Project 5 - Antivirals against pathogenic Enterovirus

项目摘要-项目5 项目5的使命是开发口服直接作用的临床候选药物，以预防或治疗 与肠道病毒感染相关的显著发病率和死亡率。据估计，肠道病毒是 每年在美国造成约2000万例感染，在全世界造成超过10亿例感染。有 目前没有有效的抗病毒治疗剂可用于预防或治疗非脊髓灰质炎病毒肠道病毒感染。这 该项目将充分表征口服可利用的核糖核苷，其具有有效的抑制活性， 并确定这些化合物在生理学相关的体外和体内的功效。 体内模型肠道病毒抗病毒治疗的研究受到缺乏合适模型的限制， 概括了这些病毒靶向的细胞和组织的独特细胞和免疫学特征， vivo.本项目中提出的研究将利用生理相关的体外人和体内小鼠 由该项目负责人开发的模型。这些模型包括原代人气道培养物、原代 干细胞衍生的人类肠模型、人脊髓类器官和人源化小鼠模型， 概括了肠道病毒临床疾病的许多方面。鉴于这些研究将利用生理学 相关的模型，所确定的化合物将是非常重要的和临床优化，因为我们的系统将 体外和体内高度相关组织类型的肠道病毒感染模型。该项目将直接协同 本U19应用程序中包含多个AC/DC核心和项目。AC/DC核心将指导 鉴定将在体外和体内进行严格抗肠道病毒活性测试的先导化合物， 上述体内模型。该项目的发现也将直接影响这些核心， 使用该项目生成的数据进一步确定潜在客户。由于许多这些相同的引线将进行测试， 针对其他RNA病毒的其他项目，这种内置的协同作用将允许直接整合跨 不同的病毒家族因此，项目5中提议的研究直接有助于中心的以下使命： 产生适用的临床候选病毒，以应对可能导致大流行的RNA病毒。

Project Summary – Project 5 The mission of Project 5 is to develop orally available direct-acting clinical candidates to prevent or treat the significant morbidity and mortality associated with enterovirus infections. It is estimated that enteroviruses are responsible for ~20 million infections in the U.S. and more than one billion worldwide each year. There are currently no effective antiviral therapeutics available to prevent or treat non-poliovirus enterovirus infections. This project will fully characterize orally-available ribonucleosides with potent inhibitory activity against clinically relevant enteroviruses and determine the efficacy of these compounds in physiologically relevant in vitro and in vivo models. Studies of enterovirus antiviral therapeutics have been limited by the lack of suitable models that recapitulate the unique cellular and immunologic features of the cells and tissues targeted by these viruses in vivo. The studies proposed in this project will utilize physiologically relevant in vitro human and in vivo mouse models developed by the lead of this project. These models include primary human airway cultures, primary stem cell-derived human enteroid models, human spinal cord organoids, and humanized mouse models that recapitulate many aspects of enterovirus clinical disease. Given that these studies will utilize physiologically relevant models, the compounds identified will be highly significant and clinically optimized, as our systems will model enterovirus infections of highly relevant tissue types in vitro and in vivo. This project will directly synergize with multiple AC/DC Cores and Projects contained within this U19 application. AC/DC Cores will direct the identification of lead compounds that will be rigorously tested for anti-enterovirus activity in the in vitro and in vivo models described above. The findings from this project will also directly influence these Cores, which will work with data generated by this project to further identify leads. As many of these same leads will be tested by other projects against other RNA viruses, this built-in synergy will allow for direct integration of leads across diverse viral families. The studies proposed in Project 5 thus contribute directly to the Center’s mission of generating applicable clinical candidates to address RNA viruses of major pandemic potential.