Center of Excellence for Encephalitic Alphavirus Therapeutics

摘要 原创U19家长奖励计划。拟建的脑炎甲型病毒卓越中心 治疗计划建议推进有效的小分子靶向药物的开发 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(Weev)，这里指V/E/Weev。宾夕法尼亚大学科学家之间的合作 路易斯维尔(UofL；Chung)，威斯康星大学麦迪逊分校(UW；Golden，Elder)，田纳西健康大学 科学中心(UTHSC；Jonsson，Meibohm，Fitzpatrick)和加尔维斯顿的德克萨斯大学医学部 (UTMB；Rossi，Weaver)提供多学科的病毒学专业知识和ABSL-3/SELECT的相关专业知识 药物、大小动物模型、药物化学、药代动力学和抗病毒评估 具有体外作用机制的化合物。此外，该网络拥有一支经验丰富的团队来 组织开发广谱抗病毒药物(Encephlavir)的商业计划，用于治疗 V/E/Weev.该中心的广泛和长期目标是：(1)优化主要的喹唑烷酮系列，以 用具有广谱活性的WeEV和EEEV确定那些具有有利条件的非GLP研究 用于V/E/Weev；(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，以帮助评估安全性和有效性、机制 的作用、靶点特异性和耐药性监测计划。拟议的多学科努力将 通过支持IND的研究推进这一领先系列。遵循严格的产品开发计划， 该中心的最终目标是走向商业上可用的预防和/或治疗方法 以VEEV、EEEV和WeEV为主要指征。

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.