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Department of Medicine and Surgery, Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS Tradate, University of Insubria, Via Crotto Roncaccio 16, Tradate, VA, Italy
Correspondence author at: Department of Medicine and Surgery, Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS Tradate, University of Insubria, Via Crotto Roncaccio 16, Tradate, VA, Italy.
Department of Medicine and Surgery, Department of Medicine and Cardiopulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS Tradate, University of Insubria, Via Crotto Roncaccio 16, Tradate, VA, ItalyIstituti Clinici Scientifici Maugeri, IRCCS Tradate, Italy
Omicron BA.5 is the most dominant strain of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), with an estimated 85% of cases in United States (https://covid.cdc.gov/). A new subvariant known as BA.2.75 (unofficially Centaurus) was detected in India in May 2022, and several cases have been recently reported. It is not clear how mutations of this subvariant in the gene encoding for receptor binding domain (RBD) of the spike (S) protein of the virus can affect rate of infectivity. Of note, the RBD of SARS-CoV-2 docks to angiotensin converting enzyme 2 (ACE2) receptors [
ACE2 Down-regulation may act as a transient molecular disease causing RAAS dysregulation and tissue damage in the microcirculatory environment among COVID-19 patients.
We studied the effect of mutations of BA.2.75 subvariant on RBD, the conformational dynamics of the S protein and its adhesivity to ACE2 receptors. After download of the proteins sequence and structure for SARS-CoV-2 and ACE2 receptor from the Protein Data Bank (https://www.wwpdb.org/), we used the Pymol mutagenesis wizard (https://pymol.org) to introduce the specific mutations at the appropriate residues in wild type SARS-CoV-2 spike in order to create Omicron BA.5 and BA.2.75 variants. In addition and to evaluate the positions of new mutations, we did a pairwise alignment of the RBD's sequence of Omicron variants with Clustal omega (https://www.ebi.ac.uk/Tools/msa/clustalo/). The online server EMBOSS Pepstats (https://www.ebi.ac.uk/Tools/seqstats/emboss_pepstats/) was used to calculate the biochemical proprieties of the two variants. To evaluate binding affinity (ΔG) and Kd prediction we used the PRODIGY webserver (https://wenmr.science.uu.nl/prodigy/). After preparing the protein, Cluspro (https://www.ebi.ac.uk/Tools/msa/clustalo/) was used to dock the reference Omicron variants to the ACE2 receptor.
Fig. 1 (upper panel) shows the position of mutations in the S protein of BA.2.75 (left side), and the aminoacidic sequences in the RBD (right side) of Omicron BA.2.75 when compared with Omicron BA.5. For effect of these mutations, Omicron BA.2.75 showed a 57-fold higher binding affinity with ACE2 when compared with the BA.5 variant (ΔG BA.5/BA.2.75=1.3E-45/2.3E-47=56.52).
Fig. 1Mutations observed in Omicron BA.2.75 variant with 3D structure of S protein (left panel), comparison alignment of the receptor binding domain's sequence of BA.5 and BA.2.75 subvariants (right panel), and conformational dynamics of S protein of both BA.5 and BA.2.75 variants (lower panel).
], and the mutated S protein of Omicron BA.2.75 is characterized by a markedly higher adhesivity to ACE2 (estimated increased affinity >3,000-fold when compared with Alpha B.1.1.7 variant)[
]. Future vaccines will have to be built on the aminoacidic sequence of newer Omicron sub-variants in order to elicit a more robust antibody response [
]. Indeed, a national surveillance consortium for SARS-CoV-2 sequencing established in Israel evaluated neutralizing antibody titres against wild type SARS-CoV-2 and four Omicron variants (BA.1, BA.2, BA.4 and BA.5) in healthcare workers who had breakthrough BA.1 infection [
COVID-19 vaccination and BA.1 breakthrough infection induce neutralising antibodies which are less efficient against BA.4 and BA.5 Omicron variants, Israel, March to June 2022.
Briefly, Kliker and co-workers demonstrated that Omicron breakthrough infection in individuals vaccinated three or four times before infection resulted in increased neutralising antibodies against the wild type virus [
COVID-19 vaccination and BA.1 breakthrough infection induce neutralising antibodies which are less efficient against BA.4 and BA.5 Omicron variants, Israel, March to June 2022.
COVID-19 vaccination and BA.1 breakthrough infection induce neutralising antibodies which are less efficient against BA.4 and BA.5 Omicron variants, Israel, March to June 2022.
ACE2 Down-regulation may act as a transient molecular disease causing RAAS dysregulation and tissue damage in the microcirculatory environment among COVID-19 patients.
COVID-19 vaccination and BA.1 breakthrough infection induce neutralising antibodies which are less efficient against BA.4 and BA.5 Omicron variants, Israel, March to June 2022.
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