Center of Excellence for Encephalitic Alphavirus Therapeutics

摘要 U19家长奖励计划拟议的脑炎甲病毒卓越中心 治疗学计划建议推进有效的小分子靶向先导物的开发 委内瑞拉马脑炎病毒（VEEV）、东部马脑炎病毒（EEEV）和西部马脑炎病毒（EEEV） 脑炎病毒（WEEV）或V/E/WEEV。科学家们在大学的合作 路易斯维尔大学（UofL; Chung），威斯康星大学麦迪逊分校（UW; Golden，Elder），田纳西大学健康 科学中心（UTHSC; Jonsson，Meibohm，菲茨帕特里克）和德克萨斯大学医学分支（位于加尔维斯顿） (UTMB; Rossi，Weaver）提供病毒学方面的多学科专业知识，并具有ABSL-3/select方面的相关专业知识 药物、小型和大型动物模型、药物化学、药代动力学和抗病毒药物评估 化合物在体外的作用机制的能力。此外，该网络拥有一支经验丰富的团队， 组织开发广谱抗病毒药物（Encephlavir）的商业计划，用于治疗 V/E/WEEV。该中心广泛的长期目标是：（1）优化喹唑啉酮铅系列， 确定具有广谱活性的WEEV和EEEV非GLP研究的有利特征 （2）确定适用于后续cGMP生产的先导原料药的放大合成; (3)进行非临床病毒学研究，以帮助评估安全性和有效性， 行动、目标特异性和耐药性监测计划。拟议的多学科努力将 通过IND赋能研究推进该电极导线系列。根据严格的产品开发计划， 该中心的最终目标是向商业化的预防和/或治疗方法迈进 以VEEV、EEEV和WEEV作为主要指示。

Abstract Original U19 Parent Award Program. 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) 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 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.