Center of Excellence for Encephalitic Alphavirus Therapeutics

程序摘要--总体 拟议的脑炎甲型病毒治疗卓越中心计划建议推进 针对委内瑞拉东部马脑炎病毒(VEEV)的有效小分子先导的开发 马脑炎病毒(EEEV)和西方马脑炎病毒(Weev)，这里指的是V/E/Weev。这个 威斯康星大学麦迪逊分校路易斯维尔大学(UofL；Chung)科学家之间的合作 (UW；Golden，Elder)，田纳西大学健康科学中心(UTHSC；Jonsson，Meibohm，Fitzpatrick， 和加尔维斯顿的德克萨斯大学医学分校(UTMB；Rossi，Weaver)提供多学科 病毒学专业知识，具有ABSL-3/选定制剂、大小动物模型、医学方面的相关专业知识 抗病毒化合物的化学、药代动力学和体外评价及其作用机制 能力。此外，该网络还拥有由UTHSC(Bares)领导的经验丰富的团队来组织广告 开发治疗V/E/Weev的广谱抗病毒药物(Encephlavir)的计划。宽阔的， 该中心的长期目标是：(1)优化主要的喹唑烷酮系列，以确定那些 对对V/E/Weev具有广谱活性的Weev和EEEV进行非GLP研究的有利条件； (2)确定适合以后生产cGMP的先导药物的放大合成；(3)进行 非临床病毒学研究，将有助于评估安全性和有效性，作用机制， 靶标特异性和耐药性监测计划。拟议的多学科努力将推动这一进程。 通过支持IND的研究进行领先系列研究。遵循严格的产品开发计划，最终目标 该中心的目标是转向可商业化的VEEV预防和/或治疗方法， EEEV、WeEV为主要指征。

Program Abstract- Overall The proposed Center of Excellence for Encephalitic Alphavirus Therapeutics program proposes to advance the development of potent small molecule leads targeting Venezuelan equine encephalitis virus (VEEV), Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV) or V/E/WEEV herein. The collaborations among the scientists at University of Louisville (UofL; Chung), University of Wisconsin-Madison (UW; Golden, Elder), University of Tennessee Health Science Center (UTHSC; Jonsson, Meibohm, Fitzpatrick, Tigabu) and University of Texas Medical Branch at Galveston (UTMB; Rossi, Weaver) provides multidisciplinary expertise in virology with relevant expertise in ABSL-3/select agents, small and large animal models, medicinal chemistry, pharmacokinetics, and assessment of antiviral compounds in vitro with mechanism of action capabilities. Moreover, the network has an experienced team led by UTHSC (Bares) to organize the commercial plan for development of the broad-spectrum antiviral (Encephlavir) for treatment against V/E/WEEV. The broad, long-range objectives of the Center are to; (1) Optimize the lead quinazolinone series to identify those with favorable profiles for nonGLP studies with WEEV and EEEV that have broad-spectrum activity for V/E/WEEV; (2) Define scale-up synthesis of the lead drug substance suitable for later cGMP manufacturing; (3) Conduct nonclinical virology studies that will aid in the evaluation of the safety and efficacy, the mechanism of action, target specificity and drug resistance monitoring plan. The proposed multidisciplinary efforts will advance this lead series through IND-enabling studies. Following the disciplined product development plan, the ultimate goal of the Center is to move toward a commercially available prophylactic and/or therapeutic treatment for VEEV, EEEV, and WEEV as the primary indication.