Stein David A
Department of Microbiology, Oregon State University, Corvallis, OR 97331, USA.
Curr Pharm Des. 2008;14(25):2619-34. doi: 10.2174/138161208786071290.
RNA virus infections cause immense human disease burdens globally, and few effective antiviral drugs are available for their treatment. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) are nuclease resistant and water-soluble single-stranded-DNA-analogues that can enter cells readily and act as steric-blocking antisense agents through stable duplex formation with complementary RNA. Recently there have been a number of publications documenting sequence-specific and dose-dependent inhibition of non-retroviral RNA virus infections by PPMO in both cell culture and murine experimental systems. PPMO have suppressed viral titers by several orders of magnitude in cell cultures, and have reduced viral replication in and/or increased survivorship of mice experimentally infected with poliovirus, coxsackievirus B3, dengue virus, West Nile virus, Venezuelan Equine encephalitis virus, respiratory syncytial virus, Ebola virus and influenza A virus. Along with evaluating PPMO efficacy and toxicity, these studies also explored PPMO mechanism of action, pharmacologic properties and the generation and characterization of resistant virus. Effective PPMO target sites in viral RNA have included regions of highly conserved sequence thought to be important in the pre-initiation or initiation of translation, or in long-range RNA-RNA interactions involved in viral RNA synthesis. These studies provide guidance for the design of steric-blocking antisense agents against RNA viruses, insights into viral molecular biology and novel strategies for the development of antiviral therapeutics. The purpose of this review is to summarize notable findings from the reports documenting antiviral activity by PPMO, with a focus on the specific regions of viral RNA that provided the most effective targets for PPMO-based inhibition of viral replication.
RNA病毒感染在全球范围内给人类带来了巨大的疾病负担，而针对其治疗的有效抗病毒药物却很少。肽缀合的磷酰胺吗啉代寡聚物（PPMO）是核酸酶抗性且水溶性的单链DNA类似物，能够轻易进入细胞，并通过与互补RNA形成稳定的双链体，作为空间位阻反义剂发挥作用。最近有许多出版物记录了在细胞培养和小鼠实验系统中，PPMO对非逆转录RNA病毒感染的序列特异性和剂量依赖性抑制作用。在细胞培养中，PPMO已将病毒滴度降低了几个数量级，并且在实验感染脊髓灰质炎病毒、柯萨奇病毒B3、登革热病毒、西尼罗河病毒、委内瑞拉马脑炎病毒、呼吸道合胞病毒、埃博拉病毒和甲型流感病毒的小鼠中，减少了病毒复制和/或提高了存活率。除了评估PPMO的疗效和毒性外，这些研究还探讨了PPMO的作用机制、药理特性以及耐药病毒的产生和特性。病毒RNA中有效的PPMO靶位点包括高度保守的序列区域，这些区域被认为在翻译起始前或起始过程中，或在病毒RNA合成中涉及的长距离RNA-RNA相互作用中很重要。这些研究为设计针对RNA病毒的空间位阻反义剂提供了指导，深入了解了病毒分子生物学，并为抗病毒治疗的开发提供了新策略。本综述的目的是总结记录PPMO抗病毒活性的报告中的显著发现，重点关注病毒RNA的特定区域，这些区域为基于PPMO的病毒复制抑制提供了最有效的靶点。
