Lee Eva, Pavy Megan, Young Nicolie, Freeman Craig, Lobigs Mario
Division of Immunology and Genetics, John Curtin School of Medical Research, The Australian National University, P.O. Box 334, Canberra, ACT 2601, Australia.
Antiviral Res. 2006 Jan;69(1):31-8. doi: 10.1016/j.antiviral.2005.08.006. Epub 2005 Nov 10.
Many viruses, including flaviviruses, display affinity for cell surface heparan sulfate (HS) proteoglycans with biological relevance in virus attachment/entry. This raises the possibility of the application of HS mimetics in antiviral therapy. We have evaluated the antiviral effect of the sulfated polysaccharides, suramin, pentosan polysulfate (PPS) and PI-88, which are currently approved or in trial for clinical use, against dengue virus (DEN) and the encephalitic flaviviruses, Japanese encephalitis virus, West Nile virus, and Murray Valley encephalitis virus. A flow cytometry-based method for the measurement of inhibition of virus infectivity was developed, which showed the in vitro antiviral activity of the three compounds, albeit with differences in efficiency which were virus-dependent. The 50% effective concentration (EC(50)) values for DEN inhibition were in the order: PPS<suramin<PI-88, and for Japanese encephalitis virus, PPS<PI-88<or=suramin. Heparin inhibited the DEN infectivity 30-fold more efficiently than the best of the test compounds, which was not the case for encephalitic flaviviruses. The in vitro anti-flaviviral effectiveness of the HS mimetics did not reliably predict their in vivo therapeutic activity. In mouse models for DEN and flaviviral encephalitis, only PI-88 demonstrated a significant beneficial effect in disease outcome.
包括黄病毒在内的许多病毒，对细胞表面硫酸乙酰肝素（HS）蛋白聚糖具有亲和力，这在病毒附着/进入过程中具有生物学相关性。这增加了HS模拟物在抗病毒治疗中应用的可能性。我们评估了目前已获批准或正在进行临床试验的硫酸化多糖苏拉明、戊聚糖多硫酸盐（PPS）和PI-88对登革热病毒（DEN）以及脑炎黄病毒、日本脑炎病毒、西尼罗河病毒和墨累谷脑炎病毒的抗病毒效果。我们开发了一种基于流式细胞术的方法来测量病毒感染性的抑制情况，该方法显示了这三种化合物的体外抗病毒活性，尽管其效率存在差异，且这种差异因病毒而异。DEN抑制的50%有效浓度（EC50）值顺序为：PPS＜苏拉明＜PI-88，对于日本脑炎病毒，PPS＜PI-88≤苏拉明。肝素抑制DEN感染性的效率比最佳测试化合物高30倍，而对于脑炎黄病毒则并非如此。HS模拟物的体外抗黄病毒有效性并不能可靠地预测其体内治疗活性。在DEN和黄病毒脑炎的小鼠模型中，只有PI-88在疾病转归方面显示出显著的有益效果。
