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: 10681347
• 负责人: Karl Y Hostetler
• 金额: $ 75.1万
• 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/10681347
• 关键词: 2019-nCoV; Animal Model; Antiviral Agents; Antiviral Therapy; 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; Lipids; Lung; Mesocricetus auratus; Metabolic; Metabolism; Modeling; Morbidity - disease rate; Nucleosides; Oils; Oral; Parents; Pathogenicity; Pharmaceutical Preparations; Prodrugs; Property; 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; Viral; Viral Physiology; analog; 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/摘要 当前COVID-19的爆发对全球发病率产生了毁灭性影响， mortality.目前没有疫苗可用，也没有有效的治疗方法来对抗 SARS-CoV-2019已获得FDA的全面批准。Remdesivir，静脉注射 一种抑制病毒RNA聚合酶的药物，已获得EUA指定 美国FDA。N4-羟基-胞苷的前药最近已进入I期试验。 我们的目标是合成COVID-19抗病毒药物，抑制病毒RNA聚合酶， 可口服或肌肉注射，特别注重于最大限度地 大量药物进入肺部。 我们将合成Remdesivir和其他核苷类抗冠状病毒的前药 活性使用创新的方法，涉及将它们转化为脂质类似物。 一些化合物将集中于口服递送，而另一些集中于肌内施用。 这些化合物将在体外进行筛选，以对抗非致病性和致病性 包括SARS-CoV-2在内的冠状病毒及其活性与未修饰的 母体核苷它们的药代动力学和毒性的最活跃的抗病毒药物将 在老鼠身上研究。将评价活性抗病毒药物的肺暴露与 未修饰的核苷最后，临床和抗病毒活性最 有希望的化合物将在叙利亚金黄仓鼠模型中进行评估， 冠状病毒病

项目成果

1-O-Octadecyl-2-O-benzyl-sn-glyceryl-3-phospho-GS-441524 (V2043). Evaluation of Oral V2043 in a Mouse Model of SARS-CoV-2 Infection and Synthesis and Antiviral Evaluation of Additional Phospholipid Esters with Enhanced Anti-SARS-CoV-2 Activity.

• DOI: 10.1021/acs.jmedchem.3c00046
• 发表时间: 2023-04-27
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Carlin, Aaron F.;Beadle, James R.;Clark, Alex E.;Gully, Kendra L.;Moreira, Fernando R.;Baric, Ralph S.;Graham, Rachel L.;Valiaeva, Nadejda;Leibel, Sandra L.;Bray, William;McMillan, Rachel E.;Freshman, Jonathan E.;Garretson, Aaron F.;McVicar, Rachael N.;Rana, Tariq;Zhang, Xing-Quan;Murphy, Joyce A.;Schooley, Robert T.;Hostetler, Karl Y.
• 通讯作者: Hostetler, Karl Y.