2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors.
2-((1H-indol-3-yl)thio)-N-phenyl-acetamides: SARS-CoV-2 RNA-dependent RNA polymerase inhibitors.
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2-((1H-吲哚-3-基)硫基)-N-苯基乙酰胺：SARS-CoV-2 RNA 依赖性 RNA 聚合酶抑制剂
DOI：
10.1016/j.antiviral.2021.105209
复制
发表时间：
2021-12
影响因子：
7.6
通讯作者：
Cen S
中科院分区：
文献类型：
--
作者：
Zhao J;Zhang G;Zhang Y;Yi D;Li Q;Ma L;Guo S;Li X;Guo F;Lin R;Luu G;Liu Z;Wang Y;Cen S
严重急性呼吸综合征冠状病毒-2(SARS-CoV-2)是冠状病毒病2019(新冠肺炎)大流行的病原体。尽管全球为发现和开发新的抗病毒疗法做出了密集的努力，但只有Remdevir被批准用于治疗新冠肺炎。因此，仍然迫切需要有效的抗病毒疗法来抗击和遏制这一大流行。SARS-CoV-2的病毒RNA依赖的RNA聚合酶(RdRp)显示出作为抗病毒药物开发的可靠靶点的高潜力。我们之前开发了一种基于细胞的测试来评估针对SARS-CoV-2RdRp的化合物的效率，以及它们对病毒外切核酸酶介导的校对的耐受性。在我们之前的研究中，我们发现2-((1H-吲哚-3-基)硫代)-N-苯基乙酰胺可以特异性地靶向呼吸道合胞病毒(RSV)和甲型流感病毒的RdRp。因此，我们推测2-((1H-吲哚-3-基)硫代)-N-苯基乙酰胺也可能通过靶向其RdRp活性来抑制SARS-CoV-2的复制。在这项研究中，我们使用基于细胞的方法测试了包含103个2-((1H-吲哚-3-基)硫代)-N-苯基乙酰胺的化合物文库对SARS-CoV-2RdRp的抑制作用。在这些化合物中，前五个候选化合物强烈抑制SARS-CoV-2RdRp活性，同时表现出低细胞毒性和对病毒外切核糖核酸酶的抗性。化合物6-72-2a具有最低的EC_(50)值1.41μM和最高的选择性指数(CC_(50)/EC_(50))(>70.92)，是最有前景的候选化合物。此外，4-46b和6-72-2a对HCoV-OC43和HCoV-NL63病毒的复制也有抑制作用，且呈剂量依赖关系。化合物4-46b和6-72-2a对HCoV-OC43病毒复制的EC50值分别为1.13%μM和0.94%μM。然而，需要更高浓度的这些化合物才能有效地阻止HCoV-NL63的复制。总之，我们的发现成功地确定了4-46b和6-72-2a是有希望的SARS-CoV-2 RdRp的抑制剂。
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19) pandemic. Despite intensive and global efforts to discover and develop novel antiviral therapies, only Remdesivir has been approved as a treatment for COVID-19. Therefore, effective antiviral therapeutics are still urgently needed to combat and halt the pandemic. Viral RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 demonstrates high potential as a reliable target for the development of antivirals. We previously developed a cell-based assay to assess the efficiency of compounds that target SARS-CoV-2 RdRp, as well as their tolerance to viral exoribonuclease-mediated proof-reading. In our previous study, we discovered that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides specifically targets the RdRp of both respiratory syncytial virus (RSV) and influenza A virus. Thus, we hypothesize that 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides may also have the ability to inhibit SARS-CoV-2 replication by targeting its RdRp activity. In this research, we test a compound library containing 103 of 2-((1H-indol-3-yl)thio)-N-phenyl-acetamides against SARS-CoV-2 RdRp, using our cell-based assay. Among these compounds, the top five candidates strongly inhibit SARS-CoV-2 RdRp activity while exhibiting low cytotoxicity and resistance to viral exoribonuclease. Compound 6-72-2a is the most promising candidate with the lowest EC50 value of 1.41 μM and highest selectivity index (CC50/EC50) (above 70.92). Furthermore, our data suggests that 4–46b and 6-72-2a also inhibit the replication of HCoV-OC43 and HCoV-NL63 virus in a dose-dependent manner. Compounds 4–46b and 6-72-2a exhibit EC50 values of 1.13 μM and 0.94 μM, respectively, on HCoV-OC43 viral replication. However, higher concentrations of these compounds are needed to effectively block HCoV-NL63 replication. Together, our findings successfully identified 4–46b and 6-72-2a as promising inhibitors against SARS-CoV-2 RdRp.
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Corilagin 通过靶向病毒 RNA 依赖性 RNA 聚合酶抑制 SARS-CoV-2 复制
DOI：
10.1016/j.apsb.2021.02.011
发表时间：
2021-06
期刊：
Acta pharmaceutica Sinica. B
影响因子：
--
作者：
Li Q;Yi D;Lei X;Zhao J;Zhang Y;Cui X;Xiao X;Jiao T;Dong X;Zhao X;Zeng H;Liang C;Ren L;Guo F;Li X;Wang J;Cen S
通讯作者：
Cen S
影响因子：
4.4
作者：
Chien M;Anderson TK;Jockusch S;Tao C;Li X;Kumar S;Russo JJ;Kirchdoerfer RN;Ju J
通讯作者：
Ju J
影响因子：
7.6
作者：
Zhao J;Guo S;Yi D;Li Q;Ma L;Zhang Y;Wang J;Li X;Guo F;Lin R;Liang C;Liu Z;Cen S
通讯作者：
Cen S
影响因子：
7.6
作者：
Jockusch, Steffen;Tao, Chuanjuan;Ju, Jingyue
通讯作者：
Ju, Jingyue
DOI：
10.1177/2472555220942123
发表时间：
2020-12
期刊：
SLAS discovery : advancing life sciences R & D
影响因子：
--
作者：
Zhu W;Chen CZ;Gorshkov K;Xu M;Lo DC;Zheng W
通讯作者：
Zheng W