Antisense Antiviral Agent for West Nile Infections

用于西尼罗河感染的反义抗病毒剂

• 批准号: 6934839
• 负责人: PATRICK L IVERSEN
• 金额: $ 36.47万
• 依托单位: AVI BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934839
• 关键词: RNA interference; West Nile virus; antisense nucleic acid; antiviral agents; arthropod borne communicable disease; drug design /synthesis /production; drug discovery /isolation; emerging infectious disease; encephalitis virus; genetic translation; microorganism disease chemotherapy; open reading frames; protein binding; protein structure; replicon; tissue /cell culture; virus genetics; virus load

DESCRIPTION (provided by applicant): AVI BioPharma has been developing an antisense phosphorodiamidate morpholino oligomer, AVI-4020 for the treatment of West Nile Virus. AVI-4020 has been shown both to reduce viral titer, and to cross the blood brain barrier. This compound targets the translation start site of the single open reading frame of WNV. Studies to date indicate AVI-4020 is a reasonable agent for continued clinical development. In order to continue development, more non-clinical studies involving improved understanding of mechanism of action, additional cell culture efficacy and more methodical animal model efficacy studies are necessary. It may be possible to identify an even more potent compound capable of 2 to 3 log greater reduction in viral titer. Hence, this grant is designed to test the feasibility of identification of a more potent agent by making direct comparisons to the existing AVI-4020 agent. If a more potent agent is identified then this will be evaluated to replace AVI-4020 in clinical trials to be proposed in the phase II grant. If no more potent agent is identified then AVI-4020 will have been more rigorously evaluated in non-clinical studies, as is necessary and AVI-4020 will be the agent proposed for clinical evaluation in the phase II grant application. The hypothesis of the study that antisense phosphorodiamidate morpholino oligomer (PMO) antisense agents designed to interfere with RNA-RNA duplex structures in the West Nile Virus (WNV) genome will be more potent the PMOs designed to interfere with initiation of translation of the only WNV ORF. Three specific aims are proposed: Aim 1: Use in vitro viral-reporter constructs to screen for additional viral sites for targeting to identify optimal PMO sequences. Aim 2: Evaluate several candidate PMO inhibitors against whole virus and against reporting replicon constructs in cell culture. Aim 3: Investigate cellular drug transport, protein binding, and physical characteristics, as well as establish a formulation for future animal pharmacokinetic and toxicology studies.

描述（由申请人提供）：AVI BioPharma一直在开发一种用于治疗西尼罗病毒的反义磷酸二酯morpholino低聚物AVI-4020。AVI-4020已被证明既能降低病毒滴度，又能穿过血脑屏障。该化合物靶向WNV单开放阅读框的翻译起始位点。迄今为止的研究表明，AVI-4020是一种合理的药物，可以继续进行临床开发。为了继续发展，需要更多的非临床研究，包括提高对作用机制的理解，额外的细胞培养功效和更有系统的动物模型功效研究。有可能鉴定出一种更有效的化合物，能够使病毒滴度降低2至3倍。因此，这项拨款的目的是通过与现有的AVI-4020药物进行直接比较，来测试识别更有效药物的可行性。如果一种更有效的药物被确定，那么它将被评估在临床试验中取代AVI-4020，并将在II期拨款中提出。如果没有发现更有效的药物，那么AVI-4020将在非临床研究中进行更严格的评估，这是必要的，AVI-4020将成为II期资助申请中临床评估的药物。该研究的假设是，设计用于干扰西尼罗病毒（WNV）基因组RNA-RNA双工结构的反义磷酸二酯morpholino oligomer （PMO）反义药物比设计用于干扰唯一的西尼罗病毒ORF翻译起始的PMO更有效。提出了三个具体目标：目标1：使用体外病毒报告基因构建体筛选额外的病毒位点，以确定最佳的PMO序列。目的2：评估几种候选PMO抑制剂对整个病毒和细胞培养中报道的复制子构建的抑制作用。目标3：研究细胞药物转运、蛋白质结合和物理特性，并为未来的动物药代动力学和毒理学研究建立一个配方。