Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp15 Endoribonuclease
Identifying SARS-CoV-2 Antiviral Compounds by Screening for Small Molecule Inhibitors of Nsp15 Endoribonuclease
复制标题
通过筛选 Nsp15 核糖核酸内切酶小分子抑制剂来鉴定 SARS-CoV-2 抗病毒化合物
DOI：
10.1101/2021.04.07.438811
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Canal B
中科院分区：
文献类型：
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作者：
Canal B
SARS-CoV-2是一种冠状病毒，于2019年出现，并在全球迅速传播，造成了致命的大流行，造成了巨大的社会和经济损失。世界各地的医疗系统承受着巨大的压力，迫切需要有效的抗病毒治疗。目前批准的唯一治疗新冠肺炎的抗病毒药物是瑞德韦，一种病毒基因组复制的抑制剂。SARS-CoV-2的增殖依赖于非结构蛋白(NSP)的酶活性，这使得它们成为开发新的抗病毒治疗的有趣靶点。为了鉴定新的SARS-CoV-2抗病毒药物，我们纯化了外切核糖核酸酶/甲基转移酶(Nsp14)及其辅因子(Nsp10)，并建立了与高通量方法兼容的生化检测方法来筛选外切核糖核酸酶抑制剂。我们已经筛选了5000多种商业化合物的文库，并在体外确定了棒曲霉毒素和金曲霉酸(ATA)是nsp14外核糖核酸酶的抑制剂。我们在Vero E6细胞培养模型中发现棒曲霉毒素和ATA抑制SARS-CoV-2的复制。这两种新的抗病毒化合物将成为进一步研究冠状病毒的宝贵工具，并可能为新冠肺炎带来新的治疗机会。
SARS-CoV-2 is a coronavirus that emerged in 2019 and rapidly spread across the world causing a deadly pandemic with tremendous social and economic costs. Healthcare systems worldwide are under great pressure, and there is an urgent need for effective antiviral treatments. The only currently approved antiviral treatment for COVID-19 is remdesivir, an inhibitor of viral genome replication. SARS-CoV-2 proliferation relies on the enzymatic activities of the non-structural proteins (nsp), which makes them interesting targets for the development of new antiviral treatments. With the aim to identify novel SARS-CoV-2 antivirals, we have purified the exoribonuclease/methyltransferase (nsp14) and its cofactor (nsp10) and developed biochemical assays compatible with high-throughput approaches to screen for exoribonuclease inhibitors. We have screened a library of over 5000 commercial compounds and identified patulin and aurintricarboxylic acid (ATA) as inhibitors of nsp14 exoribonucleasein vitro. We found that patulin and ATA inhibit replication of SARS-CoV-2 in a VERO E6 cell-culture model. These two new antiviral compounds will be valuable tools for further coronavirus research as well as potentially contributing to new therapeutic opportunities for COVID-19.