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 甲型病毒感染。因为甲型病毒的流行是零星的和不可预测的，而且是地方病 这种病很常见(估计在美洲每年有10,000例)，但很少被诊断出来，很难识别所有 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 持续的疫情。为了满足这一公共卫生需求，我们提出了第一个此类小分子 可用于V/E/Weev AS自然流行的预防和治疗潜力 以及故意释放的场景。总而言之，一项成功的努力将产生一种新的抗病毒药物 用于治疗脑炎甲型病毒；委内瑞拉(VEEV)、东部(EEEV)和西部马 脑炎病毒(Weev)。U19脑炎甲型病毒英才中心研究项目2 治疗计划将领导、支持和管理优化的铅分子在动物模型中的测试 安全性、毒性、药代动力学和疗效。拟议的多学科努力的重点是 完成研究(目标1和目标2)，与研究项目1和3一起，将为选择 技术就绪性5级研究的最佳线索(MedicalCountermeasures.gov) 方案(即目标3和4)。目标1将评估铅优化分子的广谱功效、PK和 在小鼠模型中发现剂量范围的研究，以及在1-3年的大鼠中的初步安全性。目标2将评估四个 用于治疗窗口、剂量、治疗延迟的优化分子，以定义剂量方案和 在1-3年治疗V/E/Weev致死小鼠模型的潜在适应症。AIM 3将评估铅 在非GLP和GLP大鼠和非人灵长类(NHP)安全性方面具有有利标准的候选分子，PK 与商业研究机构BASI合作进行毒物动力学研究。关键功效 目标4中的研究将评估最好的喹唑烷酮铅在两种动物物种中的疗效，即小鼠和 食蟹猴，使用之前3-4年定义的剂量方案。该中心有两个计划 与FDA的会议，计划中途的一次非正式会议和计划之前的一次正式会议 AIM 4中NHP的功效研究。这些研究将有助于我们的顾问在 莱多斯。

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.