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J. Biol. Chem., Vol. 280, Issue 37, 32193-32199, September 16, 2005

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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^*

Kicki Bergefall, Edward Trybala, Maria Johansson, Toru Uyama1, Satomi Naito, Shuhei Yamada, Hiroshi Kitagawa, Kazuyuki Sugahara, and Tomas Bergström2

From the Department of Clinical Virology, Göteborg University, Guldhedsgatan 10B, S-413 46 Göteborg, Sweden and the Department of Biochemistry, Kobe Pharmaceutical University, Higashinada-ku, Kobe 658-8558, Japan

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 IC₅₀ values ranged from 0.06 to 0.2 µg/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 IC₅₀ 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.

Received for publication, April 4, 2005 , and in revised form, July 11, 2005.

^* This work was supported in part by grants from the Mizutani Foundation for Glycoscience, the Swedish Research Council, the Sahlgren's University Hospital Läkarutbildningsavtal, the Scandinavian Society for Antimicrobial Chemotherapy, and Grant-in-aid for Scientific Research-B 16390026 from the Ministry of Education, Culture, Sports, Science and Technology, the Core Research for Evolutional Science and Technology, and the Science and Technology Agency of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Japan Society for the Promotion of Science fellowship.

² To whom correspondence should be addressed. Tel.: 46-31-3424735; Fax: 46-31-827032; E-mail: tomas.bergstrom{at}microbio.gu.se.

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