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

2020 ◽  
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.

scholarly journals Mutations derived from horseshoe bat ACE2 orthologs enhance ACE2-Fc neutralization of SARS-CoV-2

2021 ◽  
Vol 17 (4) ◽  
pp. e1009501
Author(s):  
Huihui Mou ◽  
Brian D. Quinlan ◽  
Haiyong Peng ◽  
Guanqun Liu ◽  
Yan Guo ◽  
...  
Keyword(s):  
Infectious Virus ◽  
Wild Type ◽  
Viral Receptor ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Domains ◽  
Protein Receptor ◽  
Horseshoe Bat ◽  
High Level ◽  
Horseshoe Bats

The 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 to SARS-CoV-2, has been identified in one horseshoe-bat species. Here we characterize the ability of the S-protein receptor-binding domains (RBDs) of SARS-CoV-1, SARS-CoV-2, pangolin coronavirus (PgCoV), RaTG13, and LyRa11, a bat virus similar to SARS-CoV-1, to bind a range of ACE2 orthologs. We observed that the PgCoV RBD bound human ACE2 at least as efficiently as the SARS-CoV-2 RBD, and that both RBDs bound pangolin ACE2 efficiently. We also observed a high level of variability in binding to closely related horseshoe-bat ACE2 orthologs consistent with the heterogeneity of their RBD-binding regions. However five consensus horseshoe-bat ACE2 residues enhanced ACE2 binding to the SARS-CoV-2 RBD and neutralization of SARS-CoV-2 pseudoviruses by an enzymatically inactive immunoadhesin form of human ACE2 (hACE2-NN-Fc). Two of these mutations impaired neutralization of SARS-CoV-1 pseudoviruses. An hACE2-NN-Fc variant bearing all five mutations neutralized both SARS-CoV-2 pseudovirus and infectious virus more efficiently than wild-type hACE2-NN-Fc. These data suggest that SARS-CoV-1 and -2 originate from distinct bat species, and identify a more potently neutralizing form of soluble ACE2.

scholarly journals Possible Transmission Flow of SARS-CoV-2 Based on ACE2 Features

Molecules ◽  
2020 ◽  
Vol 25 (24) ◽  
pp. 5906
Author(s):  
Sk. Sarif Hassan ◽  
Shinjini Ghosh ◽  
Diksha Attrish ◽  
Pabitra Pal Choudhury ◽  
Alaa A. A. Aljabali ◽  
...  
Keyword(s):  
Amino Acids ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Comprehensive Analysis ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Receptor

Angiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22–42, aa 79–84, and aa 330–393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

scholarly journals Naturally mutated spike proteins of SARS-CoV-2 variants show differential levels of cell entry

2020 ◽  
Author(s):  
Seiya Ozono ◽  
Yanzhao Zhang ◽  
Hirotaka Ode ◽  
Toong Seng Tan ◽  
Kazuo Imai ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Causative Agent ◽  
Cell Entry ◽  
Viral Infectivity ◽  
Converting Enzyme ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Naturally Occurring ◽  
Spike Proteins

AbstractThe causative agent of the coronavirus disease 2019 (COVID-19) pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is steadily mutating during continuous transmission among humans. Such mutations can occur in the spike (S) protein that binds to the angiotensin-converting enzyme-2 (ACE2) receptor and is cleaved by transmembrane protease serine 2 (TMPRSS2). However, whether S mutations affect SARS-CoV-2 infectivity remains unknown. Here, we show that naturally occurring S mutations can reduce or enhance cell entry via ACE2 and TMPRSS2. A SARS-CoV-2 S-pseudotyped lentivirus exhibits substantially lower entry than SARS-CoV S. Among S variants, the D614G mutant shows the highest cell entry, as supported by structural observations. Nevertheless, the D614G mutant remains susceptible to neutralization by antisera against prototypic viruses. Taken together, these data indicate that the D614G mutation enhances viral infectivity while maintaining neutralization susceptibility.

scholarly journals Interaction of severe acute respiratory syndrome-coronavirus and NL63 coronavirus spike proteins with angiotensin converting enzyme-2

2008 ◽  
Vol 89 (11) ◽  
pp. 2741-2745 ◽  
Author(s):  
Alison C. Mathewson ◽  
Alexandra Bishop ◽  
Yongxiu Yao ◽  
Fred Kemp ◽  
Junyuan Ren ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Converting Enzyme ◽  
Severe Respiratory Distress ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Lower Affinity ◽  
Common Receptor ◽  
Affinity Interaction ◽  
Receptor Binding Protein

Although in different groups, the coronaviruses severe acute respiratory syndrome-coronavirus (SARS-CoV) and NL63 use the same receptor, angiotensin converting enzyme (ACE)-2, for entry into the host cell. Despite this common receptor, the consequence of entry is very different; severe respiratory distress in the case of SARS-CoV but frequently only a mild respiratory infection for NL63. Using a wholly recombinant system, we have investigated the ability of each virus receptor-binding protein, spike or S protein, to bind to ACE-2 in solution and on the cell surface. In both assays, we find that the NL63 S protein has a weaker interaction with ACE-2 than the SARS-CoV S protein, particularly in solution binding, but the residues required for contact are similar. We also confirm that the ACE-2-binding site of NL63 S lies between residues 190 and 739. A lower-affinity interaction with ACE-2 might partly explain the different pathological consequences of infection by SARS-CoV and NL63.

scholarly journals Possible transmission flow of SARS-CoV-2 based on ACE2 features

2020 ◽  
Author(s):  
Sk. Sarif Hassan ◽  
Shinjini Ghosh ◽  
Diksha Attrish ◽  
Pabitra Pal Choudhury ◽  
Vladimir N. Uversky ◽  
...  
Keyword(s):  
Amino Acids ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Comprehensive Analysis ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Protein Receptor

AbstractAngiotensin-converting enzyme 2 (ACE2) is the cellular receptor for the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) that is engendering the severe coronavirus disease 2019 (COVID-19) pandemic. The spike (S) protein receptor-binding domain (RBD) of SARS-CoV-2 binds to the three sub-domains viz. amino acids (aa) 22-42, aa 79-84, and aa 330-393 of ACE2 on human cells to initiate entry. It was reported earlier that the receptor utilization capacity of ACE2 proteins from different species, such as cats, chimpanzees, dogs, and cattle, are different. A comprehensive analysis of ACE2 receptors of nineteen species was carried out in this study, and the findings propose a possible SARS-CoV-2 transmission flow across these nineteen species.

scholarly journals Amino Acid Substitutions in the S2 Region Enhance Severe Acute Respiratory Syndrome Coronavirus Infectivity in Rat Angiotensin-Converting Enzyme 2-Expressing Cells

2007 ◽  
Vol 81 (19) ◽  
pp. 10831-10834 ◽  
Author(s):  
Shuetsu Fukushi ◽  
Tetsuya Mizutani ◽  
Kouji Sakai ◽  
Masayuki Saijo ◽  
Fumihiro Taguchi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Host Species ◽  
Molecular Basis ◽  
Amino Acid Substitutions ◽  
Converting Enzyme ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Virus Adaptation

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.

scholarly journals Coronacept – a potent immunoadhesin against SARS-CoV-2

2020 ◽  
Author(s):  
Hadas Cohen-Dvashi ◽  
Jonathan Weinstein ◽  
Michael Katz ◽  
Maayan Eilon ◽  
Yuval Mor ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Receptor Binding ◽  
Computational Analysis ◽  
Binding Domain ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Viral Receptor ◽  
Angiotensin Converting Enzyme 2

AbstractAngiotensin-converting enzyme 2 (ACE2) is the cellular receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Computational analysis of mammalian ACE2 orthologues suggests various residues at the interface with the viral receptor binding domain that could facilitate tighter interaction compared to the human-ACE2. Introducing several mutations to the human-ACE2 resulted with significantly augmented affinity to the viral spike complex. This modified human-ACE2 fused to an Fc portion of an antibody makes a potent immunoadhesin that effectively targets SARS-CoV-2.

scholarly journals Structural Similarity Analysis of the Spike Protein of SARS-CoV-2 and Other SARS-related Coronaviruses

2020 ◽  
Author(s):  
YoungJoon Park ◽  
Ju Won Ahn ◽  
Sojung Hwang ◽  
Kyoung Su Sung ◽  
Jaejoon Lim ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Structural Similarity ◽  
Spike Protein ◽  
Similarity Analysis ◽  
Converting Enzyme ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Strong Affinity ◽  
High Infectivity

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has high infectivity in humans, attributed to the strong affinity of its spike (S) protein to angiotensin-converting enzyme 2. Here, we analysed the structural similarity of the S protein between SARS-CoV-2 and other SARS-related coronaviruses. The S1 domain of the unclassified coronavirus RaTG13 was structurally very similar to that of SARS-CoV-2, implying that RaTG13 could be the origin of SARS-CoV-2.

scholarly journals Retroviruses Pseudotyped with the Severe Acute Respiratory Syndrome Coronavirus Spike Protein Efficiently Infect Cells Expressing Angiotensin-Converting Enzyme 2

2004 ◽  
Vol 78 (19) ◽  
pp. 10628-10635 ◽  
Author(s):  
Michael J. Moore ◽  
Tatyana Dorfman ◽  
Wenhui Li ◽  
Swee Kee Wong ◽  
Yanhan Li ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Fluorescent Protein ◽  
Leukemia Virus ◽  
Converting Enzyme ◽  
Protein Variant ◽  
Live Virus ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Immunodeficiency Virus

ABSTRACT Infection of receptor-bearing cells by coronaviruses is mediated by their spike (S) proteins. The coronavirus (SARS-CoV) that causes severe acute respiratory syndrome (SARS) infects cells expressing the receptor angiotensin-converting enzyme 2 (ACE2). Here we show that codon optimization of the SARS-CoV S-protein gene substantially enhanced S-protein expression. We also found that two retroviruses, simian immunodeficiency virus (SIV) and murine leukemia virus, both expressing green fluorescent protein and pseudotyped with SARS-CoV S protein or S-protein variants, efficiently infected HEK293T cells stably expressing ACE2. Infection mediated by an S-protein variant whose cytoplasmic domain had been truncated and altered to include a fragment of the cytoplasmic tail of the human immunodeficiency virus type 1 envelope glycoprotein was, in both cases, substantially more efficient than that mediated by wild-type S protein. Using S-protein-pseudotyped SIV, we found that the enzymatic activity of ACE2 made no contribution to S-protein-mediated infection. Finally, we show that a soluble and catalytically inactive form of ACE2 potently blocked infection by S-protein-pseudotyped retrovirus and by SARS-CoV. These results permit studies of SARS-CoV entry inhibitors without the use of live virus and suggest a candidate therapy for SARS.

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