2021
DOI: 10.1101/2021.08.31.458325
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Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

Abstract: Infection and viral entry of SARS-CoV-2 crucially depends on the binding of its Spike protein to angiotensin converting enzyme 2 (ACE2) presented on host cells. Glycosylation of both proteins is critical for this interaction. Recombinant soluble human ACE2 can neutralize SARS-CoV-2 and is currently undergoing clinical tests for the treatment of COVID-19. We used 3D structural models and molecular dynamics simulations to define the ACE2 N-glycans that critically influence Spike-ACE2 complex formation. Engineeri… Show more

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Cited by 5 publications
(4 citation statements)
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References 67 publications
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“…Mutations described for the Omicron VOC are depicted in red. Shown in yellow are the glycan modifications of the spike protein (Capraz et al , 2021). BTable lists the SARS‐CoV‐2 strains and their respective mutations within the Spike protein that were used in this study. CRepresentative sensorgram images for the SPR analysis conducted with full‐length trimeric spike proteins in pre‐fusion state with APN01.…”
Section: Resultsmentioning
confidence: 99%
“…Mutations described for the Omicron VOC are depicted in red. Shown in yellow are the glycan modifications of the spike protein (Capraz et al , 2021). BTable lists the SARS‐CoV‐2 strains and their respective mutations within the Spike protein that were used in this study. CRepresentative sensorgram images for the SPR analysis conducted with full‐length trimeric spike proteins in pre‐fusion state with APN01.…”
Section: Resultsmentioning
confidence: 99%
“…Wild-type hACE2-Fc expressed in N. benthamiana showed less processed complex N-glycans and a partial underglycosylation at the N90 position in recent LC-ESI-MS analyses compared to ACE2-Fc produced in a human cell line 36 . It was previously reported that most of the hACE2 substitutions of N90 and T92, which together form a consensus N-glycosylation motif, would be beneficial for binding to the spike RBD 18 since N-glycans could hinder binding through steric clashes or electrostatic effects 37 . With a half-maximal inhibitory concentration (IC 50 ) of 0.313 μg/ mL (hACE2-Fc K31W_NB) and 1.442 μg/mL (hACE2-Fc K31W_CHO), both hACE2 mutants had a lower IC 50 value compared to the wild-type hACE2-Fc, expressed in CHO cells, with 1.856 μg/mL.…”
Section: Discussionmentioning
confidence: 99%
“…[ 48 ]. Stadlmann and coworkers focused on glycan-mediated interactions between ACE2 and the spike protein [ 49 ]. In silico modeling and molecular dynamics simulations of fully glycosylated proteins have suggested that the spike–ACE2 complex formation is disrupted by glycans attached at N90 and N322 of ACE2.…”
Section: Ace2 Mutagenesis Approaches To Achieve Increased Affinitymentioning
confidence: 99%