SARS-CoV-2 has caused a global pandemic, and has taken over 1.7 million lives as of mid-December, 2020. Although great progress has been made in the development of effective countermeasures, with several pharmaceutical companies approved or poised to deliver vaccines to market, there is still an unmet need of essential antiviral drugs with therapeutic impact for the treatment of moderate-to-severe COVID-19. Towards this goal, a high-throughput assay was used to screen SARS-CoV-2 nsp15 uracil-dependent endonuclease (endoU) function against 13 thousand compounds from drug and lead repurposing compound libraries. While over 80% of initial hit compounds were pan-assay inhibitory compounds, three hits were confirmed as nsp15 endoU inhibitors in the 1-20 uM range in vitro. Furthermore, Exebryl-1, a beta-amyloid anti-aggregation molecule for Alzheimers therapy, was shown to have antiviral activity between 10 to 66 uM, in VERO, Caco-2, and Calu-3 cells. Although the inhibitory concentrations determined for Exebryl-1 exceed those recommended for therapeutic intervention, our findings show great promise for further optimization of Exebryl-1 as an nsp15 endoU inhibitor and as a SARS-CoV-2 antiviral.

中文翻译：

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高通量筛选针对SARS-CoV2 nsp15核糖核酸内切酶的ReFRAME，Pandemic Box和COVID Box药物再利用文库，以鉴定病毒活性的小分子抑制剂。

SARS-CoV-2引发了全球性大流行，截至2020年12月中旬，已夺走了170万人的生命。尽管在制定有效对策方面已取得了巨大进展，一些医药公司已获批准或准备向市场上，仍然需要满足对中重度COVID-19的治疗作用的抗病毒药物的需求。为了实现这一目标，使用了一种高通量分析方法来筛选SARS-CoV-2 nsp15尿嘧啶依赖性核酸内切酶（endoU）的功能，以对抗来自药物和铅重新定位化合物库的13,000种化合物。尽管超过80％的初始命中化合物是泛测定抑制化合物，但在体外，三处命中被确认为nsp15 endoU抑制剂。此外，Exebryl-1 一种用于Alzheimers治疗的β-淀粉样蛋白抗聚集分子，在VERO，Caco-2和Calu-3细胞中具有10至66 uM之间的抗病毒活性。尽管确定的Exebryl-1抑制浓度超过了治疗干预的建议浓度，但我们的发现显示出进一步优化Exebryl-1作为nsp15 endoU抑制剂和SARS-CoV-2抗病毒药物的前景。