Wu Canrong, Zheng Mengzhu, Yang Yueying, Gu Xiaoxia, Yang Kaiyin, Li Mingxue, Liu Yang, Zhang Qingzhe, Zhang Peng, Wang Yali, Wang Qiqi, Xu Yang, Zhou Yirong, Zhang Yonghui, Chen Lixia, Li Hua
Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
iScience. 2020 Oct 23;23(10):101642. doi: 10.1016/j.isci.2020.101642. Epub 2020 Oct 5.
COVID-19 broke out in the end of December 2019 and is still spreading rapidly, which has been listed as an international concerning public health emergency. We found that the Spike protein of SARS-CoV-2 contains a furin cleavage site, which did not exist in any other betacoronavirus subtype B. Based on a series of analysis, we speculate that the presence of a redundant furin cut site in its Spike protein is responsible for SARS-CoV-2's stronger infectious nature than other coronaviruses, which leads to higher membrane fusion efficiency. Subsequently, a library of 4,000 compounds including approved drugs and natural products was screened against furin through structure-based virtual screening and then assayed for their inhibitory effects on furin activity. Among them, an anti-parasitic drug, diminazene, showed the highest inhibition effects on furin with an IC of 5.42 ± 0.11 μM, which might be used for the treatment of COVID-19.
2019年12月底，新型冠状病毒肺炎（COVID-19）爆发，且仍在迅速传播，已被列为国际关注的突发公共卫生事件。我们发现，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的刺突蛋白含有一个弗林蛋白酶切割位点，而在任何其他B型β冠状病毒亚型中均不存在该位点。基于一系列分析，我们推测其刺突蛋白中多余的弗林蛋白酶切割位点的存在，是SARS-CoV-2比其他冠状病毒具有更强传染性的原因，这导致了更高的膜融合效率。随后，通过基于结构的虚拟筛选，针对4000种包括已批准药物和天然产物的化合物库进行了弗林蛋白酶筛选，然后测定了它们对弗林蛋白酶活性的抑制作用。其中，一种抗寄生虫药物，二脒那嗪，对弗林蛋白酶的抑制作用最高，IC50为5.42±0.11μM，可用于治疗COVID-19。
