Norovirus 3CL Protease-Based Anti-norovirus Therapeutics

项目总结 该应用程序的首要目标是确定诺如病毒3C样蛋白酶(3CLpro)的抑制物为 针对诺如病毒的有效抗病毒和预防性药物，它是急性病毒的主要病原体 胃肠炎。诺如病毒是一个重要的公共卫生问题，也是潜在的生物恐怖主义。 威胁。目前还没有针对诺沃克病毒感染的具体预防或治疗措施。疫苗 诺如病毒的发展面临几个挑战，包括病毒多样性和短期免疫； 因此，迫切需要开发有效的抗诺如病毒药物。我们已经发起了一项 诺如病毒研究计划旨在开发治疗和/或治疗的小分子疗法 预防诺沃克病毒感染。为此，我们已经确定了一系列过渡状态抑制物 并已证明该病毒酶是开发诺如病毒的有效靶点。 抗诺沃克病毒药物。这些抑制剂的特征是对诺如病毒和相关的抗病毒活性 杯状病毒，作用机制，X射线结晶学，病毒抗性，初步吸收，分布 大鼠的代谢和排泄特性、耐受性和口服利用度。此外，一种蛋白水解酶抑制剂 该系列在诺沃克病毒感染的生猪模型中被证明是有效的。这些结果提供了 强烈支持我们的工作假设，即诺沃克病毒3CLpro是一种有效的可药物治疗的病毒靶点 小分子抗诺如病毒治疗和预防药物的发现。这一系列化合物是 适合于进一步优化；因此，我们建议开展一项优化运动， 涵盖基础和应用研究，并以最佳方式整合部署和利用 确定临床前候选对象的工具和方法。这项计划的最终长期目标是 通过提出一种候选药物来开发抗诺沃克病毒感染的抗病毒疗法 申请研究用新药(IND)的阶段。

PROJECT SUMMARY The overarching goal of this application is to identify inhibitors of norovirus 3C-like protease (3CLpro) as effective antiviral and prophylactic agents against noroviruses, the main causative agents of acute viral gastroenteritis. Noroviruses constitute an important public health problem as well as a potential bioterrorism threat. Currently there is no specific preventive or therapeutic measure against norovirus infections. Vaccine development for noroviruses faces several challenges including viral diversity and short-term immunity; consequently, there is an urgent need for the development of effective anti-noroviral drugs. We have initiated a norovirus research program aimed at developing small molecule therapeutics for the treatment and/or prevention of norovirus infections. Toward that end, we have identified a series of transition state inhibitors of norovirus 3CLpro and have demonstrated that the viral enzyme is a validated target for the development of anti-norovirus drugs. The inhibitors were characterized for antiviral activity against noroviruses and related caliciviruses, mechanism of action, X-ray crystallography, viral resistance, preliminary absorption, distribution, metabolism and excretion properties, tolerability, and oral availability in rats. Moreover, a protease inhibitor in the series was shown to be effective in the gnotobiotic pig model of norovirus infection. These results provide strong support for our working hypothesis that norovirus 3CLpro is a validated druggable viral target for the discovery of small molecule anti-norovirus therapeutics and prophylactics. The series of compounds are suitable for further optimization; consequently, we propose to embark on an optimization campaign that encompasses basic and applied studies and optimally integrates the deployment and utilization of multiple tools and methodologies to identify preclinical candidates. The ultimate long term goal of this program is the development of antiviral therapeutics against norovirus infection by advancing a drug candidate through the stage of filing for an investigational new drug (IND) application.