Nucleotide analogues as inhibitors of SARS-CoV Polymerase.
Nucleotide analogues as inhibitors of SARS-CoV Polymerase.
复制标题
DOI：
10.1002/prp2.674
复制
发表时间：
2020-12
影响因子：
2.6
通讯作者：
Russo JJ
中科院分区：
文献类型：
--
作者：
Ju J;Li X;Kumar S;Jockusch S;Chien M;Tao C;Morozova I;Kalachikov S;Kirchdoerfer RN;Russo JJ
SARS-CoV-2是冠状病毒家族的一员，已引发全球公共卫生紧急事件。基于我们对丙型肝炎病毒和冠状病毒复制的分析，以及病毒抑制剂的分子结构和活性，我们先前推断FDA批准的丙型肝炎药物EPCLUSA（Sofosbuvir/Velpatasvir）应该抑制冠状病毒，包括SARS-CoV-2。在这里，使用模型聚合酶延伸实验，我们证明了索非布韦的活性三磷酸形式被低保真聚合酶和SARS冠状病毒RNA依赖性RNA聚合酶（RdRp）掺入，并阻止这些聚合酶的进一步掺入;索非布韦的活性三磷酸形式不被宿主样高保真DNA聚合酶掺入。使用相同的分子洞察力，我们选择了3 '-氟-3'-脱氧胸苷三磷酸和3 '-叠氮基-3'-脱氧胸苷三磷酸，这是另外两种抗病毒药物Alovudine和AZT（FDA批准的HIV/AIDS药物）的活性形式，用于评估SARS-CoV RdRp的抑制剂。我们证明了这些HIV逆转录酶抑制剂中的两种能够被SARS-CoV RdRp掺入，它们也终止了进一步的聚合酶延伸。鉴于SARS-CoV和SARS-CoV-2 RdRps的98%氨基酸相似性，我们预计这些核苷酸类似物也会抑制SARS-CoV-2聚合酶。这些结果为进一步修饰这些核苷酸类似物以产生更有效的广谱抗冠状病毒药物提供了指导。Sofosbuvir的三磷酸形式被SARS冠状病毒聚合酶掺入，以终止进一步的引物延伸，从而可能阻止病毒的复制。
SARS‐CoV‐2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA‐approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS‐CoV‐2. Here, using model polymerase extension experiments, we demonstrate that the active triphosphate form of Sofosbuvir is incorporated by low‐fidelity polymerases and SARS‐CoV RNA‐dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the active triphosphate form of Sofosbuvir is not incorporated by a host‐like high‐fidelity DNA polymerase. Using the same molecular insight, we selected 3’‐fluoro‐3’‐deoxythymidine triphosphate and 3’‐azido‐3’‐deoxythymidine triphosphate, which are the active forms of two other anti‐viral agents, Alovudine and AZT (an FDA‐approved HIV/AIDS drug) for evaluation as inhibitors of SARS‐CoV RdRp. We demonstrate the ability of two of these HIV reverse transcriptase inhibitors to be incorporated by SARS‐CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS‐CoV and SARS‐CoV‐2 RdRps, we expect these nucleotide analogues would also inhibit the SARS‐CoV‐2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad‐spectrum anti‐coronavirus agents. The triphosphate form of Sofosbuvir is incorporated by SARS‐CoV polymerase to terminate further primer extension, potentially preventing replication of the virus.
登录
查看更多内容
线粒体转录和RNA聚合酶II依赖性核转录对抗病毒核糖核苷的敏感性。
影响因子：
6.7
作者：
Arnold JJ;Sharma SD;Feng JY;Ray AS;Smidansky ED;Kireeva ML;Cho A;Perry J;Vela JE;Park Y;Xu Y;Tian Y;Babusis D;Barauskus O;Peterson BR;Gnatt A;Kashlev M;Zhong W;Cameron CE
通讯作者：
Cameron CE
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：
3.2
作者：
D'Andrea, Gabriele;Brisdelli, Fabrizia;Bozzi, Argante
通讯作者：
Bozzi, Argante
DOI：
10.1073/pnas.83.21.8333
发表时间：
1986-11-01
影响因子：
11.1
作者：
FURMAN, PA;FYFE, JA;BARRY, DW
通讯作者：
BARRY, DW
影响因子：
7.4
作者：
Buonaguro, Luigi;Tagliamonte, Maria;Buonaguro, Franco M.
通讯作者：
Buonaguro, Franco M.