Norovirus 3CL Protease-Based Anti-norovirus Therapeutics

基于诺如病毒 3CL 蛋白酶的抗诺如病毒疗法

• 批准号: 8793096
• 负责人: Terry L. Bowlin
• 金额: $ 73.43万
• 依托单位: KANSAS STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8793096
• 关键词: Accounting; Acute; Adopted; Adverse effects; Animal Model; Antiviral Agents; Back; Benchmarking; Biochemical; Biological Availability; Bioterrorism; Buffers; Calicivirus; Caspase; Categories; Cells; Characteristics; Complex; Development; Disease Outbreaks; Drug Design; Drug Kinetics; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Evaluation; Excretory function; Exhibits; Face; Family suidae; Gastroenteritis; Genome; Gnotobiotic; Goals; Health; Hospitals; Human; Immunity; Infection; Interferons; Investigational New Drug Application; Lead; Measures; Metabolism; Methodology; Modeling; Molecular Conformation; Norovirus; Oral; Peptide Hydrolases; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Polyproteins; Prevention; Preventive; Process; Property; Prophylactic treatment; Protease Inhibitor; Protein Binding; Public Health; RNA; Rattus; Replicon; Research; Resolution; Ribavirin; Roentgen Rays; Safety; Schools; Series; Shipping; Ships; Solubility; Staging; Structural Protein; Structure; Structure-Activity Relationship; System; Therapeutic; Therapeutic Uses; Toxic effect; Toxicology; Vaccines; Viral; Viral Gastroenteritis; Virus; Virus Replication; Virus Shedding; Work; X-Ray Crystallography; absorption; analog; base; biodefense; chemical stability; computer studies; cytotoxicity; design; drug candidate; in vivo; indexing; inhibitor/antagonist; lead series; lipophilicity; meetings; member; novel; pathogen; peptidomimetics; pre-clinical; process optimization; programs; prophylactic; public health research; resistance mechanism; small molecule; success; tool; vaccine development; viral resistance

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.

描述（由申请人提供）：本申请的总体目标是鉴定诺如病毒3C样蛋白酶（3CLpro）的抑制剂作为针对诺如病毒的有效抗病毒和预防剂，诺如病毒是急性病毒性胃肠炎的主要病原体。诺如病毒构成了一个重要的公共卫生问题以及潜在的生物恐怖主义威胁。现在 目前没有针对诺如病毒感染的具体预防或治疗措施。诺如病毒疫苗开发面临病毒多样性和短期免疫等多项挑战；因此，迫切需要开发有效的抗诺如病毒药物。我们启动了一项诺如病毒研究计划，旨在开发用于治疗和/或预防诺如病毒感染的小分子疗法。为此，我们鉴定了一系列诺如病毒 3CLpro 的过渡态抑制剂，并证明该病毒酶是开发抗诺如病毒药物的有效靶点。这些抑制剂具有针对诺如病毒和相关杯状病毒的抗病毒活性， 作用机制、X射线晶体学、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被证明对诺如病毒感染的限生猪模型有效。这些结果为我们的工作假设提供了强有力的支持，即诺如病毒 3CLpro 是发现小分子抗诺如病毒治疗剂和预防剂的经过验证的可药物病毒靶点。该系列化合物适合进一步优化；因此，我们建议开展一项优化活动，其中包括基础研究和应用研究，并优化整合多种工具和方法的部署和利用，以确定临床前候选药物。该计划的最终长期目标是通过推进候选药物进入研究性新药（IND）申请阶段，开发针对诺如病毒感染的抗病毒疗法。