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

Xiao, Tianshu; J, Lu; Zhang, Jun; Ri, Johnson; McKay, Lindsay; Storm, Nadia; Cl, Lavine; Peng, Hanqin; Cai, Yujun; Rits-Volloch, Sophia; Lu, Shan; Bd, Quinlan; Farzan, Michael; Ms, Seaman; Griffiths, Anthony John; Chen, B

doi:10.1101/2020.09.18.301952

Cited by 16 publications

(24 citation statements)

References 52 publications

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“…APN0l has been reported safe with no immunogenicity and cardiovascular side effects in clinical trials ( Li et al, 2019 ). 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: Covid-19 Therapeuticsmentioning

confidence: 99%

Wuhan to World: The COVID-19 Pandemic

Kumar

Singh

Kaur

et al. 2021

Front. Cell. Infect. Microbiol.

173

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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Section: Covid-19 Therapeuticsmentioning

confidence: 99%

Wuhan to World: The COVID-19 Pandemic

Kumar

Singh

Kaur

et al. 2021

Front. Cell. Infect. Microbiol.

173

111

View full text Add to dashboard Cite

show abstract

“…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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“…The trans conformation was particularly observed for full-length ACE2 structures that are in the dimer state, 6 as well as for an engineered trimeric form of ACE2. 62 As Pro146 is adjacent to the dimerization loop, it is possible that isomerization is important role in function. We also note that this residue is conserved with high probability (94%) among ACE2 sequences across organisms (see ACE2 sequence alignment in Supplemental Information).…”

Section: Resultsmentioning

confidence: 99%

Perturbation of ACE2 structural ensembles by SARS-CoV-2 spike protein binding

Uyar

Dickson

2021

Preprint

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The human ACE2 enzyme serves as a critical first recognition point of coronaviruses, including SARS-CoV-2. In particular, the extracellular domain of ACE2 interacts directly with the S1 tailspike protein of the SARS-CoV-2 virion through a broad protein-protein interface. Although this interaction has been characterized by X-ray crystallography and Cryo-EM, these structures do not reveal significant differences in ACE2 structure upon S1 protein binding. In this work, using several all-atom molecular dynamics simulations, we show persistent differences in ACE2 structure upon binding. These differences are determined with the Linear Discriminant Analysis (LDA) machine learning method and validated using independent training and testing datasets, including long trajectories generated by D. E. Shaw Research on the Anton 2 supercomputer. In addition, long trajectories for 78 potent ACE2-binding compounds, also generated by D. E. Shaw Research, were projected onto the LDA classification vector in order to determine whether the ligand-bound ACE2 structures were compatible with S1 protein binding. This allows us to predict which compounds are "apo-like" vs "complex-like", as well as to pinpoint long-range ligand-induced allosteric changes of ACE2 structure.

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

Cited by 16 publications

References 52 publications

Wuhan to World: The COVID-19 Pandemic

Wuhan to World: The COVID-19 Pandemic

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

Perturbation of ACE2 structural ensembles by SARS-CoV-2 spike protein binding

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