key: cord-0710125-4tzg1xdp
authors: Desingu, Perumal A.; Nagarajan, K.
title: Omicron variant losing its critical mutations in the receptor‐binding domain
date: 2022-02-26
journal: J Med Virol
DOI: 10.1002/jmv.27667
sha: 0b4313c7ccfc847702cfe64c48e2577461d20eb7
doc_id: 710125
cord_uid: 4tzg1xdp

Recently the Omicron This article is protected by copyright. All rights reserved.

GISAID. Our previous study reported the difference in mutations in spike protein between the BA.1, BA.2, and BA.3 lineages. 4 Figure 1A,B) . Similarly, on the S1/ S2 cleavage site, BA.1lineage contains the rest in around 1% of the sequences, and this 1% represents approximately 4400 sequences ( Figure 1B) . When mutations in the Omicron variant RBD are individually assayed using a high-throughput assay in yeast-display platform, S371L, S373P, S375F, K417N, G446S, E484A, Q493R, G496S, Q498R, and Y505H mutations have been found to reduce binding to ACE2. While S477N, T478K, N501Y mutations have been found to enhance bonding with ACE2. 14 Similarly, combinations of mutations such as S477N, Q498R, and N501Y have been found to stabilize the RBD-ACE2 complex. 12 When the RBD-ACE2 binding affinity was explored using the noncompetitive ELISA approach, the Delta variant binding affinity was higher than the wild type and

Omicron. It has also been found that the binding affinity of Omicron is less than that of the wild type but has no statistically significant difference. 18 Furthermore, it is noteworthy that the Delta and Omicron variants were determined to have similar binding affinity when the RBD-ACE2 binding affinity was explored using the surface plasmon resonance approach. 19 The mutations Q493R, G496S, and Q498R in the Omicron variant RBD cause increased binding affinity by forming salt bridges and hydrogen bonds with human ACE2. 19 Similarly, when the RBD-ACE2 binding affinity was explored using the bio-layer interferometry approach, it was determined that the Omicron variant had a~3-fold enhanced binding affinity with ACE2 over the Wuhan-Hu-1 and Delta RBDs. 20 It has been found that in cells without TMPRSS2, the Omicron variant enters the cells through the endosomal route, and in cells with TMPRSS2 through fusion, the S1/S2 cleavage mutations cause fusion and syncytium formation less than the Delta variant. 20, 21 It is noteworthy that TMPRSS2 is more expressive in alveolar AT1 and AT2 pneumocytes and less expressive in the upper airway (trachea). 20 However, when mutations such as D614G, P681H, and H655Y at the S1/S2 cleavage site were examined individually, it was determined that they increased cleavage, fusion, and syncytium formation, thereby contributing to virus transmission. [22] [23] [24] [25] [26] Mutations in the RBD and S1/S2 cleavage site have been shown to exhibit one function as individuals but another as a combination of mutations. 19 This study reports that mutations in the RBD and S1/S2 cleavage sites are significantly altered. These mutation frequencies represent single mutations. Furthermore, these mutations can also be with combinations in some sequences that this analysis cannot determine. It needs to examine each sequence individually and examine their significance to see if these mutations are transformed into individuals or groups in each BA.1 sequence.

If any of these altered/changed/replaced amino acids become more likely to increases/decrease the binding capacity to ACE2 or S1/S2 cleavage site mutation increases the infection in TMPRSS2 expressing cells, it can be expected that this lineage is more likely to become a virus that causes severe infections. If BA.1 lineage spreads rapidly and becomes a virus that causes severe infections, it could shake the world's health care system. Therefore, sequences that show altered mutations within the receptor-binding domain and or S1/S2 cleavage site of the B.1.1.529 or BA.1 lineages may be used to diagnose or thoroughly examine the health status (mild, severe, hospitalized, etc), source of sample (nasal swab, throat, lung, etc), recovery, and vaccination status to predict the effect of the mutation in the disease outcome. Furthermore, viruses with these altered mutations should be examined experimentally to confirm the severity of the infection. It is hoped that this will help in controlling the spread of the disease at an early stage and preparing for vaccines, antiviral, and antibody treatment. 

The authors declare no conflicts of interest.

All the authors contributed significantly to this manuscript. Perumal A. Desingu analyzed and wrote the first draft, K. Nagarajan reviewed the manuscript. All the authors reviewed and approved the final submission.

Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. 

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