Glycobiology Advance Access originally published online on July 11, 2008
Glycobiology 2008 18(10):779-788; doi:10.1093/glycob/cwn067
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Chemoenzymatic synthesis, characterization, and application of glycopolymers carrying lactosamine repeats as entry inhibitors against influenza virus infection
3 Department of Biochemistry, University of Shizuoka, School of Pharmaceutical Sciences
4 Global COE Program for Innovation in Human Health Sciences, 52-1 Yada, Suruga-ku, Shizuoka City, Shizuoka 422-8526
5 Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, 836 Ohya, Suruga-ku, Shizuoka City, Shizuoka 422-8529
6 Department of Microbiology, Shizuoka Institute of Environment and Hygiene, 4-27-2 Kita-ando, Aoi-ku, Shizuoka City, Shziuoka 420-8637
7 Department of Biochemical Sciences, College of Life and Health Sciences, Chubu University, 1200 Matsumoto-cho, Kasugai City, Aichi 487-8501, Japan
1 To whom correspondence should be addressed: Tel: +81-54-264-5720; Fax: +81-54-264-5723; e-mail: hidari{at}u-shizuoka-ken.ac.jp
2 These authors contributed equally to this work.
Received on April 8, 2008; revised on June 17, 2008; accepted on July 9, 2008
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.
Key words: chemoenzymatic synthesis / entry inhibitor / glycopolymer / influenza virus / lactosamine repeat