Tsegay Kaleb B, Adeyemi Christiana M, Gniffke Edward P, Sather D Noah, Walker John K, Smith Stephen E P
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, United States.
St. Louis University School of Medicine, Department of Pharmacology and Physiology, St. Louis, MO, United States.
Front Pharmacol. 2021 Jun 14;12:685308. doi: 10.3389/fphar.2021.685308. eCollection 2021.
Repurposed drugs that block the interaction between the SARS-CoV-2 spike protein and its receptor ACE2 could offer a rapid route to novel COVID-19 treatments or prophylactics. Here, we screened 2,701 compounds from a commercial library of drugs approved by international regulatory agencies for their ability to inhibit the binding of recombinant, trimeric SARS-CoV-2 spike protein to recombinant human ACE2. We identified 56 compounds that inhibited binding in a concentration-dependent manner, measured the IC of binding inhibition, and computationally modeled the docking of the best inhibitors to the Spike-ACE2 binding interface. The best candidates were Thiostrepton, Oxytocin, Nilotinib, and Hydroxycamptothecin with IC50's in the 4-9 μM range. These results highlight an effective screening approach to identify compounds capable of disrupting the Spike-ACE2 interaction, as well as identify several potential inhibitors of the Spike-ACE2 interaction.
能够阻断严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白与其受体血管紧张素转换酶2（ACE2）之间相互作用的重新利用药物，可能为新型冠状病毒肺炎（COVID-19）的治疗或预防提供一条快速途径。在此，我们从国际监管机构批准的商业药物库中筛选了2701种化合物，以评估它们抑制重组三聚体SARS-CoV-2刺突蛋白与重组人ACE2结合的能力。我们鉴定出56种以浓度依赖性方式抑制结合的化合物，测量了结合抑制的半数抑制浓度（IC），并通过计算机模拟了最佳抑制剂与刺突蛋白-ACE2结合界面的对接。最佳候选药物为硫链丝菌素、催产素、尼洛替尼和羟基喜树碱，其半数抑制浓度（IC50）在4-9微摩尔范围内。这些结果突出了一种有效的筛选方法，可用于鉴定能够破坏刺突蛋白-ACE2相互作用的化合物，同时也鉴定出了几种刺突蛋白-ACE2相互作用的潜在抑制剂。
