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

抗甲病毒先导化合物的药物化学优化以及靶点和脱靶作用的阐明

• 批准号: 9886197
• 负责人: Jennifer E. Golden
• 金额: $ 104.3万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9886197
• 关键词: ADME Study; Address; Alphavirus; Alphavirus Infections; Americas; Amidines; Antiviral Agents; Binding; Cell Culture Techniques; Cells; Cellular Assay; Certification; Characteristics; Chemicals; Collaborations; DNA-Directed RNA Polymerase; Development; Disease; Dose; Drug Kinetics; Eastern Equine Encephalitis Virus; Encephalitis; Equus caballus; Formulation; Generations; Human; In Vitro; Infection; Lead; Metabolic; Modeling; Mus; Nonstructural Protein; Oral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; RNA chemical synthesis; RNA-Directed RNA Polymerase; Rattus; Research; Research Project Grants; Risk Assessment; Route; Safety; Series; Structure; Surveys; Synthesis Chemistry; Therapeutic; Toxic effect; Toxicology; Vaccines; Validation; Venezuelan; Western Equine Encephalitis Virus; analog; base; bioweapon; candidate selection; clinical candidate; design; efficacy study; health economics; improved; in vivo; lead optimization; manufacturing process; nonhuman primate; novel; pathogen; prevent; product development; programs; prophylactic; prototype; safety study; scaffold; screening; small molecule; small molecule therapeutics; therapeutic candidate; viral RNA

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.

委内瑞拉（VEEV）、西部（WEEV）和东部马脑炎病毒（WEEV）