Schäfer Alexandra, Martinez David R, Won John J, Moreira Fernando R, Brown Ariane J, Gully Kendra L, Kalla Rao, Chun Kwon, Du Pont Venice, Babusis Darius, Tang Jennifer, Murakami Eisuke, Subramanian Raju, Barrett Kimberly T, Bleier Blake J, Bannister Roy, Feng Joy Y, Bilello John P, Cihlar Tomas, Mackman Richard L, Montgomery Stephanie A, Baric Ralph S, Sheahan Timothy P
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
These authors contributed equally to this manuscript.
bioRxiv. 2021 Sep 17:2021.09.13.460111. doi: 10.1101/2021.09.13.460111.
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.
尽管已迅速推出安全有效的严重急性呼吸综合征冠状病毒2（SARS-CoV-2）疫苗，但新冠疫情仍未得到控制，这凸显了开发高效抗病毒药物的必要性。在感染和疫苗接种导致免疫力下降的情况下，突破性感染越来越常见，而治疗选择仍然有限。此外，令人担忧的SARS-CoV-2变种的出现及其逃逸治疗性单克隆抗体的可能性，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，这些药物可以迅速应用于门诊患者。在此，我们展示了GS-621763的体外抗病毒活性和体内治疗效果，GS-621763是瑞德西韦的母体核苷GS-441524的口服生物利用前药，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著的抗病毒活性。口服GS-621763后观察到的剂量比例药代动力学特征转化为感染SARS-CoV-2的小鼠体内的剂量依赖性抗病毒活性。在新冠小鼠模型中，治疗性GS-621763显著降低了病毒载量、肺部病理损伤，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莫努匹韦进行直接比较，结果证明这两种药物疗效相似。这些数据表明，使用瑞德西韦的口服前药进行治疗可以显著改善感染SARS-CoV-2小鼠的预后。因此，GS-621763支持探索GS-441524口服前药用于治疗人类新冠病毒病。
