NIH Director's Pioneer Award

NIH 院长先锋奖

• 批准号: 7195852
• 负责人: Karla Kirkegaard
• 金额: $ 78.25万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-28 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195852
• 关键词: NIH Roadmap Initiative tag; RNA virus; capsid; complementary DNA; drug discovery /isolation; functional /structural genomics; gene targeting; inhibitor /antagonist; nucleic acid structure; replicase; site directed mutagenesis; transfection; virus genetics

The high error rate of the RNA-dependent RNA polymerases responsible for RNA viral genome replication presents an enormous challenge to successful drug therapy due to the high probability of mutations that can confer resistance to any antiviral pharmaceutical. Usually, the only solutions presented are multi-drug therapy, choosing a host-encoded target, or choosing the drug target such that resistant viruses are predicted to display only limited fitness; this latter option has not proved particularly successful due to the large amount of sequence space that can be explored by these highly mutable genomes. My laboratory has devoted considerable time to understanding the transmission genetics of positive-strand RNA viruses. Recently, we have consolidated this research to show that, for poliovirus, choices of drug target can be made so that drug-sensitive genomes dominantly inhibit the outgrowth of drug-resistant genomes. The ability of relatively unfit viruses to inhibit the growth of viruses with increased fitness derives from the intracellular amplification of positive-strand RNA viral genomes, their translation into large polyproteins and the higher-order oligomerization of several of their protein products. Here, I propose to use this understanding to identify ?dominant drug targets? for other positive-strand viruses such as rhinoviruses, coxsackieviruses, hepatitis C virus, Dengue virus and West Nile virus, informed by analogy with poliovirus and tested by direct genetic and biochemical investigation. This new paradigm will facilitate the development of therapeutics for which there is reduced danger of outgrowth of the inevitable drug-resistant genomes. My thesis is that theoretical and experimental understanding of the unusual genetics of intracellular viral growth can lead to the identification of ?Achilles? heels? for each targeted positivestand RNA virus, and possibly for other intracellular pathogens as well.

RNA病毒依赖的RNA聚合酶的高错误率 基因组复制对成功的药物治疗提出了巨大的挑战，因为 可能对任何抗病毒药物产生抗药性的突变的可能性。通常，唯一的 提供的解决方案是多种药物治疗，选择宿主编码的靶点，或选择药物 目标是使耐药病毒被预测为只显示有限的适应性；后一种选择具有 由于可以探索大量的序列空间，没有被证明是特别成功的 这些高度变异的基因组。 我的实验室花了相当多的时间来了解人类的传播遗传学。 正链RNA病毒。最近，我们合并了这项研究，以表明，对于 脊髓灰质炎病毒，药物靶点的选择可以使药物敏感的基因组主要抑制 抗药性基因组的副产物。相对不适合的病毒抑制生长的能力 适合度增加的病毒来自细胞内正链RNA的扩增 病毒基因组，它们翻译成大的多蛋白和高阶齐聚 他们的几种蛋白质产品。在这里，我建议用这种理解来识别？主导 毒品目标？对于其他正链病毒，如鼻病毒、柯萨奇病毒、丙型肝炎病毒 病毒、登革热病毒和西尼罗河病毒，通过与脊髓灰质炎病毒相似的方式获知，并通过直接检测 进行遗传和生化调查。这一新的模式将促进 减少不可避免的耐药性产生的危险的治疗 基因组。我的论文是从理论和实验上理解人的不寻常遗传学。 细胞内病毒生长可导致？阿喀琉斯？高跟鞋？对于每个目标位置和 RNA病毒，也可能是其他细胞内病原体的病原体。