ACE2 glycans preferentially interact with SARS-CoV-2 over SARS-CoV

Acharya, Atanu; Lynch, Diane L.; Pavlova, Ànna; Pang, Yui Tik; Gumbart, James C.

doi:10.1039/d1cc02305e

Cited by 28 publications

(55 citation statements)

References 28 publications

(44 reference statements)

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“…Mutations that removed glycosylation in N432 and N546 were not favoured (Figure S6b), possibly because they were distant from protein interaction sites. N90, N103, and N322-glycans hover over a fraction of the binding surface [ 28 , 29 ]. Mutations that remove glycosylation at these glycan sites were significantly enriched (Figure 2 d,e): the fitness scores of both asparagine (N) and threonine (T)/serine(S) of the three glycan sites were positive (see Supplementary Figure 6b), indicating that de-glycosylation boosts binding by reducing steric strain.…”

Section: Resultsmentioning

confidence: 99%

“…Removing these two glycans increased ACE2-spike binding affinity. Most N90 mutations were enriching possibly because the N90-glycan shielded ACE2 from RBD binding [ 28 ]. Although N103 and N322 glycosylation sites are not on the ACE2-RBD binding interface, glycans formed at these sites orient toward RBD [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…Most N90 mutations were enriching possibly because the N90-glycan shielded ACE2 from RBD binding [ 28 ]. Although N103 and N322 glycosylation sites are not on the ACE2-RBD binding interface, glycans formed at these sites orient toward RBD [ 28 , 29 ]. This clash may produce steric hindrance during ACE2-RBD binding.…”

Section: Discussionmentioning

confidence: 99%

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ACE2 decoy receptor generated by high-throughput saturation mutagenesis efficiently neutralizes SARS-CoV-2 and its prevalent variants

Wang

Zhao

Liu

et al. 2022

Emerging Microbes & Infections

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The recent global pandemic was a spillover from the SARS-CoV-2 virus. Viral entry involves the receptor binding domain (RBD) of the viral spike protein interacting with the protease domain (PD) of the cellular receptor, ACE2. We hereby present a comprehensive mutational landscape of the effects of ACE2-PD point mutations on RBD-ACE2 binding using a saturation mutagenesis approach based on microarray-based oligo synthesis and a single-cell screening assay. We observed that changes in glycosylation sites and directly interacting sites of ACE2-PD significantly influenced ACE2-RBD binding. We further engineered an ACE2 decoy receptor with critical point mutations, D30I, L79W, T92N, N322V, and K475F, named C4-1. C4-1 shows a 200-fold increase in neutralization for the SARS-CoV-2 D614G pseudotyped virus compared to wild-type soluble ACE2 and a sevenfold increase in binding affinity to wild-type spike compared to the C-terminal Ig-Fc fused wild-type soluble ACE2. Moreover, C4-1 efficiently neutralized prevalent variants, especially the omicron variant (EC ng/mL), and rescued monoclonal antibodies, vaccine, and convalescent sera neutralization from viral immune-escaping. We hope to next investigate translating the therapeutic potential of C4-1 for the treatment of SARS-CoV-2.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

ACE2 decoy receptor generated by high-throughput saturation mutagenesis efficiently neutralizes SARS-CoV-2 and its prevalent variants

Wang

Zhao

Liu

et al. 2022

Emerging Microbes & Infections

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“…S8 ), perhaps resulting in intracellular concentrations insufficient to saturate the DNA-binding site on our lacZ reporter. Another possible explanation (these are not mutually exclusive) lies in the fact that both the SARS-CoV-2 spike protein and ACE2 are glycosylated in mammalian cells ( 9 , 60 ), with some studies suggesting that glycan-side chain interactions may be important in stabilizing the RBD-ACE2 interaction ( 61 , 62 ). Thus, the interaction detected in our B2H system could be compromised by the lack of mammalian-like N- and O-glycosylation in E. coli ( 63 ).…”

Section: Discussionmentioning

confidence: 99%

A Bacterial Cell-Based Assay To Study SARS-CoV-2 Protein-Protein Interactions

Springstein

Deighan

Grabe

et al. 2021

mBio

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“…In the very first step, the Spike protein of SARS‐CoV‐2 binds to the human ACE2 receptor. [ 6 , 7 , 8 , 9 ] The spike protein has a trimeric structure and each monomer is formed by several structural domains (Figure 1a ). [ 10 ] During the virus attachment stage, the receptor binding domain (RBD) of one monomer gets activated and attaches to the human ACE2 receptor followed by membrane fusion and internalization of genetic material.…”

Section: Introductionmentioning

confidence: 99%

Computational design of stapled peptide inhibitor against SARS‐CoV‐2 receptor binding domain

et al. 2022

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Since its first detection in 2019, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2) has been the cause of millions of deaths worldwide. Despite the development and administration of different vaccines, the situation is still worrisome as the virus is constantly mutating to produce newer variants some of which are highly infectious. This raises an urgent requirement to understand the infection mechanism and thereby design therapeutic‐based treatment for COVID‐19. The gateway of the virus to the host cell is mediated by the binding of the receptor binding domain (RBD) of the virus spike protein to the angiotensin‐converting enzyme 2 (ACE2) of the human cell. Therefore, the RBD of SARS‐CoV‐2 can be used as a target to design therapeutics. The α1 helix of ACE2, which forms direct contact with the RBD surface, has been used as a template in the current study to design stapled peptide therapeutics. Using computer simulation, the mechanism and thermodynamics of the binding of six stapled peptides with RBD have been estimated. Among these, the one with two lactam stapling agents has shown binding affinity, sufficient to overcome RBD‐ACE2 binding. Analyses of the mechanistic detail reveal that a reorganization of amino acids at the RBD‐ACE2 interface produces favorable enthalpy of binding whereas conformational restriction of the free peptide reduces the loss in entropy to result higher binding affinity. The understanding of the relation of the nature of the stapling agent with their binding affinity opens up the avenue to explore stapled peptides as therapeutic against SARS‐CoV‐2.

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ACE2 glycans preferentially interact with SARS-CoV-2 over SARS-CoV

Abstract: We report a distinct difference in the interactions of the glycans of the host-cell receptor, ACE2, with SARS-CoV-2 and SARS-CoV S-protein receptor-binding domains (RBDs). Our analysis demonstrates that the ACE2...

Cited by 28 publications

References 28 publications

ACE2 decoy receptor generated by high-throughput saturation mutagenesis efficiently neutralizes SARS-CoV-2 and its prevalent variants

ACE2 decoy receptor generated by high-throughput saturation mutagenesis efficiently neutralizes SARS-CoV-2 and its prevalent variants

A Bacterial Cell-Based Assay To Study SARS-CoV-2 Protein-Protein Interactions

Computational design of stapled peptide inhibitor against SARS‐CoV‐2 receptor binding domain

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