Medicinal Chemistry Optimization of Anti-Alphaviral Leads and Elucidation of Target and Off Target Engagement

委内瑞拉（VEEV）、西方（WEEV）和东方马脑炎病毒（WEEV）是 导致人类脑炎的新病原体，但没有批准的人类疫苗 或用于治疗或预防任何甲病毒感染的抗病毒剂。我们的研究目标 包括开发一种广谱抗病毒临床候选药物， 人类脑炎甲病毒感染。U19研究项目1的目标 脑炎甲病毒治疗卓越中心（CEEAT）计划专注于 两种不同的小分子支架与预防和 体内治疗功效。具体来说，该项目将通过迭代改进领先原型 多参数药物化学优化，以ADME/PK评估为指导，细胞培养 和机制研究（研究项目3）和体内评估（研究项目2） 暴露，最佳剂量和安全性在更高级的物种（即，大鼠和非人灵长类动物）。 该项目将管理所有合成化学需求，包括药物化学、非GMP 类似物的缩放和验证，CEEAT实验室的化合物分布点，以及 在CRO参与API之前实施工艺生产改进 高级GLP毒理学研究的合成。此外，制剂和稳定性分析 将进行，与UW-Madison Zeeh Formulation Station合作。几 将伴随与API和制剂生成和表征相关的活动 通过雅阁IND前要求的适当认证和分析，协调和 由CEEAT结构内的产品开发和监管顾问监督。

Venezuelan (VEEV), Western (WEEV), and Eastern Equine Encephalitis viruses (WEEV), are emerging pathogens that cause human encephalitis, yet there are no approved human vaccines or antiviral agents for treating or preventing any alphaviruses infection. Our research objectives include the development of a broad spectrum antiviral clinical candidate against these encephalitic alphavirus infections in humans. The aims of Research Project 1 within the U19 Center of Excellence for Encephalitic Alphavirus Therapeutics (CEEAT) program focus on the lead optimization activities of two distinct small molecule scaffolds with prophylactic and therapeutic in vivo efficacy. Specifically, the project will improve lead prototypes through iterative multi-parameter medicinal chemistry optimization, guided by ADME/PK assessment, cell culture and mechanistic studies (Research Project 3) and in vivo assessments (Research Project 2) for exposure, optimum dosing and safety in higher order species (i.e., rats and non-human primates). The project will manage all synthetic chemistry needs including medicinal chemistry, non-GMP scaling and validation of analogs, point of compound distribution to CEEAT labs, and implementation of process manufacturing improvements prior to CRO engagement for API synthesis to advanced GLP toxicological studies. Additionally, formulation and stability analyses will be conducted, in collaboration with the UW-Madison Zeeh Formulation Station. Several activities pertaining to API and formulation generation and characterization will be accompanied by appropriate certification and analyses in accord with pre-IND requirements, coordinated and overseen by product development and regulatory consultants within the CEEAT structure.