Norovirus 3CL Protease-Based Anti-norovirus Therapeutics

描述(由申请人提供)：本申请的主要目标是确定诺如病毒类蛋白酶抑制剂(3CLpro)是有效的抗病毒和预防诺如病毒的药物，诺如病毒是急性病毒性胃肠炎的主要病原体。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 目前还没有针对诺沃克病毒感染的具体预防或治疗措施。诺如病毒疫苗的开发面临病毒多样性和短期免疫等挑战，因此迫切需要开发有效的抗诺如病毒药物。我们已经启动了一项诺沃克病毒研究计划，旨在开发治疗和/或预防诺沃克病毒感染的小分子疗法。为此，我们已经确定了一系列诺沃克病毒3CLPro的过渡态抑制剂，并证明了病毒酶是开发抗诺沃克病毒药物的有效靶点。这些抑制剂的特征是对诺如病毒和相关杯状病毒具有抗病毒活性， 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，该系列中的一种蛋白酶抑制剂在诺沃克病毒感染的生猪模型中被证明是有效的。这些结果为我们的工作假设提供了强有力的支持，即诺沃克病毒3CLpro是发现小分子抗诺沃克病毒治疗和预防药物的有效药物靶点。该系列化合物适合进一步优化；因此，我们建议开展一项包括基础和应用研究的优化活动，并以最佳方式整合多种工具和方法的部署和使用，以确定临床前候选药物。该计划的最终长期目标是通过申请研究性新药(IND)申请阶段推进候选药物来开发抗诺沃克病毒感染的抗病毒疗法。

DESCRIPTION (provided by applicant): 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.