The COVID-19 pandemic remains uncontrolled despite the rapid rollout of safe and effective SARS-CoV-2 vaccines, underscoring the need to develop highly effective antivirals. In the setting of waning immunity from infection and vaccination, breakthrough infections are becoming increasingly common and treatment options remain limited. Additionally, the emergence of SARS-CoV-2 variants of concern with their potential to escape therapeutic monoclonal antibodies emphasizes the need to develop second-generation oral antivirals targeting highly conserved viral proteins that can be rapidly deployed to outpatients. Here, we demonstrate the in vitro antiviral activity and in vivo therapeutic efficacy of GS-621763, an orally bioavailable prodrug of GS-441524, the parental nucleoside of remdesivir, which targets the highly conserved RNA-dependent RNA polymerase. GS-621763 exhibited significant antiviral activity in lung cell lines and two different human primary lung cell culture systems. The dose-proportional pharmacokinetic profile observed after oral administration of GS-621763 translated to dose-dependent antiviral activity in mice infected with SARS-CoV-2. Therapeutic GS-621763 significantly reduced viral load, lung pathology, and improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral currently in human clinical trial, proved both drugs to be similarly efficacious. These data demonstrate that therapy with oral prodrugs of remdesivir can significantly improve outcomes in SARS-CoV-2 infected mice. Thus, GS-621763 supports the exploration of GS-441524 oral prodrugs for the treatment of COVID-19 in humans.

中文翻译：

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瑞德西韦口服核苷类似物对小鼠 SARS-CoV-2 发病机制的治疗效果

尽管安全有效的 SARS-CoV-2 疫苗迅速推出，但 COVID-19 大流行仍未得到控制，这凸显了开发高效抗病毒药物的必要性。在对感染和疫苗接种的免疫力减弱的情况下，突破性感染变得越来越普遍，治疗选择仍然有限。此外，由于 SARS-CoV-2 变体有可能逃脱治疗性单克隆抗体的出现，这强调了开发针对高度保守病毒蛋白的第二代口服抗病毒药物的必要性，这些蛋白可以快速应用于门诊患者。在这里，我们展示了 GS-621763 的体外抗病毒活性和体内治疗功效，GS-441524 是瑞德西韦的亲本核苷的一种口服生物可利用的前药，其靶向高度保守的RNA依赖性RNA聚合酶。GS-621763 在肺细胞系和两种不同的人原代肺细胞培养系统中表现出显着的抗病毒活性。口服 GS-621763 后观察到的剂量比例药代动力学曲线转化为感染 SARS-CoV-2 的小鼠的剂量依赖性抗病毒活性。治疗性 GS-621763 在 COVID-19 小鼠模型中显着降低了病毒载量、肺病理学并改善了肺功能。将 GS-621763 与目前正在进行人体临床试验的口服核苷类似物抗病毒药物 molnupiravir 进行直接比较，证明这两种药物同样有效。这些数据表明，使用瑞德西韦的口服前药治疗可以显着改善 SARS-CoV-2 感染小鼠的预后。因此，