Anti-coxsackieviral efficacy of RNA interference is highly dependent on genomic target selection and emergence of escape mutants.
Anti-coxsackieviral efficacy of RNA interference is highly dependent on genomic target selection and emergence of escape mutants.
复制标题
RNA干扰的抗柯萨奇病毒功效高度依赖于基因组靶标的选择和逃逸突变体的出现。
DOI：
10.1089/oli.2007.0057
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
R. Wessely
中科院分区：
文献类型：
--
作者：
S. Merl;R. Wessely
肠道病毒疾病广泛存在，在医学上具有重要意义。虽然与肠道病毒相关的疾病如心肌炎、胰腺炎、肝炎或脑脊髓炎的结局可能是致命的，但目前还没有特异性的抗病毒治疗。我们和其他人已经表明，RNA干扰（RNAi）有效地限制了小核糖核酸病毒的复制和致细胞病变性，并提高了易感小鼠的存活率。然而，关于短干扰RNA（siRNA）功效对靶区域选择的依赖性和可能限制RNAi效果的病毒逃逸突变体的出现知之甚少。我们的研究结果表明，抗病毒siRNA应优先靶向非结构蛋白编码区，因为siRNA的功效一直被发现是优于非编码或结构蛋白编码区相比，上级。此外，在siRNA结合基序的中心部分具有单点突变的病毒逃逸突变体的出现是限制早期治疗性siRNA功效的主要因素。病毒逃逸突变体的出现可以通过组合施用至少三种不同的siRNA分子来充分抑制。因此，基因组靶标选择和病毒逃逸突变体是限制针对肠道病毒基因组的早期RNAi的最关键因素。这两个障碍都可以通过适当的靶标选择和组合的siRNA施用来规避。
Enteroviral diseases are widespread and impose significant importance in medicine. Although the outcome of diseases that are associated with enteroviruses such as myocarditis, pancreatitis, hepatitis, or encephalomyelitis might be fatal, no specific antiviral therapy is yet available. We and others have shown that RNA interference (RNAi) effectively limits picornaviral replication and cytopathogenicity and improves survival in susceptible mice. However, little is known about the dependence of short interfering RNA (siRNA) efficacy on target region selection and emergence of viral escape mutants that may limit the effect of RNAi. The results of our study indicate that antiviral siRNA should be targeted preferentially to nonstructural protein coding regions because siRNA efficacy was consistently found to be superior compared to noncoding or structural protein coding regions. Further more, emergence of viral escape mutants that harbor single point mutations in the central part of the siRNA binding motif are the major factor that limits early therapeutic siRNA efficacy. The appearance of viral escape mutants can be sufficiently suppressed by combined administration of at least three distinct siRNA molecules. Therefore, genomic target selection and viral escape mutants are the most critical factors that limit early RNAi directed against enteroviral genomes. Both obstacles can be circumvented by appropriate target selection and combined siRNA administration.
影响因子：
4.4
作者：
C. Zaragoza;C. J. Ocampo;M. Saura;C. Bao;M. Leppo;A. Lafond-Walker;D. Thiemann;R. Hruban;C. Lowenstein
通讯作者：
C. Zaragoza;C. J. Ocampo;M. Saura;C. Bao;M. Leppo;A. Lafond-Walker;D. Thiemann;R. Hruban;C. Lowenstein
影响因子：
6
作者：
Feuer, R;Mena, I;Whitton, JL
通讯作者：
Whitton, JL
心肌中复制限制性肠道病毒基因组的转基因表达可诱导缺陷性兴奋-收缩耦合和扩张型心肌病。
DOI：
10.1172/jci1972
发表时间：
1998
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Wessely,R;Klingel,K;Santana,LF;Dalton,N;Hongo,M;JonathanLederer,W;Kandolf,R;Knowlton,KU
通讯作者：
Knowlton,KU