Study reveals how worrisome SARS-CoV-2 variants modulate receptor and antibody binding

In a pioneering engineering effort, Canadian and US researchers indicate that the emergence of new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) stems from advanced glycoprotein mutations that confer either increased affinity for the host cell receptor, or increased antibody escape. The document is currently available on the bioRxiv * preprint server while it is peer reviewed.

Genomic surveillance efforts that are being used to track the global spread of SARS-CoV-2, a causative agent of the current 2019 coronavirus disease (COVID-19) pandemic, have highlighted the emergence and rapid spread several notable viral variants, also called variants. of concern.

These variants have several mutations primarily in the spike glycoprotein receptor binding domain (RBD) which protrudes from the viral surface and allows viral entry into cells using its binding receptor on human cells – the enzyme converting angiotensin 2 (ACE2).

In addition, the peak glycoprotein RBD also represents a privileged target of the humoral immune response and the region targeted by a majority of neutralizing antibodies. Consequently, the vaccines currently in use essentially exploit this protein as the main antigenic component.

Of course, a problem with mutations within the RBD of the viral spike protein is that they can confer improved viral fitness and increased expression of the protein. This is why a research group from the University of British Columbia in Canada and the University of Pittsburgh Medical Center in the United States sought to understand the specific aspects of RBD mutations on common variants. of SARS-CoV-2 of concern.

Structural and biochemical experiments

Using eleven cutting-edge SARS-CoV-2 glycoproteins with various complementary mutations, this research group led by Dr Dhiraj Mannar and Dr James W. Saville systematically assessed the contributions of the main variants known to be of concern to increasing affinity of ACE2 and avoid neutralizing antibodies.

This was primarily done with the use of structural analysis of cryogenic electron microscopy; However, the researchers also developed novel and so far unreported combinations of mutations to explore the properties of variants that could possibly emerge in the future.

Specifically, advanced proteins have been designed to express these disturbing mutations of the RBD variant, either as single traits or in different combinations. Subsequently, structural analysis with cryogenic electron microscopy in combination with biochemical tests was used to analyze the effects.

ACE2 affinity and antibody binding effects

Briefly, their results showed that individual mutations in SARS-CoV-2 RBD can be classified as resulting in either increased affinity for the ACE2 receptor alone, reduced ACE2 affinity and reduced antibody binding or a simultaneous increase in l ACE2 affinity and reduced antibody binding. However, these mutations may be associated with individual preserved effects.

It should be noted that the majority of human-derived neutralizing antibodies developed can bind RBD with fingerprints that span at least one of the positions corresponding to the RBD mutation in variants of concern, which will be an important consideration in the development of future ones. treatment modalities.

The study also showed that novel combinations of RBD mutations are able to retain antibody evasion properties when tested for antibody binding with a panel of monoclonal antibodies.

Elucidate the evolutionary trajectory

“Overall, our results suggest that the emergence of new peaks of SARS-CoV-2 variants may be rationalized following mutations that confer either increased affinity to ACE2 or increased antibody evasion,” or both, providing a framework for dissecting the molecular factors that drive evolutionary variant of concern ”, underline the authors of the study in this bioRxiv paper.

Although we have focused the present study on the RBD mutations present in the variants of concern, it is possible that mutations elsewhere in the spike glycoprotein (particularly in the N-terminal domain) also play an important role in the escape of antibody and can affect ACE2 binding, ”they caution.

With a few small exceptions, these results, which describe the effects on ACE2 binding and antibody evasion following RBD mutations in the SARS-CoV-2 variants of concern tested, are in full agreement with d other recently published scientific reports.

In addition, the study implies that the evolution of RBD essentially follows a trajectory aimed at a concomitant increase in receptor affinity and a reduction in the binding of neutralizing antibodies. Future studies will be needed to further elucidate these relevant aspects of SARS-CoV-2 infection.

*Important Notice

bioRxiv publishes preliminary scientific reports which are not peer reviewed and, therefore, should not be considered conclusive, guide clinical practice / health-related behavior, or treated as established information.