Abstract：
The severe acute respiratory syndrome coronavirus (SARS-CoV-2) pandemic has triggered a significant impact on global public health security, it is urgent to develop effective antiviral drugs. Previous studies have found that binding to ACE2 is a key step in the invasion of SARS-CoV-2 into host cells, so virus invasion can be inhibited by blocking ACE2, but there are few reports on this kind of specific inhibitor. Our previous study found that Harringtonine (HT) can inhibit the entry of SARS-CoV-2 spike pseudovirus into ACE2h cells, but its relatively high cytotoxicity limits its further development. Amino acid modification of the active components can increase their solubility and reduce their cytotoxicity. Therefore, in this study, seven new derivatives were synthesized by amino acid modification of its core structure Cephalotaxine. The target compounds were evaluated by cell viability assay and the SARS-CoV-2 spike pseudovirus entry assay. Compound CET-1 significantly inhibited the entry of pseudovirus into ACE2h cells and showed less cytotoxicity than HT. Molecular docking results showed that CET-1 could bind TYR83, an important residue of ACE2, just like HT. In conclusion, our study provided a novel compound with more potential activity and lower toxicity than HT on inhibiting the SARS-CoV-2 spike pseudovirus infection, which makes it possible to be a lead compound as an antiviral drug in the future.
摘要：
严重急性呼吸道综合症冠状病毒（SARS-CoV-2）大流行对全球公共卫生安全产生了重大影响，迫切需要开发有效的抗病毒药物。先前的研究发现，与ACE2结合是SARS-CoV-2侵入宿主细胞的关键步骤，因此，阻断ACE2可以抑制病毒的侵袭，但很少有关于这种特异性抑制剂的报道。我们先前的研究发现，三尖杉酯碱（HT）可以抑制SARS-CoV-2刺突假病毒进入ACE2h细胞，但其相对较高的细胞毒性限制了其进一步发展。活性组分的氨基酸修饰可以增加其溶解度并降低其细胞毒性。因此,在这项研究中，通过对其核心结构的氨基酸修饰合成了七种新的衍生物。通过细胞活力测定和SARS-CoV-2刺突假病毒进入测定来评估目标化合物。化合物CET-1显著抑制假病毒进入ACE2h细胞,并且显示出比HT更小的细胞毒性。分子对接结果表明，CET-1与HT一样，可以与ACE2的重要残基TYR83结合。总之,我们的研究提供了一种新的化合物，在抑制SARS-CoV-2尖峰假病毒感染方面具有比HT更高的潜在活性和更低的毒性，这使得将来成为抗病毒药物的先导化合物成为可能。
