Evaluation of Optimized Lead Candidates for Encephalitic Alphaviruses in Animal Models

计划摘要-项目2 目前，还没有获得许可的人类疫苗或抗病毒药物来治疗或预防任何脑炎， 甲病毒感染由于甲病毒的流行是零星的和不可预测的， 这种疾病很常见（在美洲每年估计有10，000例），但很少被诊断出来，因此很难确定所有 需要接种疫苗的人群;因此，需要一种有效的暴露后治疗方法来中断 持续爆发。为了解决这一公共卫生需求，我们提出了第一种小分子， 预防和治疗潜力，可能与V/E/WEEV的自然流行有关， 也是故意释放总之，成功的努力将导致一类新的抗病毒药物 用于治疗脑炎甲病毒;委内瑞拉（VEEV）、东方（EEEV）和西方马 脑炎病毒（WEEV）。U19脑炎甲病毒卓越中心的研究项目2 治疗学项目将领导、支持和管理动物模型中优化的铅分子的测试， 安全性、毒性、药代动力学和功效。拟议的多学科努力的重点是 完成研究（目标1和2），与研究项目1和3一起，将为选择 技术准备5级研究的最佳线索（medicalcountermeasures. gov） 目标3和目标4）。目标1将评估先导优化分子的广谱功效、PK和 小鼠模型中的剂量范围探索研究和大鼠中第1-3年的初步安全性研究。目标2将评估四个 引导用于治疗窗、给药、治疗延迟的优化分子，以定义给药方案， 1-3年V/E/WEEV致死小鼠模型的潜在治疗适应症。目标3将评价电极导线 在非GLP和GLP大鼠和非人灵长类动物（NHP）安全性、PK方面符合有利标准的候选分子 与商业研究机构BASi合作进行毒代动力学研究。关键疗效 目标4中的研究将评价最佳喹唑啉酮先导化合物在两种动物物种（小鼠和 食蟹猴，使用之前3-4年定义的给药方案。该中心有两个计划 与FDA的会议，一个非正式会议中途通过该计划和一个正式会议之前， 目标4中的NHP疗效研究。这些研究结果将载于我们的顾问拟备的报告内， 雷多斯

Program Abstract- Project 2 Currently, there are no licensed human vaccines or antivirals for treating or preventing any encephalitic alphavirus infection. Because epidemics of alphaviruses are sporadic and unpredictable, and endemic disease is common (estimated 10,000 cases annually in the Americas) but rarely diagnosed, it is difficult to identify all populations requiring vaccination; thus, an effective post-exposure treatment method is needed to interrupt ongoing outbreaks. To address this public health need, we propose a first of its kind small molecule with prophylactic and therapeutic potential that could be relevant for use both in natural epidemics of V/E/WEEV as well as a deliberate release scenario. In summary, a successful effort will result in a new class of antiviral drugs for treatment of encephalitic alphaviruses; Venezuelan (VEEV), Eastern (EEEV) and Western equine encephalitis viruses (WEEV). Research Project 2 within the U19 Center of Excellence for Encephalitic Alphavirus Therapeutics program will lead, support and manage testing of optimized lead molecules in animal models for safety, toxicity, pharmacokinetics and efficacy. The proposed multidisciplinary efforts are focused on accomplishing studies (Aims 1 and 2) that together with Research Project 1 and 3 will inform selection of the best leads for Technology Readiness Level 5 studies (medicalcountermeasures.gov) mid-way through the program (i.e. Aims 3 and 4). Aim 1 will assess lead optimized molecules for broad spectrum efficacy, PK and dose range finding studies in mouse models and preliminary safety in rat in years 1-3. Aim 2 will assess four lead optimized molecules for therapeutic window, dosing, delay of treatment to define dosing regimen and potential indications for treatment in lethal mouse models of V/E/WEEV in years 1-3. Aim 3 will evaluate lead candidate molecules with favorable criteria in nonGLP and GLP rat and non-human primate (NHP) safety, PK and toxicokinetic studies in collaboration with BASi, a commercial research organization. The pivotal efficacy studies in Aim 4 will evaluate the efficacy of the best lead quinazolinone in two animal species, mouse and cynomolgus monkeys, using dosing regimens defined in the preceding 3-4 years. The Center has two planned meetings with the FDA, one informal meeting mid-way through the program and one formal meeting prior to the efficacy studies in NHP in Aim 4. These studies will contribute to the reports to be readied by our consultants at Leidos.