Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase
Broad spectrum antiviral remdesivir inhibits human endemic and zoonotic deltacoronaviruses with a highly divergent RNA dependent RNA polymerase
复制标题
DOI：
10.1016/j.antiviral.2019.104541
复制
发表时间：
2019-09-01
影响因子：
7.6
通讯作者：
Sheahan, Timothy P.
中科院分区：
文献类型：
--
作者：
Brown, Ariane J.;Won, John J.;Sheahan, Timothy P.
遗传多样性的正冠状病毒（CoV）家族易于在人类和牲畜中跨物种传播和疾病出现。在野生动物和家畜中传播的与已知流行毒株相似的病毒进一步增加了未来出现的概率。目前，对于任何存在明显未满足医疗需求的人类CoV，还没有批准的治疗方法。Remdesivir（RDV，GS-5734）是腺苷类似物的单磷酰胺酯前药，通过靶向病毒RNA依赖性RNA聚合酶（RdRp），对一系列RNA病毒家族具有有效活性，包括丝状病毒科、副粘病毒科、肺炎病毒科和正冠状病毒亚科。我们开发了多种检测方法，以进一步确定RDV对CoV家族的抗病毒活性的广度。在这里，我们显示了RDV对地方性人类CoV OC 43（HCoV-OC 43）和229 E（HCoV-229 E）的有效抗病毒活性，具有亚微摩尔EC 50值。在已知的CoV中，与SARS-和MERS-CoV相比，三角洲冠状病毒属的成员具有最不同的RdRp，并且禽类和猪的成员都在RdRp中具有赋予β-CoV抗性的天然残基。然而，RDV对猪三角洲冠状病毒（PDCoV）高度有效。这些数据进一步扩展了RDV的已知广度和抗病毒活性，包括当代人类和高度分化的人畜共患病CoV，并可能增强我们对抗未来新出现的CoV的能力。
The genetically diverse Orthocoronavirinae (CoV) family is prone to cross species transmission and disease emergence in both humans and livestock. Viruses similar to known epidemic strains circulating in wild and domestic animals further increase the probability of emergence in the future. Currently, there are no approved therapeutics for any human CoV presenting a clear unmet medical need. Remdesivir (RDV, GS-5734) is a monophosphoramidate prodrug of an adenosine analog with potent activity against an array of RNA virus families including Filoviridae, Paramyxoviridae, Pneumoviridae, and Orthocoronavirinae, through the targeting of the viral RNA dependent RNA polymerase (RdRp). We developed multiple assays to further define the breadth of RDV antiviral activity against the CoV family. Here, we show potent antiviral activity of RDV against endemic human CoVs OC43 (HCoV-OC43) and 229E (HCoV-229E) with submicromolar EC50 values. Of known CoVs, the members of the deltacoronavirus genus have the most divergent RdRp as compared to SARS- and MERS-CoV and both avian and porcine members harbor a native residue in the RdRp that confers resistance in beta-CoVs. Nevertheless, RDV is highly efficacious against porcine deltacoronavirus (PDCoV). These data further extend the known breadth and antiviral activity of RDV to include both contemporary human and highly divergent zoonotic CoV and potentially enhance our ability to fight future emerging CoV.