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.

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。

项目成果

Piperazinobenzodiazepinones: New Encephalitic Alphavirus Inhibitors via Ring Expansion of 2-Dichloromethylquinazolinones.

• DOI: 10.1021/acsmedchemlett.1c00539
• 发表时间: 2022-04-14
• 期刊: ACS medicinal chemistry letters
• 影响因子: 4.2
• 作者: Ryan MC;Kim E;Cao X;Reichard W;Ogorek TJ;Das P;Jonsson CB;Baudry J;Chung D;Golden JE
• 通讯作者: Golden JE

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。

• DOI: 10.1016/j.antiviral.2019.104674
• 发表时间: 2020
• 期刊: Antiviral research
• 影响因子: 7.6
• 作者: Skidmore,AndrewM;Adcock,RobertS;Jonsson,ColleenB;Golden,JenniferE;Chung,Dong-Hoon
• 通讯作者: Chung,Dong-Hoon

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

• DOI: 10.1128/jvi.00317-20
• 发表时间: 2020-10-27
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Lee J;Parvathareddy J;Yang D;Bansal S;O'Connell K;Golden JE;Jonsson CB
• 通讯作者: Jonsson CB

Deep spatial profiling of Venezuelan equine encephalitis virus reveals increased genetic diversity amidst neuroinflammation and cell death during brain infection.

• DOI: 10.1128/jvi.00827-23
• 发表时间: 2023-08-31
• 期刊: Journal of virology
• 影响因子: 5.4

Time to 'Mind the Gap' in novel small molecule drug discovery for direct-acting antivirals for SARS-CoV-2.

• DOI: 10.1016/j.coviro.2021.06.008
• 发表时间: 2021-10
• 期刊: Current opinion in virology
• 影响因子: 5.9
• 作者: Jonsson CB;Golden JE;Meibohm B
• 通讯作者: Meibohm B