Trimeric receptor-binding domain of SARS-CoV-2 acts as a potent inhibitor of ACE2 receptor-mediated viral entry

Shrikanth C Basavarajappa; Angela Rose Liu; Anna Bruchez; Zhenlu Li; Vinicius G Suzart; Zhonghua Liu; Yinghua Chen; Tsan Sam Xiao; Matthias Buck; Parameswaran Ramakrishnan

doi:10.1016/j.isci.2022.104716

Trimeric receptor-binding domain of SARS-CoV-2 acts as a potent inhibitor of ACE2 receptor-mediated viral entry

iScience. 2022 Aug 19;25(8):104716. doi: 10.1016/j.isci.2022.104716. Epub 2022 Jul 4.

Authors

Shrikanth C Basavarajappa¹, Angela Rose Liu¹, Anna Bruchez¹, Zhenlu Li², Vinicius G Suzart¹, Zhonghua Liu¹, Yinghua Chen², Tsan Sam Xiao¹, Matthias Buck^{2

3

4

5}, Parameswaran Ramakrishnan^{1

3

6}

Affiliations

¹ Department of Pathology, School of Medicine, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106, USA.
² Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Robbins Building, 2210 Circle Dr, Cleveland, OH 44106, USA.
³ The Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Wolstein Research Building, 2103 Cornell Road, Cleveland, OH 44106, USA.
⁴ Department of Neuroscience, School of Medicine, Case Western Reserve University, Robbins Building, 2210 Circle Dr, Cleveland, Ohio 44106, USA.
⁵ Department of Pharmacology, School of Medicine, Case Western Reserve University, Wood Building, 2109 Adelbert Road, Cleveland, Ohio 44106, USA.
⁶ Department of Biochemistry, School of Medicine, Case Western Reserve University, Wood Building, 2109 Adelbert Road, Cleveland, OH 44106, USA.

Abstract

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.

Keywords: Molecular structure; Virology.

Abstract

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