Ding Shilei, Ullah Irfan, Gong Shang Yu, Grover Jonathan R, Mohammadi Mohammadjavad, Chen Yaozong, Vézina Dani, Beaudoin-Bussières Guillaume, Verma Vijay Tailor, Goyette Guillaume, Gaudette Fleur, Richard Jonathan, Yang Derek, Smith Amos B, Pazgier Marzena, Côté Marceline, Abrams Cameron, Kumar Priti, Mothes Walther, Uchil Pradeep D, Finzi Andrés, Baron Christian
Centre de recherche du CHUM, Montréal, QC, Canada.
Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA.
iScience. 2022 Jul 15;25(7):104528. doi: 10.1016/j.isci.2022.104528. Epub 2022 Jun 3.
SARS-CoV-2 infection of host cells starts by binding the Spike glycoprotein (S) to the ACE2 receptor. The S-ACE2 interaction is a potential target for therapies against COVID-19 as demonstrated by the development of immunotherapies blocking this interaction. VE607 - a commercially available compound composed of three stereoisomers - was described as an inhibitor of SARS-CoV-1. Here, we show that VE607 broadly inhibits pseudoviral particles bearing the Spike from major VOCs (D614G, Alpha, Beta, Gamma, Delta, Omicron - BA.1, and BA.2) as well as authentic SARS-CoV-2 at low micromolar concentrations. docking, mutational analysis, and smFRET revealed that VE607 binds to the receptor binding domain (RBD)-ACE2 interface and stabilizes RBD in its "up" conformation. Prophylactic treatment with VE607 did not prevent SARS-CoV-2-induced mortality in K18-hACE2 mice, but it did reduce viral replication in the lungs by 37-fold. Thus, VE607 is an interesting lead for drug development for the treatment of SARS-CoV-2 infection.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染宿主细胞始于刺突糖蛋白（S）与血管紧张素转换酶2（ACE2）受体结合。如通过开发阻断这种相互作用的免疫疗法所证明的，S-ACE2相互作用是抗2019冠状病毒病（COVID-19）治疗的一个潜在靶点。VE607是一种由三种立体异构体组成的市售化合物，曾被描述为严重急性呼吸综合征冠状病毒1（SARS-CoV-1）的抑制剂。在此，我们表明，VE607在低微摩尔浓度下可广泛抑制携带来自主要变异株（D614G、阿尔法、贝塔、伽马、德尔塔、奥密克戎-BA.1和BA.2）的刺突蛋白的假病毒颗粒以及真实的SARS-CoV-2。对接、突变分析和单分子荧光共振能量转移显示，VE607与受体结合域（RBD）-ACE2界面结合，并使RBD稳定在其“向上”构象。用VE607进行预防性治疗并不能预防SARS-CoV-2诱导的K18-hACE2小鼠死亡，但它确实使肺部的病毒复制减少了37倍。因此，VE607是治疗SARS-CoV-2感染药物开发的一个有吸引力的先导物。
