ABSTRACT
The newly emerging variants of SARS-CoV-2 from South Africa (B.1.351/501Y.V2) and Brazil (P.1/501Y.V3) have led to a higher infection rate and reinfection of COVID-19 patients. We found that the mutations K417N, E484K, and N501Y within the receptor-binding domains (RBDs) of the virus could confer ~2-fold higher binding affinity to the human receptor, angiotensin converting enzyme 2 (ACE2), compared to the wildtype RBD. The mutated version of RBD also completely abolishes the binding of bamlanivimab, a therapeutic antibody, in vitro. Detailed analysis shows that the ~10-fold gain of binding affinity between ACE2 and Y501-RBD, which also exits in the high contagious variant B.1.1.7/501Y.V1 from the United Kingdom, is compromised by additional introduction of the K417/N/T mutation. Mutation of E484K leads to the loss of bamlanivimab binding to RBD, although this mutation does not affect the binding between RBD and ACE2.
Subject(s)
Antibodies, Monoclonal, Humanized/metabolism , Antiviral Agents/metabolism , COVID-19/virology , Mutation , SARS-CoV-2/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , Binding Sites , COVID-19/diagnosis , Host-Pathogen Interactions , Humans , Molecular Docking Simulation , Protein Binding , Protein Interaction Domains and Motifs , Receptors, Virus/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , COVID-19 Drug TreatmentSubject(s)
SARS-CoV-2/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/metabolism , Antibodies, Monoclonal, Humanized/immunology , Antibodies, Neutralizing/immunology , Antigen-Antibody Reactions , COVID-19/pathology , COVID-19/virology , Humans , Kinetics , Mutation , Protein Binding , SARS-CoV-2/isolation & purification , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Surface Plasmon ResonanceABSTRACT
We generated several versions of the receptor binding domain (RBD) of the Spike protein with mutations existing within newly emerging variants from South Africa and Brazil. We found that the mutant RBD with K417N, E484K, and N501Y exchanges has higher binding affinity to the human receptor compared to the wildtype RBD. This mutated version of RBD also completely abolishes the binding to a therapeutic antibody, Bamlanivimab, in vitro .
ABSTRACT
Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing a world-wide pandemic. A variant of SARS-COV-2 (20I/501Y.V1) recently discovered in the United Kingdom has a single mutation from N501 to Y501 within the receptor binding domain (Y501-RBD), of the Spike protein of the virus. This variant is much more contagious than the original version (N501-RBD). We found that this mutated version of RBD binds to human Angiotensin Converting Enzyme 2 (ACE2) a ~10 times more tightly than the native version (N501-RBD). Modeling analysis showed that the N501Y mutation would allow a potential aromatic ring-ring interaction and an additional hydrogen bond between the RBD and ACE2. However, sera from individuals immunized with the Pfizer-BioNTech vaccine still efficiently block the binding of Y501-RBD to ACE2 though with a slight compromised manner by comparison with their ability to inhibit binding to ACE2 of N501-RBD. This may raise the concern whether therapeutic anti-RBD antibodies used to treat COVID-19 patients are still efficacious. Nevertheless, a therapeutic antibody, Bamlanivimab, still binds to the Y501-RBD as efficiently as its binds to N501-RBD.
