactosamine. A swine virus also showed the same recognition properties as those from human hosts. In contrast, avian and equine viruses were not inhibited by any of the glycopolymers examined carrying single, tandem, or triplet lactosamine repeats. Hemagglutination inhibition and solid-phase binding analyses indicated that binding affinity of glycopolymers with influenza viruses contributes dominantly to the inhibitory activity against viral infection. Sequence analysis and molecular modeling of human viruses indicated that specific amino acid substitutions on hemagglutinin may affect binding affinity of glycopolymers carrying lactosamine repeats with viruses. In conclusion, glycopolymers carrying lactosamine repeats of different lengths are useful to define molecular mechanisms of virus recognition. The core carbohydrate portion as well as sialyl linkages on the receptor glycoconjugate may affect host cell recognition of human and swine viruses.
authors.affiliation: Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences, Shizuoka, Japan. hidari@u-shizuoka-ken.ac.jp
authors.forename: Kazuya I P J
authors.initials: KI
authors.lastname: Hidari
authors.forename: Takeomi
authors.initials: T
authors.lastname: Murata
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Yo-hei
authors.initials: YH
authors.lastname: Minamijima
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Miwa
authors.forename: Satoshi
authors.initials: S
authors.lastname: Adachi
authors.forename: Makoto
authors.initials: M
authors.lastname: Ogata
authors.forename: Taiichi
authors.initials: T
authors.lastname: Usui
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000606:Amino Sugars / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001704:Biopolymers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D050260:Carbohydrate Metabolism; D002241:Carbohydrates / Q000737:chemistry; D002460:Cell Line; D004285:Dogs; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007251:Influenza, Human / Q000188:drug therapy*; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000606:Amino Sugars; D000998:Antiviral Agents; D001704:Biopolymers; D002241:Carbohydrates; D019267:Hemagglutinin Glycoproteins, Influenza Virus; C032233:lactosamine