Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

Capraz, Tümay; Kienzl, Nikolaus F.; Laurent, Elisabeth; Perthold, Jan Walther; Föderl-Höbenreich, Esther; Grünwald‐Gruber, Clemens; Maresch, Daniel; Monteil, Vanessa; Niederhöfer, Janine; Wirnsberger, Gerald; Mirazimi, Alì; Zatloukal, Kurt; Mach, Lukas; Penninger, Josef; Oostenbrink, Chris; Stadlmann, Johannes

doi:10.7554/elife.73641

Cited by 29 publications

(44 citation statements)

References 74 publications

(101 reference statements)

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“… 27 Both the spike protein and ACE2 also contain several glycans. 4 , 35 − 38 These glycans act as a shield to the host immune response. 39 − 41 Also, several studies have revealed that these glycans play important roles in developing favorable conformation of the receptor binding domain (RBD) for binding with ACE2.…”

Section: Introductionmentioning

confidence: 99%

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All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

2022

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The spike protein of SARS-CoV-2 is known to interact with the human ACE2 protein via its receptor binding domain (RBD). We have investigated the molecular nature of this interprotein interaction and the associated free energy diagrams for the unbinding of the two proteins for SARS-CoV-2 and some of its known variants through all-atom simulations. The present work involves generation and analysis of 2.5 μs of unbiased and 4.2 μs of biased molecular dynamics trajectories in total for five explicitly solvated RBD-ACE2 systems at full atomic level. First, we have made a comparative analysis of the details of residue-wise specific interactions of the spike protein with ACE2 for SARS-CoV-1 and SARS-CoV-2. It is found that the average numbers of both direct interprotein and water-bridged hydrogen bonds between the RBD and ACE2 are higher for SARS-CoV-2 than SARS-CoV-1. These higher hydrogen bonded interactions are further aided by enhanced nonspecific electrostatic attractions between the two protein surfaces for SARS-CoV-2. The free energy calculations reveal that there is an increase in the free energy barrier by ∼1.5 kcal/mol for the unbinding of RBD from ACE2 for SARS-CoV-2 compared to that for SARS-CoV-1. Subsequently, we considered the RBDs of three variants of SARS-CoV-2, namely N501Y, E484Q/L452R, and N440K. The free energy barrier of protein unbinding for the N501Y variant is found to be ∼4 kcal/mol higher than the wild type SARS-CoV-2 which can be attributed to additional specific interactions involving Tyr501 of RBD and Lys353 and Tyr42 of ACE2 and also enhanced nonspecific electrostatic interaction between the protein surfaces. For the other two mutant variants of E484Q/L452R and N440K, the free energy barrier for protein unbinding increases by ∼2 and ∼1 kcal/mol, respectively, compared with the wild type SARS-CoV-2, which can be attributed to an increase in the number of interprotein hydrogen bonds for the former and also to enhanced positive electrostatic potential on the RBD surfaces for both of the variants. The successive breaking of interprotein hydrogen bonds along the free energy pathway of the unbinding process is also found out for all five systems studied here.

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Section: Introductionmentioning

confidence: 99%

“… 39 − 41 Also, several studies have revealed that these glycans play important roles in developing favorable conformation of the receptor binding domain (RBD) for binding with ACE2. 35 , 39 …”

Section: Introductionmentioning

confidence: 99%

All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

2022

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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 ). Table lists the SARS‐CoV‐2 strains and their respective mutations within the Spike protein that were used in this study.…”

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 ).…”

Section: Resultsmentioning

confidence: 99%

Clinical grade ACE2 as a universal agent to block SARS‐CoV ‐2 variants

Monteil

Eaton²,

Postnikova³

et al. 2022

EMBO Mol Med

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The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to both reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is, therefore, paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here, we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, Delta, and Omicron, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by all current VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic.

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“…A structure-guided glyco-engineering approach has also received recognition for optimizing ACE2 for efficient virus inhibition. [131] In complementation with molecular dynamics (MD) simulations, the approach revealed some attractive N-glycan hotspots on ACE2 that improves binding affinity and neutralization competency of SARS-CoV-2 and associated viruses.…”

Section: Promising Bionanotechnology Approaches To Achieve Improved T...mentioning

confidence: 99%

Multivalent ACE2 engineering—A promising pathway for advanced coronavirus nanomedicine development

Obeng

Fianu²,

Danquah

2022

Nano Today

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Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

Cited by 29 publications

References 74 publications

All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

All-Atom Simulations of Human ACE2-Spike Protein RBD Complexes for SARS-CoV-2 and Some of its Variants: Nature of Interactions and Free Energy Diagrams for Dissociation of the Protein Complexes

Clinical grade ACE2 as a universal agent to block SARS‐CoV ‐2 variants

Multivalent ACE2 engineering—A promising pathway for advanced coronavirus nanomedicine development

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