The Cholestanol-Conjugated Sulfated Oligosaccharide PG545 Disrupts the Lipid Envelope of Herpes Simplex Virus Particles
The Cholestanol-Conjugated Sulfated Oligosaccharide PG545 Disrupts the Lipid Envelope of Herpes Simplex Virus Particles
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DOI：
10.1128/aac.02132-15
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发表时间：
2016-02-01
影响因子：
4.9
通讯作者：
Bergstrom, Tomas
中科院分区：
文献类型：
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作者：
Said, Joanna S.;Trybala, Edward;Bergstrom, Tomas
单纯疱疹病毒（HSV）和许多其它病毒（包括HIV）通过与细胞表面蛋白聚糖的糖胺聚糖（GAG）链结合来启动宿主细胞的感染。虽然GAG模拟物，如硫酸寡糖和多糖，在培养的细胞中表现出有效的抗病毒活性，这些抑制剂作为阴道杀微生物剂的预防性应用未能保护暴露于HIV的妇女。这种失败的一个可能的解释是，硫酸寡糖和多糖没有表现出典型的杀病毒活性，因为它们与病毒颗粒的相互作用在很大程度上是静电和可逆的，从而容易与生殖道的GAG结合蛋白竞争。在这里，我们报告说，胆甾烷醇结合的硫酸寡糖PG 545，而不是其他几个缺乏这种修饰的硫酸寡糖，表现出的HSV-2颗粒的脂质包膜破坏的杀病毒活性。PG 545的病毒颗粒破坏活性的重要性也在实验动物中得到证实，因为与未修饰的硫酸化寡糖相比，该化合物可保护小鼠免受HSV-2的生殖器感染。因此，PG 545提供了一种新的预防选择，以防止由GAG结合病毒引起的感染。
Herpes simplex virus (HSV) and many other viruses, including HIV, initiate infection of host cells by binding to glycosaminoglycan (GAG) chains of cell surface proteoglycans. Although GAG mimetics, such as sulfated oligo-and polysaccharides, exhibit potent antiviral activities in cultured cells, the prophylactic application of these inhibitors as vaginal microbicides failed to protect women upon their exposure to HIV. A possible explanation for this failure is that sulfated oligo- and polysaccharides exhibit no typical virucidal activity, as their interaction with viral particles is largely electrostatic and reversible and thereby vulnerable to competition with GAG-binding proteins of the genital tract. Here we report that the cholestanol-conjugated sulfated oligosaccharide PG545, but not several other sulfated oligosaccharides lacking this modification, exhibited virucidal activity manifested as disruption of the lipid envelope of HSV-2 particles. The significance of the virus particle-disrupting activity of PG545 was also demonstrated in experimental animals, as this compound, in contrast to unmodified sulfated oligosaccharide, protected mice against genital infection with HSV-2. Thus, PG545 offers a novel prophylaxis option against infections caused by GAG-binding viruses.