Engineered Trimeric ACE2 Binds and Locks “Three-up” Spike Protein to Potently Inhibit SARS-CoVs and Mutants

Guo, Liang; Bi, Wenwen; Wang, Xinling; Xü, Wei; Yan, Renhong; Zhang, Yuanyuan; Zhao, Kai; Li, Yaning; Zhang, Mingfeng; Bao, Xingyue; Cai, Xiujun; Li, Yutang; Qu, Di; Jiang, Shibo; Xie, Youhua; Zhou, Qiang; Lu, Lu; Dang, Bobo

doi:10.1101/2020.08.31.274704

Cited by 7 publications

(6 citation statements)

References 76 publications

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“…The dramatic opening we observe explains the observation that antibodies, and other therapeutics, can bind to regions of the RBD that are deeply buried and seemingly inaccessible in existing experimental snapshots. [34][35][36][37] For example, exposure of the cryptic epitope for the antibody CR3022 is seen clearly in our conformational ensemble ( Fig. 2C).…”

Section: Unmasking the Spike Complexmentioning

confidence: 98%

SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome

Zimmerman

Porter

Ward

et al. 2020

Preprint

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AbstractThe SARS-CoV-2/COVID-19 pandemic continues to threaten global health and socioeconomic stability. Experiments have revealed snapshots of many of the viral components but remain blind to moving parts of these molecular machines. To capture these essential processes, over a million citizen scientists have banded together through the Folding@home distributed computing project to create the world’s first Exascale computer and simulate protein dynamics. An unprecedented 0.1 seconds of simulation of the viral proteome reveal how the spike complex uses conformational masking to evade an immune response, conformational changes implicated in the function of other viral proteins, and ‘cryptic’ pockets that are absent in experimental snapshots. These structures and mechanistic insights present new targets for the design of therapeutics.This living document will be updated as we perform further analysis and make the data publicly accessible.

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Section: Unmasking the Spike Complexmentioning

confidence: 98%

SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome

Zimmerman

Porter

Ward

et al. 2020

Preprint

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“…Other studies have attempted to increase the valency of ACE2 or ACE2 mutants by linking them to a trimerization domain instead of an IgG1 Fc to generate mutant ACE2 trimers, demonstrating, in some cases, better potency than ACE2-Fc dimers [ 143 , 144 ]. Another approach linked an NTD binding mAb to ACE2-Fc, resulting in ~100 fold improvement over ACE2-Fc in binding and neutralization [ 145 ].…”

Section: Mab Against Sars-cov-2mentioning

confidence: 99%

Challenges and opportunities for antiviral monoclonal antibodies as COVID-19 therapy

Cruz-Teran

Tiruthani

McSweeney³

et al. 2021

Advanced Drug Delivery Reviews

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“…Downregulation of ACE2 and accumulation of angiotensin II because of spike binding is also associated with acute respiratory distress syndrome (ARDS) and acute lung failure (27)(28)(29)(30)(31), contributing to SARS-associated symptoms. As such, the S glycoprotein and ACE2-S complex are considered key targets for drug and antibody development efforts aiming to curtail the virus' remarkable transmissibility and negative effect on human health (1,(32)(33)(34)(35), including exploiting the ACE2-S high affinity with recombinant soluble ACE2-antibody constructs (35)(36)(37)(38).…”

Section: Introductionmentioning

confidence: 99%

The flexibility of ACE2 in the context of SARS-CoV-2 infection

Barros

Casalino

Gaieb

et al. 2021

Biophysical Journal

111

120

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The coronavirus disease 2019 (COVID-19) pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine development efforts are underway, there are many outstanding questions on the mechanism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and host cell entry. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular spike glycoprotein and at the receptor-binding domain (RBD)-receptor interface, suggesting a role in infection. Here, we perform explicitly solvated, all-atom, molecular dynamics simulations of the glycosylated, full-length, membrane-bound ACE2 receptor in both an apo and spike RBD-bound state to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full-length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer and suggests a mechanical contribution of the host receptor toward the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can potentially be exploited for the rational design of effective SARS-CoV-2 therapeutics.

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Engineered Trimeric ACE2 Binds and Locks “Three-up” Spike Protein to Potently Inhibit SARS-CoVs and Mutants

Cited by 7 publications

References 76 publications

SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome

SARS-CoV-2 Simulations Go Exascale to Capture Spike Opening and Reveal Cryptic Pockets Across the Proteome

Challenges and opportunities for antiviral monoclonal antibodies as COVID-19 therapy

The flexibility of ACE2 in the context of SARS-CoV-2 infection

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