A tetrameric ACE2 protein broadly neutralizes SARS-CoV-2 spike variants of concern with elevated potency

Abstract

The SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2) was previously engineered into a high affinity tetravalent format (ACE2-Fc-TD) that is a potential decoy protein in SARS-CoV-2 infection.We report that this protein shows greatly enhanced binding to SARS-CoV-2 spike proteins of the SARS-CoV-2 variants of concern B.1.1.7 (alpha variant, originally isolated in the United Kingdom) and B.1.351 (beta variant, originally isolated in South Africa) with picomolar compared with nanomolar Kd values. In addition, ACE2-Fc-TD displays greater neutralization of SARS-CoV-2 pseudotype viruses compared to a dimeric ACE2-Fc, with enhanced activity on variant B.1.351. This tetrameric decoy protein would be a valuable addition to SARS-CoV-2 therapeutic approaches, especially where vaccination cannot be used but also should there be any future coronavirus pandemics.

Generalized Methodology for the Quick Prediction of Variant SARS-CoV-2 Spike Protein Binding Affinities with Human Angiotensin-Converting Enzyme II

“…Since the publication of our methodology for the fast prediction of Spike/ACE2 binding affinities, multiple publications have reported the dissociation constants of prolific variants of the SARS-CoV-2 Spike protein with ACE2. − With these data in hand, our model can be updated to better predict the binding affinity of emerging variants of concern such as the Omicron variant . Briefly, for each variant, the SARS-CoV-2 Spike protein (consisting of the Spike RBD region binding with ACE2) crystal structure (PDB: 7KMB) was mutated using the PyMol mutagenesis tool, making sure to choose the lowest-energy rotamer of the mutated residue.…”

Phylogenetic analysis of SARS-CoV-2 viruses circulating in the South American region: Genetic relations and vaccine strain match

“…Therefore, there is a concern that VOCs and/or VOIs may reduce the efficacy of the anti-SARS-CoV-2 induced-antibodies or eventually evade them completely ( Leach et al, 2021 ; Salleh et al, 2021 ).…”

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

“…A subsequent study by the same group revealed that the tetrameric format greatly enhanced VOCs neutralization. [143] …”