Inhibition of dengue virus translation and RNA synthesis by a morpholino oligomer targeted to the top of the terminal 3′ stem-loop structure
Inhibition of dengue virus translation and RNA synthesis by a morpholino oligomer targeted to the top of the terminal 3′ stem-loop structure
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DOI：
10.1016/j.virol.2005.08.034
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发表时间：
2006-01-20
期刊：
影响因子：
3.7
通讯作者：
Harris, E
中科院分区：
文献类型：
--
作者：
Holden, KL;Stein, DA;Harris, E
登革病毒（DEN）是全球一个主要的公共卫生问题，可引发一系列疾病，目前尚无抗病毒治疗方法。与登革病毒5'茎环（5'SL）和3'环化序列（3'CS）互补的肽偶联磷酰二胺吗啉代寡聚物（P - PMO）可抑制登革病毒复制，推测是通过阻断病毒翻译和/或RNA合成中涉及的关键RNA - RNA或RNA -蛋白质相互作用。在此，第三种与3'茎环顶部（3'SLT）互补的P - PMO可抑制登革病毒在BHK细胞中的复制。利用一种新型登革病毒2型报告基因复制子和一种登革病毒2型报告基因mRNA，我们确定5'SL P - PMO抑制病毒翻译，3'CS P - PMO阻断病毒RNA合成但不抑制病毒翻译，3'SLT P - PMO既抑制病毒翻译又抑制RNA合成。这些结果表明3'CS和3'SL结构域调控登革病毒的翻译和RNA合成，并进一步证明P - PMO作为抗病毒药物具有潜在用途。（C）2005爱思唯尔公司。保留所有权利。
Dengue virus (DEN) is a major public health problem worldwide and causes a spectrum of diseases, for which no antiviral treatments exist. Peptide-conjugated phosphorodiamidate morpholino oligomers (P-PMOs) complementary to the DEN 5' stem-loop (5'SL) and to the DEN 3' cyclization sequence (3'CS) inhibit DEN replication, presumably by blocking critical RNA-RNA or RNA-protein interactions involved in viral translation and/or RNA synthesis. Here, a third P-PMO, complementary to the top of the 3' stem-loop (3'SLT), inhibited DEN replication in BHK cells. Using a novel DEN2 reporter replicon and a DEN2 reporter mRNA, we determined that the 5'SL P-PMO inhibited viral translation, the 3'CS P-PMO blocked viral RNA synthesis but not viral translation, and the 3'SLT P-PMO inhibited both viral translation and RNA synthesis. These results show that the 3'CS and the 3'SL domains regulate DEN translation and RNA synthesis and further demonstrate that P-PMOs are potentially useful as antiviral agents. (C) 2005 Elsevier Inc. All rights reserved.