Sofosbuvir terminated RNA is more resistant to SARS-CoV-2 proofreader than RNA terminated by Remdesivir.
Sofosbuvir terminated RNA is more resistant to SARS-CoV-2 proofreader than RNA terminated by Remdesivir.
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DOI：
10.1038/s41598-020-73641-9
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发表时间：
2020-10-06
影响因子：
4.6
通讯作者：
Ju J
中科院分区：
文献类型：
--
作者：
Jockusch S;Tao C;Li X;Chien M;Kumar S;Morozova I;Kalachikov S;Russo JJ;Ju J
SARS-CoV-2是COVID-19的罪魁祸首，导致了一百多年来最大的流行病。在检查了丙型肝炎病毒抑制剂的分子结构和活性并比较了丙型肝炎病毒和冠状病毒的复制后，我们先前假设FDA批准的丙型肝炎药物EPCLUSA（Sofosbuvir/Velpatasvir）可能抑制SARS-CoV-2。我们随后证明了Sofosbuvir三磷酸被相对低保真度的SARS-CoV和SARS-CoV-2 RNA依赖性RNA聚合酶（RdRps）掺入，作为即时聚合酶反应终止剂，但不被宿主样高保真DNA聚合酶掺入。此后，其他研究人员证明了Sofosbuvir抑制SARS-CoV-2在肺和脑细胞中复制的能力;此外，EPCLUSA和Sofosbuvir + Daclatasvir的COVID-19临床试验已在几个国家启动。SARS-CoV-2有一个基于核酸外切酶的校对器，以保持病毒基因组的完整性。任何针对SARS-CoV-2 RdRp的有效抗病毒药物都必须对这种校正活性表现出一定程度的抗性。我们在这里报告说，索非布韦终止的RNA对核酸外切酶去除的抵抗力远高于瑞德西韦（另一种用作COVID-19治疗药物的药物）终止的RNA。这些结果提供了支持索非布韦与其他药物联合用于COVID-19临床试验的分子基础。
SARS-CoV-2 is responsible for COVID-19, resulting in the largest pandemic in over a hundred years. After examining the molecular structures and activities of hepatitis C viral inhibitors and comparing hepatitis C virus and coronavirus replication, we previously postulated that the FDA-approved hepatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) might inhibit SARS-CoV-2. We subsequently demonstrated that Sofosbuvir triphosphate is incorporated by the relatively low fidelity SARS-CoV and SARS-CoV-2 RNA-dependent RNA polymerases (RdRps), serving as an immediate polymerase reaction terminator, but not by a host-like high fidelity DNA polymerase. Other investigators have since demonstrated the ability of Sofosbuvir to inhibit SARS-CoV-2 replication in lung and brain cells; additionally, COVID-19 clinical trials with EPCLUSA and with Sofosbuvir plus Daclatasvir have been initiated in several countries. SARS-CoV-2 has an exonuclease-based proofreader to maintain the viral genome integrity. Any effective antiviral targeting the SARS-CoV-2 RdRp must display a certain level of resistance to this proofreading activity. We report here that Sofosbuvir terminated RNA resists removal by the exonuclease to a substantially higher extent than RNA terminated by Remdesivir, another drug being used as a COVID-19 therapeutic. These results offer a molecular basis supporting the current use of Sofosbuvir in combination with other drugs in COVID-19 clinical trials.
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