Basavarajappa Shrikanth C, Liu Angela Rose, Bruchez Anna, Li Zhenlu, Suzart Vinicius G, Liu Zhonghua, Chen Yinghua, Xiao Tsan Sam, Buck Matthias, Ramakrishnan Parameswaran
Department of Pathology, School of Medicine, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106, USA.
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Robbins Building, 2210 Circle Dr, Cleveland, OH 44106, USA.
iScience. 2022 Aug 19;25(8):104716. doi: 10.1016/j.isci.2022.104716. Epub 2022 Jul 4.
The COVID-19 pandemic has caused over four million deaths and effective methods to control CoV-2 infection, in addition to vaccines, are needed. The CoV-2 binds to the ACE2 on human cells through the receptor-binding domain (RBD) of the trimeric spike protein. Our modeling studies show that a modified trimeric RBD (tRBD) can interact with three ACE2 receptors, unlike the native spike protein, which binds to only one ACE2. We found that tRBD binds to the ACE2 with 58-fold higher affinity than monomeric RBD (mRBD) and blocks spike-dependent pseudoviral infection over 4-fold more effectively compared to the mRBD. Although mRBD failed to block CoV-2 USA-WA1/2020 infection, tRBD efficiently blocked the true virus infection in plaque assays. We show that tRBD is a potent inhibitor of CoV-2 through both competitive binding to the ACE2 and steric hindrance, and has the potential to emerge as a first-line therapeutic method to control COVID-19.
新冠疫情已导致四百多万人死亡，除疫苗外，还需要有效的方法来控制新冠病毒2型（CoV-2）感染。CoV-2通过三聚体刺突蛋白的受体结合域（RBD）与人细胞上的血管紧张素转换酶2（ACE2）结合。我们的模型研究表明，与仅结合一个ACE2的天然刺突蛋白不同，一种经过修饰的三聚体RBD（tRBD）可以与三个ACE2受体相互作用。我们发现，tRBD与ACE2结合的亲和力比单体RBD（mRBD）高58倍，并且与mRBD相比，其阻断刺突蛋白依赖性假病毒感染的效率高出4倍多。尽管mRBD未能阻断CoV-2 USA-WA1/2020感染，但在噬斑测定中，tRBD有效地阻断了真实病毒感染。我们表明，tRBD通过与ACE2的竞争性结合和空间位阻作用，是一种有效的CoV-2抑制剂，并且有潜力成为控制新冠疫情的一线治疗方法。
