Chondroitin sulfate characterized by the E-disaccharide unit is a potent inhibitor of herpes simplex virus infectivity and provides the virus binding sites on gro2C cells.
Although cell surface chondroitin sulfate (CS) is regarded as an auxiliary receptor for binding of herpes simplex virus to cells, and purified CS chain types A, B, and C are known to interfere poorly or not at all with the virus infection of cells, we have found that CS type E (CS-E), derived from squid cartilage, exhibited potent antiviral activity. The IC(50) values ranged from 0.06 to 0.2 mug/ml and substantially exceeded the antiviral potency of heparin, the known inhibitor of virus binding to cells. Furthermore, in mutant gro2C cells that express CS but not heparan sulfate, CS-E showed unusually high anti-herpes virus activity with IC(50) values of <1 ng/ml. Enzymatic degradation of CS-E with chondroitinase ABC abolished its antiviral activity. CS-E inhibited the binding to cells of the purified virus attachment protein gC. A direct interaction of gC with immobilized CS-E and inhibition of this binding by CS-E oligosaccharide fragments greater than octasaccharide were demonstrated. Likewise, the gro2C-specific CS chains interfered with the binding of viral gC to these cells and were found to contain a considerable proportion (13%) of the E-disaccharide unit, suggesting that this unit is an essential component of the CS receptor for herpes simplex virus on gro2C cells and that the antiviral activity of CS-E was due to interference with the binding of viral gC to a CS-E-like receptor on the cell surface. Knowledge of the determinants of antiviral properties of CS-E will help in the development of inhibitors of herpes simplex virus infections in humans.
Bergefall
Kicki
K
Department of Clinical Virology, Göteborg University, Sweden.
Trybala
Edward
E
Johansson
Maria
M
Uyama
Toru
T
Naito
Satomi
S
Yamada
Shuhei
S
Kitagawa
Hiroshi
H
Sugahara
Kazuyuki
K
Bergström
Tomas
T
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001665:Binding Sites; D002356:Cartilage / Q000378:metabolism; D002522:Chlorocebus aethiops; D019765:Chondroitin ABC Lyase / Q000737:chemistry; D002809:Chondroitin Sulfates / Q000737:chemistry*; D049832:Decapodiformes; D004187:Disaccharides / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D006497:Heparan Sulfate / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D051379:Mice; D009844:Oligosaccharides / Q000737:chemistry; D011485:Protein Binding; D018139:Simplexvirus / Q000378:metabolism*
D000998:Antiviral Agents; D019765:Chondroitin ABC Lyase; D002809:Chondroitin Sulfates; D004187:Disaccharides; D006497:Heparan Sulfate; D008024:Ligands; D009844:Oligosaccharides