Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease.
Identifying SARS-CoV-2 antiviral compounds by screening for small molecule inhibitors of nsp14/nsp10 exoribonuclease.
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DOI：
10.1042/bcj20210198
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发表时间：
2021-07-16
期刊：
影响因子：
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通讯作者：
Diffley JFX
中科院分区：
文献类型：
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作者：
Canal B;McClure AW;Curran JF;Wu M;Ulferts R;Weissmann F;Zeng J;Bertolin AP;Milligan JC;Basu S;Drury LS;Deegan TD;Fujisawa R;Roberts EL;Basier C;Labib K;Beale R;Howell M;Diffley JFX
SARS-CoV-2是一种冠状病毒，于2019年出现，并迅速在世界各地蔓延，造成致命的大流行，造成巨大的社会和经济成本。全球的医疗系统都面临巨大的压力，迫切需要有效的抗病毒治疗。目前唯一获批的COVID-19抗病毒治疗药物是瑞德西韦，一种病毒基因组复制抑制剂。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。为了鉴定新型SARS-CoV-2抗病毒药物，我们纯化了核糖核酸外切酶/甲基转移酶（nsp 14）及其辅因子（nsp 10），并开发了与高通量方法兼容的生化检测方法来筛选核糖核酸外切酶抑制剂。我们已经筛选了超过5000个商业化合物的库，并确定展青霉素和金精三羧酸（ATA）作为体外nsp 14核糖核酸外切酶的抑制剂。我们发现，展青霉素和ATA抑制复制SARS-CoV-2在VERO E6细胞培养模型。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COVID-19提供新的治疗机会。
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 exoribonuclease in 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.