A 193-Amino Acid Fragment of the SARS Coronavirus S Protein Efficiently Binds Angiotensin-converting Enzyme 2

ABSTRACT To clarify the molecular basis of severe acute respiratory syndrome coronavirus (SARS-CoV) adaptation to different host species, we serially passaged SARS-CoV in rat angiotensin-converting enzyme 2 (ACE2)-expressing cells. After 15 passages, the virus (Rat-P15) came to replicate effectively in rat ACE2-expressing cells. Two amino acid substitutions in the S2 region were found on the Rat-P15 S gene. Analyses of the infectivity of the pseudotype-bearing S protein indicated that the two substitutions in the S2 region, especially the S950F substitution, were responsible for efficient infection. Therefore, virus adaptation to different host species can be induced by amino acid substitutions in the S2 region.

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Susceptibility to SARS coronavirus S protein-driven infection correlates with expression of angiotensin converting enzyme 2 and infection can be blocked by soluble receptor

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2004.05.114 ◽

2004 ◽

Vol 319 (4) ◽

pp. 1216-1221 ◽

Cited By ~ 143

Author(s):

Heike Hofmann ◽

Martina Geier ◽

Andrea Marzi ◽

Mandy Krumbiegel ◽

Matthias Peipp ◽

...

Keyword(s):

Angiotensin Converting Enzyme ◽

Soluble Receptor ◽

Converting Enzyme ◽

Sars Coronavirus ◽

S Protein ◽

Angiotensin Converting Enzyme 2

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In-silico drug repurposing study: Amprenavir, enalaprilat, and plerixafor, potential drugs for destabilizing the SARS-CoV-2 S-protein-angiotensin-converting enzyme 2 complex

Results in Chemistry ◽

10.1016/j.rechem.2020.100094 ◽

2020 ◽

pp. 100094

Author(s):

Ivonne Buitrón-González ◽

Giovanny Aguilera-Durán ◽

Antonio Romo-Mancillas

Keyword(s):

Angiotensin Converting Enzyme ◽

In Silico ◽

Drug Repurposing ◽

Converting Enzyme ◽

S Protein ◽

Angiotensin Converting Enzyme 2

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Do sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression explain increased severity and mortality of COVID-19 in males?

Diagnosis ◽

10.1515/dx-2020-0054 ◽

2020 ◽

Vol 7 (4) ◽

pp. 385-386 ◽

Cited By ~ 3

Author(s):

Jens Vikse ◽

Giuseppe Lippi ◽

Brandon Michael Henry

Keyword(s):

Mortality Rate ◽

Severe Acute Respiratory Syndrome ◽

Lung Injury ◽

Angiotensin Converting Enzyme ◽

Converting Enzyme ◽

Sars Coronavirus ◽

Immunomodulatory Treatment ◽

Angiotensin Converting Enzyme 2 ◽

Cytopathic Effects ◽

Severe Lung

AbstractCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), shares similarities with the former SARS outbreak, which was caused by SARS-CoV-1. SARS was characterized by severe lung injury due to virus-induced cytopathic effects and dysregulated hyperinflammatory state. COVID-19 has a higher mortality rate in men both inside and outside China. In this opinion paper, we describe how sex-specific immunobiological factors and differences in angiotensin converting enzyme 2 (ACE2) expression may explain the increased severity and mortality of COVID-19 in males. We highlight that immunomodulatory treatment must be tailored to the underlying immunobiology at different stages of disease. Moreover, by investigating sex-based immunobiological differences, we may enhance our understanding of COVID-19 pathophysiology and facilitate improved immunomodulatory strategies.

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ACE2 the Janus-faced protein – from cardiovascular protection to severe acute respiratory syndrome-coronavirus and COVID-19

Clinical Science ◽

10.1042/cs20200363 ◽

2020 ◽

Vol 134 (7) ◽

pp. 747-750 ◽

Cited By ~ 20

Author(s):

Rhian M. Touyz ◽

Hongliang Li ◽

Christian Delles

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Basic Science ◽

Physiological Role ◽

Ang Ii ◽

Converting Enzyme ◽

Sars Coronavirus ◽

Multifunctional Protein ◽

Angiotensin Converting Enzyme 2

Abstract Angiotensin converting enzyme 2 (ACE2) is the major enzyme responsible for conversion of Ang II into Ang-(1-7). It also acts as the receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, which causes Coronavirus Disease (COVID)-19. In recognition of the importance of ACE2 and to celebrate 20 years since its discovery, the journal will publish a focused issue on the basic science and (patho)physiological role of this multifunctional protein.

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Mutations from bat ACE2 orthologs markedly enhance ACE2-Fc neutralization of SARS-CoV-2

10.1101/2020.06.29.178459 ◽

2020 ◽

Cited By ~ 8

Author(s):

Huihui Mou ◽

Brian D. Quinlan ◽

Haiyong Peng ◽

Yan Guo ◽

Shoujiao Peng ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Angiotensin Converting Enzyme ◽

Converting Enzyme ◽

Viral Receptor ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Binding Domains ◽

Protein Receptor ◽

Horseshoe Bat ◽

Horseshoe Bats

SUMMARYThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein mediates infection of cells expressing angiotensin-converting enzyme 2 (ACE2). ACE2 is also the viral receptor of SARS-CoV (SARS-CoV-1), a related coronavirus that emerged in 2002-2003. Horseshoe bats (genus Rhinolophus) are presumed to be the original reservoir of both viruses, and a SARS-like coronavirus, RaTG13, closely related SARS-CoV-2, has been isolated from one horseshoe-bat species. Here we characterize the ability of S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, and RaTG13 to bind a range of ACE2 orthologs. We observed that the SARS-CoV-2 RBD bound human, pangolin, and horseshoe bat (R. macrotis) ACE2 more efficiently than the SARS-CoV-1 or RaTG13 RBD. Only the RaTG13 RBD bound rodent ACE2 orthologs efficiently. Five mutations drawn from ACE2 orthologs of nine Rhinolophus species enhanced human ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 by an immunoadhesin form of human ACE2 (ACE2-Fc). Two of these mutations impaired neutralization of SARS-CoV-1. An ACE2-Fc variant bearing all five mutations neutralized SARS-CoV-2 five-fold more efficiently than human ACE2-Fc. These data narrow the potential SARS-CoV-2 reservoir, suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of ACE2-Fc.

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Amino acids 484 and 494 of SARS-CoV-2 spike are hotspots of immune evasion affecting antibody but not ACE2 binding

10.1101/2021.04.22.441007 ◽

2021 ◽

Author(s):

Marta Alenquer ◽

Filipe Ferreira ◽

Diana Lousa ◽

Mariana Valério ◽

Mónica Medina-Lopes ◽

...

Keyword(s):

Amino Acids ◽

Amino Acid ◽

Angiotensin Converting Enzyme ◽

Immune Evasion ◽

Neutralizing Antibodies ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Antibody Neutralization ◽

Angiotensin Converting Enzyme 2 ◽

The Core

AbstractUnderstanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike and, predominantly, of its receptor-binding-domain (RBD). Mutations in spike impacting antibody or ACE2 binding are known, but the effect of mutation synergy is less explored. We engineered 22 spike-pseudotyped lentiviruses containing individual and combined mutations, and confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent sera. This amino acid emerges as an additional hotspot for immune evasion and a target for therapies, vaccines and diagnostics.One-Sentence SummaryAmino acids in SARS-CoV-2 spike protein implicated in immune evasion are biased for binding to neutralizing antibodies but dispensable for binding the host receptor angiotensin-converting enzyme 2.

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Angiotensin-Converting Enzyme 2 (ACE2) in the Pathogenesis of ARDS in COVID-19

Frontiers in Immunology ◽

10.3389/fimmu.2021.732690 ◽

2021 ◽

Vol 12 ◽

Author(s):

Keiji Kuba ◽

Tomokazu Yamaguchi ◽

Josef M. Penninger

Keyword(s):

Angiotensin Converting Enzyme ◽

Neutralizing Antibodies ◽

Cell Entry ◽

Converting Enzyme ◽

Sars Coronavirus ◽

Angiotensin Converting Enzyme 2 ◽

Infected People ◽

Critical Attention ◽

Novel Coronavirus

Seventeen years after the epidemic of SARS coronavirus, a novel coronavirus SARS-CoV-2-emerged resulting in an unprecedented pandemic. Angiotensin-converting enzyme 2 (ACE2) is an essential receptor for cell entry of SARS-CoV-2 as well as the SARS coronavirus. Despite many similarities to SARS coronavirus, SARS-CoV-2 exhibits a higher affinity to ACE2 and shows higher infectivity and transmissibility, resulting in explosive increase of infected people and COVID-19 patients. Emergence of the variants harboring mutations in the receptor-binding domain of the Spike protein has drawn critical attention to the interaction between ACE2 and Spike and the efficacies of vaccines and neutralizing antibodies. ACE2 is a carboxypeptidase which degrades angiotensin II, B1-bradykinin, or apelin, and thereby is a critical regulator of cardiovascular physiology and pathology. In addition, the enzymatic activity of ACE2 is protective against acute respiratory distress syndrome (ARDS) caused by viral and non-viral pneumonias, aspiration, or sepsis. Upon infection, both SARS-CoV-2 and SARS coronaviruses downregulates ACE2 expression, likely associated with the pathogenesis of ARDS. Thus, ACE2 is not only the SARS-CoV-2 receptor but might also play an important role in multiple aspects of COVID-19 pathogenesis and possibly post-COVID-19 syndromes. Soluble forms of recombinant ACE2 are currently utilized as a pan-variant decoy to neutralize SARS-CoV-2 and a supplementation of ACE2 carboxypeptidase activity. Here, we review the role of ACE2 in the pathology of ARDS in COVID-19 and the potential application of recombinant ACE2 protein for treating COVID-19.

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Receptor utilization of angiotensin converting enzyme 2 (ACE2) indicates a narrower host range of SARS-CoV-2 than that of SARS-CoV

10.1101/2020.06.13.149930 ◽

2020 ◽

Author(s):

Ye Qiu ◽

Qiong Wang ◽

Jin-Yan Li ◽

Ce-Heng Liao ◽

Zhi-Jian Zhou ◽

...

Keyword(s):

Amino Acid ◽

Angiotensin Converting Enzyme ◽

Host Range ◽

Amino Acid Sequences ◽

Interspecies Transmission ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Key Factor ◽

Entry Assay ◽

Virus Tracing

AbstractCoronavirus pandemics have become a huge threat to the public health worldwide in the recent decades. Typically, SARS-CoV caused SARS pandemic in 2003 and SARS-CoV-2 caused the COVID-19 pandemic recently. Both viruses have been reported to originate from bats. Thus, direct or indirect interspecies transmission from bats to humans is required for the viruses to cause pandemics. Receptor utilization is a key factor determining the host range of viruses which is critical to the interspecies transmission. Angiotensin converting enzyme 2 (ACE2) is the receptor of both SARS-CoV and SARS-CoV-2, but only ACE2s of certain animals can be utilized by the viruses. Here, we employed pseudovirus cell-entry assay to evaluate the receptor-utilizing capability of ACE2s of 20 animals by the two viruses and found that SARS-CoV-2 utilized less ACE2s than SARS-CoV, indicating a narrower host range of SARS-CoV-2. Meanwhile, pangolin CoV, another SARS-related coronavirus highly homologous to SARS-CoV-2 in its genome, yet showed similar ACE2 utilization profile with SARS-CoV rather than SARS-CoV-2. To clarify the mechanism underlying the receptor utilization, we compared the amino acid sequences of the 20 ACE2s and found 5 amino acid residues potentially critical for ACE2 utilization, including the N-terminal 20th and 42nd amino acids that may determine the different receptor utilization of SARS-CoV, SARS-CoV-2 and pangolin CoV. Our studies promote the understanding of receptor utilization of pandemic coronaviruses, potentially contributing to the virus tracing, intermediate host screening and epidemic prevention for pathogenic coronaviruses.

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