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In vivo virology core

体内病毒学核心

基本信息

批准号：
10512625
负责人：
Adolfo Garcia-Sastre
金额：
$ 376.07万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-16 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10512625
关键词：
2019-nCoV Address Animal Model Antiviral resistance Bunyavirales Canada Clinical Trials Coronavirus Dengue Virus Development Disease Dose Drug Combinations Drug resistance Enterovirus Epidemic Family Family Picornaviridae Flavivirus Future Generations Genetic Variation Goals Human Immunization Programs In Vitro Institutes Laboratories Lead Letters Maximum Tolerated Dose Microbiology Morbidity - disease rate Mus Mutation Oral Orthobunyavirus Outpatients Paris, France Patients Pattern Pharmaceutical Chemistry Play Prophylactic treatment Public Health RNA Viruses RNA-Directed RNA Polymerase Reaction Time Research Personnel Resistance Resistance profile Risk Role SARS-CoV-2 antiviral SARS-CoV-2 variant Safety Study models Supervision Testing Therapeutic Time Togaviridae Toxic effect Treatment Efficacy Vaccines Viral Virus Virus Diseases Virus Inhibitors Virus Replication Work Zoonoses anti-viral efficacy antiviral drug development clinical development coronavirus disease disability drug candidate drug discovery emerging pathogen experience experimental study fitness human pathogen improved in vitro activity in vivo in vivo evaluation industry partner influenzavirus lead optimization medical schools mortality mouse model pandemic disease pathogen programs rational design resistance mutation response transmission process variants of concern viral fitness viral resistance virology weapons

项目摘要

CORE 7: IN VIVO VIROLOGY SUMMARY SARS-CoV-2 continues to cause severe morbidity and mortality in the current pandemic, and future RNA virus epidemics or pandemics are inevitable. To improve patient mortality rates, the development of antiviral therapeutics is critical. However, currently available SARS-CoV-2 antiviral treatments are limited in efficacy. Furthermore, it is imperative that we have access to an arsenal of compounds against all RNA viruses of pandemic potential ready to be deployed into clinical trials at the earliest stages of future pandemics to save millions of lives and reduce long-term disabilities associated with disease. The goal of the QCRG Pandemic Response Program is the identification and development of oral drug candidates with suitable safety profiles for broad use in the outpatient setting. The In Vivo Virology Core plays an essential role in the QCRG Drug Discovery Platform in the Hit-to-Lead and Lead Optimization stages, working closely with Projects 1-6 and the In Vitro Virology and Medicinal Chemistry Cores. Our goal is to determine the therapeutic efficacy of antiviral hits and leads against coronaviruses, flaviviruses, togaviruses, picornaviruses and Bunyavirales in advanced animal models of viral infection. We have assembled a team of investigators with decades of experience in advanced animal models for the analysis of antiviral countermeasures against the target viral families. We will first analyze hit compounds in animal models using single concentration prophylactic treatment of maximal tolerated dose. Compounds that show antiviral activity against viruses in vitro (established by the In Vitro Virology core) and have a favorable PK and toxicity profile in vivo (Medicinal Chemistry Core), will be tested for their ability to inhibit viral replication and disease in mice challenged with coronaviruses, flaviviruses, enteroviruses, togaviruses, and bunyaviruses. For compounds with antiviral activity in vivo in single-dose treatments, we will determine dose responses, time of administration post-challenge for therapeutic activity, and spectrum of activity against multiple strains and viruses (Aim 1). We expect to identify 8-12 or 8-10 Lead Compounds for coronaviruses and other pandemic- potential RNA viruses, respectively. Next, in Aim 2, we will determine antiviral resistance patterns and fitness of resistant mutantsIn addition, beneficial compound combinations identified in vitro (In Vitro Virology Core), will be tested in drug combinations studies in the appropriate animal model, both with known virus inhibitors and with each other. We anticipate being a key component for antiviral development and expect to iterate with Projects and Cores to obtain 3-6 Optimized Leads that will be transferred to our industry partner Roche for clinical development.

核心7：体内病毒学