Inhibition of alphavirus infection in cell culture and in mice with antisense morpholino oligomers
Inhibition of alphavirus infection in cell culture and in mice with antisense morpholino oligomers
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DOI：
10.1016/j.virol.2008.03.032
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发表时间：
2008-07-05
期刊：
影响因子：
3.7
通讯作者：
Zacks, Michele A.
中科院分区：
文献类型：
--
作者：
Paessler, Slobodan;Rijnbrand, Rene;Zacks, Michele A.
甲病毒属包含威胁人类健康的成员，既是天然病原体，也是潜在的生物武器。肽缀合的磷酰二胺吗啉代寡聚体（PPMO）容易进入细胞，并且可以通过病毒RNA的序列特异性空间阻断来抑制病毒复制。辛德毕斯病毒（SINV）在人类中具有低致病性，并且经常被用作模型甲病毒。靶向SINV基因组的5 '末端和AUG翻译起始位点区域的PPMO阻断了组织培养中感染性SINV的产生。针对委内瑞拉马脑炎病毒（VEEV）中的相应区域设计的PPMO同样被发现在体外对几种VEEV毒株有效。在VEEV感染之前和之后用PPMO处理的小鼠被完全保护免于致死结果，而仅接受感染后PPMO处理的小鼠被部分保护。组织样本中的病毒水平与动物存活率相关。未感染的小鼠没有明显的不良反应，从PPMO治疗。因此，PPMO似乎有希望作为针对甲病毒的治疗开发的候选物。(C)2008年爱思唯尔公司All rights reserved.
The genus Alphavirus contains members that threaten human health, both as natural pathogens and as potential biological weapons. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) enter cells readily and can inhibit viral replication through sequence-specific steric blockade of viral RNA. Sindbis virus (SINV) has low pathogenicity in humans and is regularly utilized as a model alphavirus. PPMO targeting the 5'-terminal and AUG translation start site regions of the SINV genome blocked the production of infectious SINV in tissue culture. PPMO designed against corresponding regions in Venezuelan equine encephalitis virus (VEEV) were likewise found to be effective in vitro against several strains of VEEV. Mice treated with PPMO before and after VEEV infection were completely protected from lethal outcome while mice receiving only post-infection PPMO treatment were partially protected. Levels of virus in tissue samples correlated with animal survival. Uninfected mice suffered no apparent ill-effects from PPMO treatment. Thus, PPMO appear promising as candidates for therapeutic development against alphaviruses. (C) 2008 Elsevier Inc. All rights reserved.