Ayooshi Mitra, Amity University, Kolkata
The crucial mechanism for severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections initializes with the binding of the viral spike protein to angiotensin-converting enzyme II (ACE2) human receptor protein. In order to create a set of ACE2 variants optimized for affinity and also be enzymatically inactivated, a structured engineering approach was presented that was seen to strongly block SARS-CoV-2 cell infection.
These advanced receptors link tightly to the viral spike protein’s receptor-binding domain (RBD) and prevent entry into host cells. The ACE2-RBD interface was first computerized using a two-stage supple protein backbone design process that improved RBD affinity by up to 12 times. Through random mutagenesis and selection using yeast surface display, these designed receptor variants were made affinity matured of an additional 14-fold. Seven amino acid changes were present in the highest-affinity variant and bound to the RBD 170-fold more tightly than wild-type ACE2. With the adding of the natural ACE2 collection domain and fusion of the human immunoglobulin crystallizable fragment (Fc) domain for improved stabilization and specificity, the most efficient ACE2 receptor traps the neutralized SARS-CoV-2-pseudotype lentivirus and authentic SARS-CoV-2 virus with half-maximal inhibitory concentrations (IC50s) in the 10- to 100-ng / mL range. Orchestrated ACE2 receptor traps present a suitable route to combat SARS-CoV-2 and other coronavirus-using ACE2 infections, with the major benefit that viral resistance is also likely to damage viral entry. In addition, without the need for neutralizing antibodies isolated from convalescent patients, such traps can be pre-designed for viruses with known entry receptors for faster therapeutic response.
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References: Glasgow, Anum, Jeff Glasgow, Daniel Limonta, Paige Solomon, Irene Lui, Yang Zhang, Matthew A. Nix et al. “Engineered ACE2 receptor traps potently neutralize SARS-CoV-2.” BioRxiv (2020). https://www.researcher-app.com/paper/6145549?deeplink=researcher://feed?paper_id%3D6145549
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