Ding Shilei, Gong Shang Yu, Grover Jonathan, Mohammadi Mohammadjavad, Chen Yaozong, Vézina Dani, Beaudoin-Bussières Guillaume, Verma Vijay Tailor, Goyette Guillaume, Richard Jonathan, Yang Derek, Smith Amos B, Pazgier Marzena, Côté Marceline, Abrams Cameron, Mothes Walther, Finzi Andrés, Baron Christian
bioRxiv. 2022 Feb 22:2022.02.03.479007. doi: 10.1101/2022.02.03.479007.
SARS-CoV-2 infection of host cells starts by binding of 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. Here, we present the commercially available VE607, comprised of three stereoisomers, that was originally described as an inhibitor of SARS-CoV-1. We show that VE607 specifically inhibits infection of SARS-CoV-1 and SARS-CoV-2 S-expressing pseudoviral particles as well as authentic SARS-CoV-2. VE607 stabilizes the receptor binding domain (RBD) in its "up" conformation. docking and mutational analysis map the VE607 binding site at the RBD-ACE2 interface. The IC values are in the low micromolar range for pseudoparticles derived from SARS-CoV-2 Wuhan/D614G as well as from variants of concern (Alpha, Beta, Gamma, Delta and Omicron), suggesting that VE607 has potential for the development of drugs against SARS-CoV-2 infections.
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）受体的结合。S与ACE2的相互作用是抗2019冠状病毒病（COVID-19）疗法的一个潜在靶点，阻断这种相互作用的免疫疗法的开发证明了这一点。在此，我们展示了市售的VE607，它由三种立体异构体组成，最初被描述为一种严重急性呼吸综合征冠状病毒1（SARS-CoV-1）抑制剂。我们表明，VE607特异性抑制SARS-CoV-1和表达SARS-CoV-2 S的假病毒颗粒以及正宗SARS-CoV-2的感染。VE607将受体结合域（RBD）稳定在其“向上”构象。对接和突变分析确定了VE607在RBD-ACE2界面的结合位点。对于源自SARS-CoV-2武汉株/D614G以及关注变体（阿尔法、贝塔、伽马、德尔塔和奥密克戎）的假颗粒，IC值处于低微摩尔范围，这表明VE607有开发抗SARS-CoV-2感染药物的潜力。
