A recent study published in the journal Science Brings a detailed chemical and molecular perspective on improved evasion of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and strong interactions with the receptor as two key factors underlying the infamous transmission potential of SARS-CoV does the retention. -2 Omicron version.
Study: SARS-CoV-2 Omicron type: antibody evasion and cryo-EM structure of the spike protein-ACE2 complex. Image credit: crocothy/Shutterstock
The B.220.127.116.119 variant of SARS-CoV-2, officially named the Omicron variant by the World Health Organization (WHO), was initially reported in November 2021 and was quickly recognized as a significant concern. version was recognized. The problem with this specific type is that it is currently spreading even among doubly vaccinated individuals, with massive public health implications.
We already know that SARS-CoV-2 uses its spike glycoprotein for host cell entry by recognizing the angiotensin-converting enzyme 2 (ACE2) receptor, which was the rationale behind the development of the vaccine. However, the omicron variant harbors the spike protein 37 mutation and represents the most mutated variant of this virus to date.
Therefore, placing the repercussions of these mutations for ACE2 receptor binding and the antibody evasion process is critical for the development of efficacious therapeutics aimed at limiting the spread of the Omicron variant, but also those that may emerge later. .
And this work was in the focus of a research group from the University of British Columbia’s Department of Biochemistry and Molecular Biology, as well as the BC Center for Disease Control Public Health Laboratory in Vancouver, Canada.
From cryogenic electron microscopy to neutralization studies
In their recent paper published in the top-tier journal Science, the use of cryogenic electron microscopy (cryo-EM) was one of the main methodological approaches to evaluate the structure of the oomicron spike protein in unprecedented detail.
In addition, in order to precisely measure the effect of omicron spike glycoprotein mutations on the binding affinity for the ACE2 receptor on human cells, the researchers performed surface plasmon resonance studies and subsequently compared the resulting apparent binding affinity to the glycoproteins of wild-type and delta. is to increase. strains
They have also used a panel of neutralizing monoclonal antibodies that include antibodies directed to the receptor-binding domain (RBD) and the N-terminal domain (NTD) of the SARS-CoV-2 spike glycoprotein, which is responsible for the omicron RBD and NTD mutations. evaluate the effect of. Monoclonal antibody escape.
Cryo-EM structure of the Omicron spike protein. (A) A schematic diagram showing the domain arrangement of the spike protein. Mutations present in Omicron type spike proteins are labeled. (B) Cryo-EM map of the Omicron spike protein at 2.79 resolution. The protomers are colored in various shades of purple. (C) Cryo-EM structure of the Omicron spike protein showing the locations of the modeling mutations on a protomer. (D) Omicron spike receptor-binding domain (RBD) shown in two orthogonal orientations with the Cα positions of the mutated residues shown as red regions.
Mutations that restore binding efficiency
Briefly, a structural analysis of the Omicron variant spike glycoprotein with cryo-ER in complex with human ACE2 revealed new salt bridges and hydrogen bonds that were formed by mutated residues R493, S496 and R498 in the RBD with ACE2 .
This is an important finding, as these interactions seem to compensate for other oomicron mutations that are known to reduce ACE2 binding affinity (such as K417N) – giving rise to similar biochemical ACE2 binding affinity for both delta and omicron variants. give.
Furthermore, the cryo-EM structure of the complex between the spike glycoprotein and the ACE2 receptor uncovers a structural explanation for this phenomenon. More specifically, interactions that involve novel mutations in the Omicron variant at residues 493, 496, 498, and 501, re-enforce ACE2 binding efficiency that would be lost due to other mutations (such as the aforementioned K417N).
Therefore, the remarkably broad mutation in the oomicron variant spike glycoprotein appears to lead to a broad antibody escape relative to the previously emerged and circulating variants of SARS-CoV-2.
The study also showed that sera from previously infected patients had a decreased neutralization ability against the Omicron variant relative to the delta variant, especially with drops specific to patients who had previously been infected with the alpha and delta forms Was.
Evolutionary processes at play
The findings reported in this study are in line with other recent reports that support the notion of increased resistance to the neutralization of the Omicron variant. This is contingent on either prior infection with an earlier version or vaccination and is actually more pronounced than other forms of concern that have emerged during the coronavirus disease 2019 (COVID-19) pandemic.
“The large number of mutations on the surface of spike proteins, including immunodominant RBDs, would help the virus evade antibodies emanating from vaccination or prior infection,” say the study authors. “It is interesting that the Omicron variant evolved to retain its ability to bind efficiently to ACE2 despite these widespread mutations”, they emphasize. Science paper.
In any case, the currently ubiquitous omicron variant has evolved to selectively balance its ability to better avoid the neutralization process with its tendency to interact efficiently with the ACE2 receptor.
In conclusion, increasing antibody evasion and maintaining strong interactions at the ACE2 interface are major factors contributing to the increased transmission of the omicron variant, along with biological and important public health implications.