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
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
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DOI：
10.1074/jbc.m503645200
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发表时间：
2005-09-16
影响因子：
4.8
通讯作者：
Bergström, T
中科院分区：
文献类型：
--
作者：
Bergefall, K;Trybala, E;Bergström, T
尽管细胞表面硫酸软骨素(CS)被认为是单纯疱疹病毒与细胞结合的辅助受体，纯化的CS链A、B和C型对细胞的病毒感染干扰很弱或根本不干扰，但我们发现来源于鱿鱼软骨的CS E型(CS-E)具有很强的抗病毒活性。IC50值从0.06到0.2微克/毫升，大大超过肝素的抗病毒效力，肝素是已知的病毒与细胞结合的抑制剂。此外，在表达CS但不表达硫酸乙酰肝素的突变的gro2C细胞中，CS-E表现出异常高的抗疱疹病毒活性，其IC50值为1 ng/ml。CS-E被软骨素酶ABC酶降解后，其抗病毒活性消失。CS-E可抑制纯化的病毒附着蛋白GC与细胞的结合。GC与固定化CS-E之间存在直接相互作用，并且CS-E寡糖片段比八糖更能抑制这一结合。同样，gro2C特异的CS链干扰了病毒GC与这些细胞的结合，并发现相当大比例(13%)的E-二糖单位，这表明该单位是Gro2C细胞上单纯疱疹病毒CS受体的重要组成部分，CS-E的抗病毒活性是由于干扰了病毒GC与细胞表面类似CS-E受体的结合。了解CS-E抗病毒特性的决定因素将有助于开发人类单纯疱疹病毒感染的抑制剂。
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 mu g/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.