Center of Excellence for Encephalitic Alphavirus Therapeutics

脑炎甲病毒治疗卓越中心

• 批准号: 10631703
• 负责人: Colleen B Jonsson
• 金额: $ 93.43万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-12 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10631703
• 关键词: Advanced Development; Aerosols; Alphavirus; Amidines; Animal Model; Animals; Antiviral Agents; Award; Case Fatality Rates; Chemicals; Chemistry; Collaborations; Culicidae; Cyclic GMP; Data; Development; Development Plans; Discipline; Disease; Dose; Drug Kinetics; Drug resistance; Eastern Equine Encephalitis Virus; Elderly; Encephalitis; Epidemic; Evaluation; Excretory function; Exhibits; Formulation; Goals; Health Sciences; Human; In Vitro; Intravenous; Lead; Life; Medical; Metabolism; Modeling; Monitor; Oral; Parents; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Polymerase; Population; Property; Proteins; Publishing; Research Project Grants; Resistance profile; Route; Safety; Scientist; Series; Small Business Innovation Research Grant; Specificity; Structure; Structure-Activity Relationship; Tennessee; Texas; Therapeutic; Toxic effect; Toxicology; Universities; Vaccines; Venezuelan Equine Encephalitis Virus; Viral; Virus; Western Equine Encephalitis Virus; Wisconsin; absorption; animal model development; base; biothreat; design; drug candidate; efficacy study; experience; improved; in vitro Assay; in vitro activity; in vivo; inhibitor; lead candidate; lead optimization; lead series; meetings; mouse model; multidisciplinary; pre-clinical; product development; programs; prophylactic; prototype; scaffold; scale up; small molecule; subcutaneous; therapeutically effective; virology

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.

抽象的 原创 U19 家长奖励计划。拟议的脑炎甲病毒卓越中心 治疗计划提议推进有效的小分子先导药物的开发 委内瑞拉马脑炎病毒（VEEV）、东方马脑炎病毒（EEEV）和西方马脑炎病毒 本文中的脑炎病毒(WEEV)或V/E/WEEV。大学科学家之间的合作 路易斯维尔大学（UofL；Chung）、威斯康星大学麦迪逊分校（UW；Golden、Elder）、田纳西大学健康分校 科学中心（UTHSC；Jonsson、Meibohm、Fitzpatrick）和德克萨斯大学加尔维斯顿医学分校 （UTMB；Rossi，Weaver）提供病毒学方面的多学科专业知识以及 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评估 具有体外作用机制的化合物。此外，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。该中心的广泛、长期目标是： (1) 对喹唑啉酮先导系列进行优化 识别具有广谱活性的 WEEV 和 EEEV 的非 GLP 研究的有利特征 适用于 V/E/WEEV； (2) 确定适合后续cGMP生产的先导原料药的放大合成； (3) 开展非临床病毒学研究，有助于评估安全性、有效性、机制 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 支持研究推进该先导系列。遵循严格的产品开发计划， 该中心的最终目标是走向商业化的预防和/或治疗方法 将 VEEV、EEEV 和 WEEV 作为主要适应症。

项目成果

Advances in the Development of Small Molecule Antivirals against Equine Encephalitic Viruses.

针对马脑炎病毒的小分子抗病毒药物的开发进展。

• 发表时间: 2023-02-01
• 作者: Ogorek, Tyler J;Golden, Jennifer E
• 通讯作者: Golden, Jennifer E

Clinical and Translational Pharmacology Considerations for Anti-infectives Approved Under the FDA Animal Rule.

根据 FDA 动物规则批准的抗感染药物的临床和转化药理学考虑因素。

• 发表时间: 2023-07
• 影响因子: 4.5
• 作者: Temrikar, Zaid H;Golden, Jennifer E;Jonsson, Colleen B;Meibohm, Bernd
• 通讯作者: Meibohm, Bernd

Benzamidine ML336 inhibits plus and minus strand RNA synthesis of Venezuelan equine encephalitis virus without affecting host RNA production.

Benzamidine ML336 抑制委内瑞拉马脑炎病毒的正链和负链 RNA 合成，而不影响宿主 RNA 的产生。

• 发表时间: 2020-02
• 影响因子: 7.6
• 作者: Skidmore, Andrew M;Adcock, Robert S;Jonsson, Colleen B;Golden, Jennifer E;Chung, Dong
• 通讯作者: Chung, Dong

Efficacy of a brain-penetrant antiviral in lethal Venezuelan and eastern equine encephalitis mouse models.

脑渗透性抗病毒药物在致命的委内瑞拉和东部马脑炎小鼠模型中的功效。

• 发表时间: 2023-04-12
• 影响因子: 17.1
• 作者: Cao, Xufeng;Yang, Dong;Parvathareddy, Jyothi;Chu, Yong;Kim, Eun Jung;Fitz;Li, Xiaoyu;Lukka, Pradeep B;Parmar, Keyur R;Temrikar, Zaid H;Dhole, Priya;Adcock, Robert Scott;Gabbard, Jon;Bansal, Shruti;Lee, Jasper;Zalduond
• 通讯作者: Zalduond

Emergence and Magnitude of ML336 Resistance in Venezuelan Equine Encephalitis Virus Depend on the Microenvironment.

委内瑞拉马脑炎病毒中 ML336 耐药性的出现和程度取决于微环境。

• 发表时间: 2020-10-27
• 作者: Lee, Jasper;Parvathareddy, Jyothi;Yang, Dong;Bansal, Shruti;O'Connell, Kathryn;Golden, Jennifer E;Jonsson, Colleen B
• 通讯作者: Jonsson, Colleen B