Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2
Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2
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DOI：
10.1007/s13238-020-00768-w
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发表时间：
2020-08-04
期刊：
影响因子：
21.1
通讯作者：
Xu, Ke
中科院分区：
文献类型：
--
作者：
Xiong, Rui;Zhang, Leike;Xu, Ke
新出现和重新出现的RNA病毒偶尔会在世界范围内引起流行病和大流行病，例如正在爆发的新型冠状病毒SARS-CoV-2。在此，我们鉴定了两种有效的人DHODH抑制剂S312和S416，具有良好的药物相似性和药代动力学特征，它们都显示出对各种RNA病毒的广谱抗病毒作用，包括流感病毒A，寨卡病毒，埃博拉病毒，特别是对SARS-CoV-2。值得注意的是，据报道S416是迄今为止最有效的抑制剂，在感染细胞中的EC（50）为17 nmol/L，SI值为10，505.88。我们的研究结果首次证实DHODH是一个有吸引力的宿主靶点，因为它在体内具有高的抗病毒效力，而在DHODH敲除细胞中病毒复制率低。本研究表明，S312/S416和具有抗病毒和免疫调节双重作用的老药（来氟米特/特立氟米特）可能具有治疗SARS-CoV-2或其他全球流行的RNA病毒的临床潜力，无论这些病毒是否发生突变。
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC(50)of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacyin vivoand low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.