Studies show that SARS-CoV-2 is escape mutants that can re-infect immune individuals.


A recent study by US researchers shows how the 501Y.V2 variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), characterized by multiple mutations, is the current first wave antagonist SARS-CoV-. Is capable of avoiding neutralization 2 antibodies and potentially re-infected COVID-19 convocation individuals. Paper currently available Biorexive * Prepaid Server.

Several variants of SARS-CoV-2 emerge and later displace first-wave viruses, which is important in evaluating their relative transmittance and deformity not only in causing coronovirus disease (COVID-19), but They also have a tendency to avoid antibody neutralization.

Of extreme interest are mutational mutations that can affect the interaction of the viral spike receptor-binding domain (S RBD) with the viral receptor on host cells, angiotensin-altered enzyme 2 (ACE2), providing an entry point for the coronavirus Does.

Variations with more binding affinity for ACE2 are likely to be more diffuse. In addition, transmitability is associated with mortality, because the novel variants will result in an inevitable increase in infection rates resulting in higher disease and death.

However, these severe consequences of more acute and widespread infections may be complicated by the lack of efficacy of currently available antibody-based therapies and vaccines and the lack of protective immunity in individuals infected with a ‘first wave’ virus.

To improve our understanding of the risks posed by an individual or combined mutation in these ‘second wave’ variants, a research group at the ImmunityBio company in California performed a computational analysis of S RBD’s interactions with human ACB2.

The K484 substitution in the novel South African version increases the affinity of the spike receptor binding domain (S RBD) for ACE2.  (a, b) Positives of E484K (rad), K417N (cyan), and N501K (purple) are shown in the interface of the 501Y.V2 variant S RBD - hACEH interface.  The hACE2 residues closest to the muted RBD residues are presented as thin sticks.  The E484K mutation is located in a highly flexible loop region of the interface, in the low-probability region of the K417N contact, and at the second point of the N501K high-affinity contact.  (c) The range of movement available for loops containing residue 484 is shown by the PCA of the MD simulation of the first-wave sequence 11.113.  (D) MD simulations in the presence of all 3 substitutions show that the loop region is tightly connected (black arrow).  A main contact ion pair is circled.  (e) Compared to K484, when E484 ('wildtype') exists only with the Y501 variant, the loop is not as tightly connected (arrow).

The K484 substitution in the novel South African version increases the affinity of the spike receptor-binding domain (S RBD) for ACE2. (a, b) Positives of E484K (rad), K417N (cyan), and N501K (purple) are shown in the interface of the 501Y.V2 variant S RBD – hACEH interface. The hACE2 residues closest to the muted RBD residues are presented as thin sticks. The E484K mutation is located in the highly flexible loop region of the interface, in the low-probability region of the K417N contact, and at the second point of the N501K high-affinity contact. (c) The range of movement available for loops containing residue 484 is shown by the PCA of the MD simulation of the first-wave sequence 11.113. (D) MD simulations in the presence of all 3 substitutions show that the loop region is tightly connected (black arrow). A main contact ion pair is circled. (e) Compared to K484, when E484 (‘wildtype’) exists only with the Y501 variant, the loop is not as tightly connected (arrow).

In silico Simulation methods

In this study, researchers have used millisecond-scale MD simulation methods to investigate mutations (E484K, K417N, and N501Y) in the fast-spreading South African continent 501Y.V2 at the S RBD-ACE2 interface – and RBD. Their effects on compulsive affinity. And manufacture of spike glycoproteins.

The wild-type ACE2 / RBD complex was constructed from cryo-electron microscopy structure. In addition, ten copies of each rbd mutant were minimal, equivalent, and simulated, and processed inferiority occurred in two steps.

Finally, principal component analysis (PCA) was performed using a complete set of simulations for triple mutants, the E484K and N501Y systems. The simulation constructs were additionally divided on the eigenvectors for each mutation system.

Great escape from neutrality

The study revealed greater affinity of K484 S RBD for ACE2 as compared to E484, as well as greater potential for modified improvement compared to the original structure. This may indeed represent the mechanisms by which the new 501Y.V2 viral variant was able to replace the original SARS-CoV-2 strains.

More specifically, both E484K and N501Y mutations were shown to have increased affinity of S RBD for the human ACE2 receptor, whereas E484K was able to switch the charge on the flexible loop region of RBD, resulting in the formation of novel favorable contacts.

The aforementioned improved affinity is a potential culprit for this type of more rapid proliferation due to greater variability, which is a major reason why it is important to track these mutations and function in a timely manner.

In addition, re-removal by existing anti-SARS-COV-2 antibodies is responsible for the escape of the 501Y.V2 variant (distinct from the B.1.1 UK variant by the presence of the E484K mutation). -Collective COVID-19 Convocations.

Implications for further vaccine design

“We believe the MD simulation approach used here represents a tool used in the arsenal against persistent epidemics, as it alone provides insight into probability mutations or may have such effects in combination. That reduce the efficacy of existing vapors or vaccines “, the authors of this study say.

We add vaccines whose effectiveness depends largely on humoral responses to S antigens that are limited only by the emergence of novel strains and often rely on redesigns, ”he says.

On the other hand, a vaccine that develops a vigorous T-cell response is much less subject to mutations causing mutations and, thus, provides a better and more efficient approach to protection from the disease.

Finally, the ideal vaccine would also include a second, conserved antigen (such as the SARS-CoV-2 nucleocapsid protein), which would presumably elicit an effective humor and cell-mediated immune response – even a rapidly changing virus. with.

* Important Information

Biorxiv Publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be considered as conclusive, guiding clinical practice / health-related behavior, or as established information.

.

Leave a Reply

Your email address will not be published.