tetano
Editor, Senior Moderator
iScience
. 2022 Jul 4;104716.
doi: 10.1016/j.isci.2022.104716. Online ahead of print.
Trimeric Receptor Binding Domain of SARS-CoV-2 Acts as a Potent Inhibitor of ACE2 Receptor-Mediated Viral Entry
Shrikanth C Basavarajappa[SUP] 1 [/SUP], Angela Rose Liu[SUP] 1 [/SUP], Anna Bruchez[SUP] 1 [/SUP], Zhenlu Li[SUP] 2 [/SUP], Vinicius G Suzart[SUP] 1 [/SUP], Zhonghua Liu[SUP] 1 [/SUP], Yinghua Chen[SUP] 2 [/SUP], Tsan Sam Xiao[SUP] 1 [/SUP], Matthias Buck[SUP] 2 3 4 5 [/SUP], Parameswaran Ramakrishnan[SUP] 1 3 6 [/SUP]
Affiliations
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 four-fold more effectively compared to the mRBD. While 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: ACE2; CoV-2 inhibitor; Coronavirus; Covid19; spike protein; trimeric RBD.
. 2022 Jul 4;104716.
doi: 10.1016/j.isci.2022.104716. Online ahead of print.
Trimeric Receptor Binding Domain of SARS-CoV-2 Acts as a Potent Inhibitor of ACE2 Receptor-Mediated Viral Entry
Shrikanth C Basavarajappa[SUP] 1 [/SUP], Angela Rose Liu[SUP] 1 [/SUP], Anna Bruchez[SUP] 1 [/SUP], Zhenlu Li[SUP] 2 [/SUP], Vinicius G Suzart[SUP] 1 [/SUP], Zhonghua Liu[SUP] 1 [/SUP], Yinghua Chen[SUP] 2 [/SUP], Tsan Sam Xiao[SUP] 1 [/SUP], Matthias Buck[SUP] 2 3 4 5 [/SUP], Parameswaran Ramakrishnan[SUP] 1 3 6 [/SUP]
Affiliations
- PMID: 35813876
- PMCID: PMC9251894
- DOI: 10.1016/j.isci.2022.104716
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 four-fold more effectively compared to the mRBD. While 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: ACE2; CoV-2 inhibitor; Coronavirus; Covid19; spike protein; trimeric RBD.