Development of Inhibitors Targeting Flavivirus Methyltransferase

摘要： 黄病毒主要由昆虫传播，与全球发病率和死亡率有关，并在每一 有人居住的大陆。不幸的是，目前治疗与这些病毒相关的疾病的治疗方案 是有限的。所有黄病毒都编码N-7和2‘-O的甲基转移酶(MTase)-黄病毒NS5 病毒基因组RNA的甲基化。N-7 MTase功能对于病毒RNA基因组的复制是必不可少的， 而2‘-O MTase功能是病毒逃避宿主天然免疫反应所必需的。这些活动 在黄病毒中是保守的。对于此项目，我们的协作团队将优化当前的领导 化合物，执行高通量筛选(HTS)以确定其他候选铅，进行化学优化 领导候选人，并定义结构活动关系。用切割法优化现有的铅化合物 边缘药物化学，团队将使用创新的荧光进行大规模的HTS活动 化学探针，以确定附加的小分子抑制黄病毒RNA封端的金属硫代酶。我们会 利用体外生物化学、结构分析等手段，深入研究其作用模式和抗病毒效果 生物学、病毒学、体内药代动力学和体内动物模型，这将使新的， 针对这两种黄病毒的有效、广谱和类似药物的治疗剂。已取得初步进展 在鉴定这些MTase的初始铅抑制剂方面取得了进展，显示出低纳摩尔的抗病毒作用 活动。我们将推进这些化合物，以进一步开发有效的抗病毒化合物，同时进行大规模的 同时进行规模筛选，以发现更多的结构脚手架。我们之间的专业知识互补 调查人员将协同并加快这项研究的进展。我们的合作目标是提供 治疗或预防这些病毒感染的一流候选药物。

Abstract: Flaviviruses are primarily insect-borne, associated with global morbidity and mortality, and found on every inhabited continent. Unfortunately, current therapeutic options for treating diseases associated with these viruses are limited. All flaviviruses encode methyltransferases (MTases)—flaviviral NS5 for both N-7 and 2'-O methylations of viral genomic RNA. The N-7 MTase function is essential for replication of the viral RNA genome, whereas 2'-O MTase function is required for the virus to evade the host innate immune response. These activities are conserved among the flaviviruses. For this project, our collaborative team will optimize the current lead compounds, perform high throughput screening (HTS) to identify additional lead candidates, chemically optimize the lead candidates, and define structure activity relationships. Optimizing current lead compounds using cutting- edge medicinal chemistry, the team will perform a large scale HTS campaign using innovative fluorescence chemical probes to identify additional small molecule inhibitors of flavivirus RNA capping MTases. We will perform an in-depth investigation of the model of action and antiviral efficacy using in vitro biochemistry, structural biology, virology, in vivo pharmacokinetics, and in vivo animal models, which will allow the development of novel, effective, broad-spectrum, and druglike therapeutic agents against both flaviviruses. Preliminary progress has been made in the identification of initial lead inhibitors of these MTases, demonstrating low nanomolar antiviral activity. We will advance these compounds to further develop potent antiviral compounds while conducting large- scale screening in parallel for additional structural scaffold discoveries. Complementary expertise among our investigators will synergize and expedite the progress of this research. Our collaborative objective is to provide first-in-class drug candidates for the treatment or prevention of these viral infections.