Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, College of Science, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
Medi-X, Academy for Advanced Interdisciplinary Studies, Southern University of Science and Technology, Shenzhen, Guangdong 518055, China.
J Med Chem. 2022 Feb 24;65(4):2785-2793. doi: 10.1021/acs.jmedchem.0c01929. Epub 2021 Feb 1.
The outbreak of coronavirus disease 2019 (COVID-19) has resulted in a global pandemic due to the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the time of this manuscript's publication, remdesivir is the only COVID-19 treatment approved by the United States Food and Drug Administration. However, its effectiveness is still under question due to the results of the large Solidarity Trial conducted by the World Health Organization. Herein, we report that the parent nucleoside of remdesivir, GS-441524, potently inhibits the replication of SARS-CoV-2 in Vero E6 and other cell lines. Challenge studies in both an AAV-hACE2 mouse model of SARS-CoV-2 and in mice infected with murine hepatitis virus, a closely related coronavirus, showed that GS-441524 was highly efficacious in reducing the viral titers in CoV-infected organs without notable toxicity. Our results support that GS-441524 is a promising and inexpensive drug candidate for treating of COVID-19 and other CoV diseases.
2019 年冠状病毒病（COVID-19）的爆发由于严重急性呼吸系统综合症冠状病毒 2（SARS-CoV-2）的迅速传播而导致成为全球性大流行。在本文发表之时，瑞德西韦是唯一获得美国食品和药物管理局批准的 COVID-19 治疗药物。然而，由于世界卫生组织进行的大型团结试验的结果，其有效性仍存在疑问。在此，我们报告瑞德西韦的母核核苷 GS-441524 能够有效抑制 SARS-CoV-2 在 Vero E6 和其他细胞系中的复制。在 SARS-CoV-2 的 AAV-hACE2 小鼠模型和感染密切相关的冠状病毒鼠肝炎病毒的小鼠中的攻毒研究表明，GS-441524 能高效降低感染 CoV 的器官中的病毒滴度，而没有明显的毒性。我们的结果支持 GS-441524 是一种有前途且廉价的治疗 COVID-19 和其他 CoV 疾病的候选药物。
