A trimeric human angiotensin-converting enzyme 2 as an anti-SARS-CoV-2 agent

Xiao, Tianshu; Lü, Jianming; Zhang, Jun; Johnson, Rebecca; McKay, Lindsay; Storm, Nadia; Lavine, Christy L.; Peng, Hanqin; Cai, Yongfei; Rits-Volloch, Sophia; Lu, Shan; Quinlan, Brian D.; Farzan, Michael; Seaman, Michael S.; Griffiths, Anthony John; Chen, Bing

doi:10.1038/s41594-020-00549-3

Cited by 114 publications

(132 citation statements)

References 62 publications

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“…Recently engineered trimeric ACE-2 variant have also been reported to be anti-SARS-CoV-2 and hence helpful for treating COVID-19 patients (Xiao et al, 2021).…”

Section: Chloroquine and Hydroxychloroquinementioning

confidence: 99%

Wuhan to World: The COVID-19 Pandemic

Kumar

Singh

Kaur

et al. 2021

Front. Cell. Infect. Microbiol.

145

111

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COVID-19 is a Severe Acute Respiratory Syndrome (SARS), caused by SARS-CoV-2, a novel virus which belongs to the family Coronaviridae. It was first reported in December 2019 in the Wuhan city of China and soon after, the virus and hence the disease got spread to the entire world. As of February 26, 2021, SARS-CoV-2 has infected ~112.20 million people and caused ~2.49 million deaths across the globe. Although the case fatality rate among SARS-CoV-2 patient is lower (~2.15%) than its earlier relatives, SARS-CoV (~9.5%) and MERS-CoV (~34.4%), the SARS-CoV-2 has been observed to be more infectious and caused higher morbidity and mortality worldwide. As of now, only the knowledge regarding potential transmission routes and the rapidly developed diagnostics has been guiding the world for managing the disease indicating an immediate need for a detailed understanding of the pathogen and the disease-biology. Over a very short period of time, researchers have generated a lot of information in unprecedented ways in the key areas, including viral entry into the host, dominant mutation, potential transmission routes, diagnostic targets and their detection assays, potential therapeutic targets and drug molecules for inhibiting viral entry and/or its replication in the host including cross-neutralizing antibodies and vaccine candidates that could help us to combat the ongoing COVID-19 pandemic. In the current review, we have summarized the available knowledge about the pathogen and the disease, COVID-19. We believe that this readily available knowledge base would serve as a valuable resource to the scientific and clinical community and may help in faster development of the solution to combat the disease.

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“…Recently engineered trimeric ACE-2 variant have also been reported to be anti-SARS-CoV-2 and hence helpful for treating COVID-19 patients (Xiao et al, 2021).…”

Section: Chloroquine and Hydroxychloroquinementioning

confidence: 99%

Wuhan to World: The COVID-19 Pandemic

Kumar

Singh

Kaur

et al. 2021

Front. Cell. Infect. Microbiol.

145

111

View full text Add to dashboard Cite

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“…Structures resolved using cryo-electron microscopy (cryo-EM) combined with docking have shown that ACE2-RBD binding requires spike trimers to be open, and that two spike trimers can be accommodated on one ACE2 dimer (Yan et al, 2020). Additional cryo-EM structures have shown that up to three soluble ACE2 monomers can bind to the same spike trimer, which may result in exposure of the S2 trimeric core (Benton et al, 2020); indeed, soluble ACE2 trimers were recently demonstrated as an effective inhibitor of SARS-CoV-2 (Xiao et al, 2021). Both modalities are potentially important for viral avidity, and furthermore, likely dependent upon the flexibility exhibited by both the spike trimer stalk (Turoňová et al, 2020) and ACE2 domain (Barros et al), as well as the stochastic nature of RBD opening observed throughout the spike trimer (Cai et al, 2020;Ke et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

Pak

et al. 2021

Preprint

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The molecular events that permit the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to bind, fuse, and enter cells are important to understand for both fundamental and therapeutic reasons. Spike proteins consist of S1 and S2 domains, which recognize angiotensin-converting enzyme 2 (ACE2) receptors and contain the viral fusion machinery, respectively. Ostensibly, the binding of spike trimers to ACE2 receptors promotes the preparation of the fusion machinery by dissociation of the S1 domains. We report the development and use of coarse-grained models and simulations to investigate the dynamical mechanisms involved in viral binding and exposure of the S2 trimeric core. We show that spike trimers cooperatively bind to multiple ACE2 dimers. The multivalent interaction cyclically and processively induces S1 dissociation, thereby exposing the S2 core containing the fusion machinery. Our simulations thus reveal an important concerted interaction between spike trimers and ACE2 dimers that primes the virus for membrane fusion and entry.

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“…At low transfection levels, G614 S had higher fusion activity than the D614 S, but the difference diminished with the increased amount of transfected DNA, which suggests that the high expression levels can compensate for lower fusion efficiency of the D614 S protein. The G614 trimer remains sensitive to inhibition by an engineered trimeric ACE2-based inhibitor that competes with the receptor on the target cells ( 35 ) (fig. S2B).…”

mentioning

confidence: 99%

Structural impact on SARS-CoV-2 spike protein by D614G substitution

Zhang

Cai

Xiao

et al. 2021

Science

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363

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Substitution for aspartic acid by glycine at position 614 in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 appears to facilitate rapid viral spread. The G614 strain and its recent variants are now the dominant circulating forms. We report here cryo-EM structures of a full-length G614 S trimer, which adopts three distinct prefusion conformations differing primarily by the position of one receptor-binding domain. A loop disordered in the D614 S trimer wedges between domains within a protomer in the G614 spike. This added interaction appears to prevent premature dissociation of the G614 trimer, effectively increasing the number of functional spikes and enhancing infectivity, and to modulate structural rearrangements for membrane fusion. These findings extend our understanding of viral entry and suggest an improved immunogen for vaccine development.

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A trimeric human angiotensin-converting enzyme 2 as an anti-SARS-CoV-2 agent

Cited by 114 publications

References 62 publications

Wuhan to World: The COVID-19 Pandemic

Wuhan to World: The COVID-19 Pandemic

Cooperative multivalent receptor binding promotes exposure of the SARS-CoV-2 fusion machinery core

Structural impact on SARS-CoV-2 spike protein by D614G substitution

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