Revising Anti-coronavirus Compounds to Enhance Activity and Optimize Delivery

修改抗冠状病毒化合物以增强活性并优化递送

• 批准号: 10240178
• 负责人: Karl Y Hostetler
• 金额: $ 76.62万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240178
• 关键词: 2019-nCoV; Animal Model; Antiviral Agents; Antiviral Therapy; Bioavailable; Biological Availability; COVID-19; COVID-19 outbreak; Cell Line; Clinical; Collection; Coronavirus; Coronavirus Infections; Cytidine; DNA-Directed RNA Polymerase; Disease; Dose; Drug Design; Drug Formulations; Drug Kinetics; Enzymes; Exposure to; FDA approved; Formulation; GS-441524; Goals; In Vitro; Injections; Intramuscular; Intravenous; Lead; Lipids; Lung; Mesocricetus auratus; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Nucleosides; Oils; Oral; Parents; Pathogenicity; Pharmaceutical Preparations; Prodrugs; Property; Rat-1; Rattus; SARS coronavirus; SARS-CoV-2 antiviral; SARS-CoV-2 infection; Series; Structure of parenchyma of lung; Synthesis Chemistry; Therapeutic; Tissues; Toxic effect; Toxicokinetics; Vaccines; analog; base; coronavirus disease; coronavirus treatment; design; improved; innovation; lipophilicity; mortality; novel; nucleoside monophosphate; parent grant; phase I trial; remdesivir; scale up; uptake; viral RNA

Project Summary/Abstract The current outbreak of COVID-19 has had devastating global effects on morbidity and mortality. Currently no vaccine is available and no therapeutic with efficacy against SARS-CoV-2019 have been fully approved by the FDA. Remdesivir, an intravenous drug which inhibits the viral RNA polymerase enzyme, has received an EUA designation by the US FDA. A prodrug of N4-hydroxy-cytidine has recently entered Phase 1 trials. Our goal is to synthesize COVID-19 antivirals that inhibit the viral RNA polymerase and can be used orally or intramuscularly with a special focus on delivering maximal amounts of drug to the lungs. We will synthesize prodrugs of remdesivir and other nucleosides with anti-coronavirus activity using an innovative approach that involves converting them to lipid analogs. Some compounds will focus on oral delivery and others on intramuscular administration. The compounds will be screened in vitro against nonpathogenic and pathogenic coronaviruses including SARS-CoV-2 and their activity compared with the unmodified parent nucleosides. Their pharmacokinetics and toxicity of the most active antivirals will be studied in rats. The active antivirals will be evaluated for exposure to lung versus their unmodified nucleosides. Finally, the clinical and antiviral activity of the most promising compounds will be evaluated in the Syrian Golden hamster model of coronavirus disease.

项目总结/文摘