Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice.
Therapeutic treatment with an oral prodrug of the remdesivir parental nucleoside is protective against SARS-CoV-2 pathogenesis in mice.
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口服瑞德西韦亲本核苷前药对小鼠SARS-CoV-2发病机制具有保护作用。
DOI：
10.1126/scitranslmed.abm3410
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发表时间：
2022-05-04
影响因子：
17.1
通讯作者：
Sheahan TP
中科院分区：
文献类型：
--
作者：
Schäfer A;Martinez DR;Won JJ;Meganck RM;Moreira FR;Brown AJ;Gully KL;Zweigart MR;Conrad WS;May SR;Dong S;Kalla R;Chun K;Du Pont V;Babusis D;Tang J;Murakami E;Subramanian R;Barrett KT;Bleier BJ;Bannister R;Feng JY;Bilello JP;Cihlar T;Mackman RL;Montgomery SA;Baric RS;Sheahan TP
尽管安全有效的SARS-CoV-2疫苗迅速推出，但2019冠状病毒病（COVID-19）大流行仍未得到控制，这突显了开发高效抗病毒药物的必要性。在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常见，治疗选择仍然有限。此外，SARS-CoV-2变异体的出现令人担忧，它们有可能逃避治疗性单克隆抗体的中和作用，这强调了开发第二代口服抗病毒药物的必要性，这些药物靶向高度保守的病毒蛋白，可以迅速部署到门诊患者。在这里，我们证明了GS-621763的体外抗病毒活性和体内治疗功效，GS-441524是Remdesivir的母体核苷，其靶向高度保守的病毒RNA依赖性RNA聚合酶，GS-621763是GS-441524的口服生物可利用的前药。GS-621763在肺细胞系和两种不同的人原代肺细胞培养系统中显示出抗SARS-CoV-2的抗病毒活性。GS-621763还对一种基因上不相关的新型冠状病毒中东呼吸综合征CoV（MERS-CoV）具有强效抗病毒作用。口服GS-621763后观察到的与剂量成比例的药代动力学特征转化为感染SARS-CoV-2的小鼠的剂量依赖性抗病毒活性。治疗性GS-621763给药降低了病毒载量和肺病理学;治疗还改善了COVID-19小鼠模型的肺功能。GS-621763与最近获得EUA批准的口服核苷类似物抗病毒药物molnupiravir的直接比较证明，这两种药物在小鼠中具有相似的有效性。这些数据支持探索GS-441524口服前药用于治疗COVID-19。口服前药GS-621763在体内外均具有抗SARS-CoV-2的作用。
The coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome coronavirus 2 (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 neutralization by 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 parent nucleoside of remdesivir, which targets the highly conserved virus RNA-dependent RNA polymerase. GS-621763 exhibited antiviral activity against SARS-CoV-2 in lung cell lines and two different human primary lung cell culture systems. GS-621763 was also potently antiviral against a genetically unrelated emerging coronavirus, Middle East Respiratory Syndrome CoV (MERS-CoV). 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 administration reduced viral load and lung pathology; treatment also improved pulmonary function in COVID-19 mouse model. A direct comparison of GS-621763 with molnupiravir, an oral nucleoside analog antiviral which has recently received EUA approval, proved both drugs to be similarly efficacious in mice. These data support the exploration of GS-441524 oral prodrugs for the treatment of COVID-19. The oral prodrug, GS-621763, is potently antiviral against SARS-CoV-2 in vitro and in vivo.
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影响因子：
64.5
作者：
Hou, Yixuan J.;Okuda, Kenichi;Baric, Ralph S.
通讯作者：
Baric, Ralph S.
影响因子：
7.6
作者：
Brown, Ariane J.;Won, John J.;Sheahan, Timothy P.
通讯作者：
Sheahan, Timothy P.
影响因子：
7.3
作者：
Mackman, Richard L.;Hui, Hon C.;Cihlar, Tomas
通讯作者：
Cihlar, Tomas
影响因子：
158.5
作者：
Grein, J.;Ohmagari, N.;Flanigan, T.
通讯作者：
Flanigan, T.
SARS-COV-2 RNA复制复合物在全球循环分离株中的遗传保护，最近从人类中出现了变体，这表明对Remdesivir的耐药性最小。
影响因子：
7.6
作者：
Martin R;Li J;Parvangada A;Perry J;Cihlar T;Mo H;Porter D;Svarovskaia E
通讯作者：
Svarovskaia E