Garrison Aura R, Giomarelli Barbara G, Lear-Rooney Calli M, Saucedo Carrie J, Yellayi Srikanth, Krumpe Lauren R H, Rose Maura, Paragas Jason, Bray Mike, Olinger Gene G, McMahon James B, Huggins John, O'Keefe Barry R
Department of Viral Therapeutics, Virology Division, United States Army Medical Research Institute of Infectious Disease, Ft. Detrick, Frederick, MD 21702, United States.
Molecular Targets Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, United States.
Antiviral Res. 2014 Dec;112:1-7. doi: 10.1016/j.antiviral.2014.09.012. Epub 2014 Oct 5.
The cyanobacterial lectin scytovirin (SVN) binds with high affinity to mannose-rich oligosaccharides on the envelope glycoprotein (GP) of a number of viruses, blocking entry into target cells. In this study, we assessed the ability of SVN to bind to the envelope GP of Zaire Ebola virus (ZEBOV) and inhibit its replication. SVN interacted specifically with the protein's mucin-rich domain. In cell culture, it inhibited ZEBOV replication with a 50% virus-inhibitory concentration (EC50) of 50 nM, and was also active against the Angola strain of the related Marburg virus (MARV), with a similar EC50. Injected subcutaneously in mice, SVN reached a peak plasma level of 100 nm in 45 min, but was cleared within 4h. When ZEBOV-infected mice were given 30 mg/kg/day of SVN by subcutaneous injection every 6h, beginning the day before virus challenge, 9 of 10 animals survived the infection, while all infected, untreated mice died. When treatment was begun one hour or one day after challenge, 70-90% of mice survived. Quantitation of infectious virus and viral RNA in samples of serum, liver and spleen collected on days 2 and 5 postinfection showed a trend toward lower titers in treated than control mice, with a significant decrease in liver titers on day 2. Our findings provide further evidence of the potential of natural lectins as therapeutic agents for viral infections.
蓝藻凝集素scytovirin(SVN)能与多种病毒包膜糖蛋白(GP)上富含甘露糖的寡糖高亲和力结合,从而阻止病毒进入靶细胞。在本研究中,我们评估了SVN与扎伊尔埃博拉病毒(ZEBOV)包膜GP结合并抑制其复制的能力。SVN与该蛋白富含粘蛋白的结构域特异性相互作用。在细胞培养中,它能抑制ZEBOV复制,50%病毒抑制浓度(EC50)为50 nM,对相关的马尔堡病毒(MARV)安哥拉毒株也有活性,EC50相似。在小鼠皮下注射后,SVN在45分钟内血浆水平达到峰值100 nM,但在4小时内被清除。当在病毒攻击前一天开始,每6小时给ZEBOV感染的小鼠皮下注射30 mg/kg/天的SVN时,10只动物中有9只在感染中存活,而所有未治疗的感染小鼠均死亡。当在攻击后1小时或1天开始治疗时,70 - 90%的小鼠存活。对感染后第2天和第5天采集的血清、肝脏和脾脏样本中的感染性病毒和病毒RNA进行定量分析,结果显示,与对照小鼠相比,治疗组小鼠的病毒滴度有降低趋势,第2天肝脏中的病毒滴度显著下降。我们的研究结果进一步证明了天然凝集素作为病毒感染治疗药物的潜力。