Chemoenzymatic synthesis and application of glycopolymers containing multivalent sialyloligosaccharides with a poly(L-glutamic acid) backbone for inhibition of infection by influenza viruses.
Highly water-soluble glycopolymers with poly(alpha-L-glutamic acid) (PGA) backbones carrying multivalent sialyl oligosaccharides units were chemoenzymatically synthesized as polymeric inhibitors of infection by human influenza viruses. p-Aminophenyl disaccharide glycosides were coupled with gamma-carboxyl groups of PGA side chains and enzymatically converted to Neu5Acalpha2-3Galbeta1-4GlcNAcbeta-, Neu5Acalpha2-6Galbeta1-4GlcNAcbeta-, Neu5Acalpha2-3Galbeta1-3GalNAcalpha-, and Neu5Acalpha2-3Galbeta1-3GalNAcbeta- units, respectively, by alpha2,3- or alpha2,6-sialytransferases. The glycopolymers synthesized were used for neutralization of human influenza A and B virus infection as assessed by measurement of the degree of cytopathic inhibitory effect in virus-infected MDCK cells. Among the glycopolymers tested, alpha2,6-sialo-PGA with a high molecular weight (260 kDa) most significantly inhibited infection by an influenza A virus, strain A/Memphis/1/71 (H3N2), which predominantly binds to alpha2-6 Neu5Ac residue. The alpha2,6-sialo-PGA also inhibited infection by an influenza B virus, B/Lee/40. The binding preference of viruses to terminal sialic acids was affected by core determinants of the sugar chain, Galbeta1-4GlcNAcbeta- or Galbeta1-3GalNAcalpha/beta- units. Inhibition of infection by viruses was remarkably enhanced by increasing the molecular weight and sialic acid content of glycopolymers.
Totani
Kazuhide
K
Department of Applied Biological Chemistry, Shizuoka University, Ohya 836, Shizuoka 422-8529, Japan.
Kubota
Takeshi
T
Kuroda
Takao
T
Murata
Takeomi
T
Hidari
Kazuya I-P Jwa
KI
Suzuki
Takashi
T
Suzuki
Yasuo
Y
Kobayashi
Kazukiyo
K
Ashida
Hisashi
H
Yamamoto
Kenji
K
Usui
Taichi
T
D000818:Animals; D002240:Carbohydrate Sequence; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004285:Dogs; D007106:Immune Sera / Q000494:pharmacology; D009980:Influenza A virus / Q000187:drug effects / Q000502:physiology; D009981:Influenza B virus / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008969:Molecular Sequence Data; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology; D009976:Orthomyxoviridae Infections / Q000517:prevention & control*; D011099:Polyglutamic Acid / Q000737:chemistry*; D011134:Polysaccharides / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology; D012795:Sialoglycoproteins / Q000138:chemical synthesis* / Q000276:immunology; D013329:Structure-Activity Relationship
D007106:Immune Sera; D009844:Oligosaccharides; D011134:Polysaccharides; D012795:Sialoglycoproteins; C016735:sialooligosaccharides; D011099:Polyglutamic Acid