Developing small molecule therapeutics for West Nile virus

开发西尼罗河病毒的小分子疗法

• 批准号: 7492834
• 负责人: Jodi Beattie
• 金额: $ 71.22万
• 依托单位: APATH, LLC
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-10 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7492834
• 关键词: Address; Animals; Antiviral Agents; Antiviral Therapy; Biological Assay; Bioterrorism; Categories; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Class; Clinical Trials; Cost Savings; Cultured Cells; Dengue; Dengue Virus; Development; Diagnostic; Diamond; Drug Kinetics; Early identification; Family; Flaviviridae; Flavivirus; Flavivirus Infections; Future; Goals; Health; Housing; Human; In Vitro; Japanese Encephalitis; Laboratories; Lead; Measures; Metabolic; Numbers; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plasma Proteins; Preclinical Drug Development; Production; Property; Protein Binding; Public Health; Replicon; Research; Safety; Screening procedure; Solubility; St. Louis Encephalitis; Structure-Activity Relationship; Testing; Therapeutic; Tick-Borne Encephalitis; Tick-Borne Encephalitis Virus; Tick-Borne Encephalitis Viruses; Toxic effect; Toxicokinetics; Toxicology; Treatment Protocols; United States National Institutes of Health; Universities; Viral; Viral Physiology; Virus; Virus Diseases; Washington; West Nile virus; Work; Yellow Fever; base; biodefense; cytotoxicity; drug development; high throughput screening; humanized monoclonal antibodies; improved; in vivo; inhibitor/antagonist; member; mouse model; novel; pathogen; pre-clinical; preclinical study; programs; research study; response; small molecule

DESCRIPTION (provided by applicant): Currently, there is no specific antiviral therapy available for the treatment of flavivirus infections, including West Nile Virus (WNV), a Biodefense Category B agent. Therefore, the development of novel classes of antiviral agents is of high priority for public health and defense against a possible bioterrorism attack. For this initiative, our goal is to develop small molecule inhibitors of WNV. In our preliminary experiments, we used a WNV replicon-based cell .culture high throughput screening platform to identify several candidate lead compounds and confirmed their inhibitory activity in WNV and other flavivirus infection assays in cell culture. Our collaborative group will bring the potential anti-viral lead compounds we discovered in our screens through a preclinical drug development program that includes lead optimization using structure-activity relationships (SAP) to enhance compound potency and drug-like properties. Preclinical toxicology and pharmacokinetic (PK) studies will be performed to help predict how the antiviral compounds distribute and behave in vivo and will include an analysis of cytotoxicity, solubility, metabolic stability, cell permeability, and plasma protein binding. As a cost-saving measure, we will perform preliminary preclinical toxicology studies in-house, for early identification of compounds that merit further consideration in advanced in vitro and In vivo toxicokinetics preclinical studies in small animals. Compounds with acceptable toxicity and PK profiles will be tested in efficacy studies using a well-characterized mouse model of WNV infection. The ability of our small molecule anti-WNV compounds to synergize with a neutralizing humanized monoclonal antibody to generate a more potent combination therapeutic regimen will also be studied. For the lead compounds with the greatest WNV anti-viral potential in vivo, virological studies will be performed to define the mechanism of action. It is expected that these studies will result in the production of an antiviral drug for future clinical trials to determine safety and efficacy against WNV, and possibly other flavivirus infections. Project Narrative There are currently no effective therapies against the Category B agent WNV to address the immediate health needs of the public in case of a bioterrorism incident. In this project, we are proposing to use the combined expertise of Apath.LLC and the Diamond laboratory at Washington University in St. Louis to develop anti-WNV compounds we discovered in our screening program into an antiviral drug to be tested in future clinical trials.

描述（由申请人提供）： 目前，尚无特定的抗病毒疗法可用于治疗黄病毒感染，包括西尼罗河病毒 (WNV)（一种生物防御 B 类病毒）。因此，开发新型抗病毒药物对于公共卫生和防御可能的生物恐怖袭击具有高度优先性。对于这一举措，我们的目标是开发西尼罗河病毒的小分子抑制剂。在我们的初步实验中，我们使用基于 WNV 复制子的细胞培养高通量筛选平台来鉴定几种候选先导化合物，并在细胞培养中的 WNV 和其他黄病毒感染测定中证实了它们的抑制活性。我们的合作小组将通过临床前药物开发计划带来我们在筛选中发现的潜在抗病毒先导化合物，其中包括使用构效关系 (SAP) 进行先导化合物优化，以增强化合物的效力和类药特性。将进行临床前毒理学和药代动力学（PK）研究，以帮助预测抗病毒化合物在体内的分布和行为方式，并将包括细胞毒性、溶解度、代谢稳定性、细胞通透性和血浆蛋白结合的分析。作为节省成本的措施，我们将在内部进行初步的临床前毒理学研究，以便及早鉴定值得在小动物的先进体外和体内毒代动力学临床前研究中进一步考虑的化合物。具有可接受毒性和 PK 特性的化合物将在功效研究中使用经过充分表征的西尼罗河病毒感染小鼠模型进行测试。还将研究我们的小分子抗 WNV 化合物与中和人源化单克隆抗体协同产生更有效的联合治疗方案的能力。对于体内具有最大抗 WNV 病毒潜力的先导化合物，将进行病毒学研究以确定其作用机制。预计这些研究将生产出一种抗病毒药物，用于未来的临床试验，以确定针对西尼罗河病毒以及可能的其他黄病毒感染的安全性和有效性。 项目叙述 目前尚无针对 B 类病原体 WNV 的有效治疗方法，无法满足公众在发生生物恐怖主义事件时的直接健康需求。在这个项目中，我们建议利用 Apath.LLC 和圣路易斯华盛顿大学 Diamond 实验室的综合专业知识，将我们在筛选计划中发现的抗西尼罗河病毒化合物开发成抗病毒药物，以便在未来的临床试验中进行测试。