Revising Anti-coronavirus Compounds to Enhance Activity and Optimize Delivery

项目摘要/摘要 目前新冠肺炎的爆发在全球范围内对发病率和 死亡率。目前还没有疫苗可用，也没有有效的治疗方法。 SARS-CoV-2019已获得FDA的全面批准。Remdevir，静脉注射 抑制病毒RNA聚合酶的药物已获得EUA认证 由美国食品和药物管理局批准。N4-羟基胞苷的一种前药最近进入了第一阶段试验。 我们的目标是合成抑制病毒RNA聚合酶和新冠肺炎的抗病毒药物 可口服或肌肉注射，特别注重提供最大限度的 肺部的药量。 我们将与抗冠状病毒一起合成瑞司他韦和其他核苷的前体药物 使用一种创新的方法进行活动，包括将它们转化为类脂类似物。 一些化合物将侧重于口服给药，而另一些化合物将侧重于肌肉注射。 这些化合物将在体外进行非致病和致病筛选。 包括SARS-CoV-2在内的冠状病毒及其与未经修饰的病毒活性的比较 母体核苷。它们对最有效的抗病毒药物的药代动力学和毒性 在大鼠身上进行研究。活性抗病毒药物将被评估与肺部暴露相比 它们未经修饰的核苷。最后，对大黄连的临床和抗病毒活性 有希望的化合物将在叙利亚金黄地鼠模型中进行评估 冠状病毒病。

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.