NIH Director's Pioneer Award

负责RNA病毒的RNA依赖性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， 突变的可能性，可以赋予任何抗病毒药物的耐药性。通常，唯一的 提出的解决方案是多药治疗，选择宿主编码的靶点，或选择药物 靶向使得抗性病毒被预测为仅显示有限适应性;后一种选择具有 由于可以探索的序列空间量很大， 这些高度可变的基因组。 我的实验室花了相当多的时间来了解 正链RNA病毒。最近，我们巩固了这项研究，表明，对于 脊髓灰质炎病毒，可以选择药物靶点，使药物敏感基因组主要抑制 抗药性基因组的产物相对不适合的病毒抑制生长的能力 适应性增强的病毒的主要来源于正链RNA的细胞内扩增 病毒基因组，它们翻译成大的多聚蛋白和更高阶的寡聚化， 一些蛋白质产品。在这里，我建议用这种理解来识别？主导 药物靶点？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类比并通过直接 遗传学和生物化学研究。这一新模式将促进 降低了不可避免的耐药性细菌生长的危险 基因组我的论文是，从理论和实验上理解不寻常的遗传学， 细胞内病毒的生长可以导致识别？阿基里斯？高跟鞋？对于每个靶向阳性支架， RNA病毒，也可能是其他细胞内病原体。

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.