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Knowing the new Omicron BA.2.75 variant (‘Centaurus’): A simulation study

  • Martina Zappa
    Affiliations
    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
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  • Paolo Verdecchia
    Affiliations
    Fondazione Umbra Cuore e Ipertensione-ONLUS and Division of Cardiology, Hospital S. Maria della Misericordia, Perugia, Italy
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  • Fabio Angeli
    Correspondence
    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.
    Affiliations
    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

    Istituti Clinici Scientifici Maugeri, IRCCS Tradate, Italy
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Published:August 15, 2022DOI:https://doi.org/10.1016/j.ejim.2022.08.009

      Abbreviations:

      SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), RBD (receptor binding domain), ACE2 (angiotensin converting enzyme 2), S (spike)
      Dear Editor,
      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 [
      • Zhang H
      • Penninger JM
      • Li Y
      • Zhong N
      • Slutsky AS.
      Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target.
      ], gains entry into cells and dysregulates the renin-angiotensin system leading to an Angiotensin II storm [
      • Ramos SG
      • Rattis B
      • Ottaviani G
      • Celes MRN
      • Dias EP.
      ACE2 Down-regulation may act as a transient molecular disease causing RAAS dysregulation and tissue damage in the microcirculatory environment among COVID-19 patients.
      ,
      • Verdecchia P
      • Cavallini C
      • Spanevello A
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ,
      • Angeli F
      • Reboldi G
      • Trapasso M
      • Zappa M
      • Spanevello A
      • Verdecchia P.
      COVID-19, vaccines and deficiency of ACE2 and other angiotensinases. Closing the loop on the "Spike effect".
      ,
      • Angeli F
      • Zappa M
      • Oliva FM
      • Spanevello A
      • Verdecchia P.
      Blood pressure increase during hospitalization for COVID-19.
      ,
      • Angeli F
      • Zappa M
      • Reboldi G
      • Trapasso M
      • Cavallini C
      • Spanevello A
      • et al.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection: one year later.
      ,
      • Angeli F
      • Reboldi G
      • Ageing Verdecchia P.
      ACE2 deficiency and bad outcome in COVID-19.
      ].
      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 1
      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).
      In conclusion, the evolution of SARS-CoV-2 S protein [
      • Kumar R
      • Murugan NA
      • Srivastava V.
      Improved binding affinity of Omicron's spike protein for the human angiotensin-converting enzyme 2 receptor is the key behind its increased virulence.
      ], 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)[
      • Kumar R
      • Murugan NA
      • Srivastava V.
      Improved binding affinity of Omicron's spike protein for the human angiotensin-converting enzyme 2 receptor is the key behind its increased virulence.
      ]. This new variant is therefore expected to spread quicker and possibly enhance the Angiotensin II “intoxication”[
      • Sfera A
      • Osorio C
      • Jafri N
      • Diaz EL
      • Campo Maldonado JE
      Intoxication with endogenous angiotensin II: a COVID-19 hypothesis.
      ] and Angiotensin1-7 deficiency [
      • Verdecchia P
      • Cavallini C
      • Spanevello A
      • Angeli F.
      The pivotal link between ACE2 deficiency and SARS-CoV-2 infection.
      ]. 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 [
      • Angeli F
      • Spanevello A
      • Reboldi G
      • Visca D
      • Verdecchia P.
      SARS-CoV-2 vaccines: lights and shadows.
      ] and to avoid immune evasion [
      • Hewins B
      • Richardson C
      • Rubino S
      • Kelvin A
      • Toloue Ostadgavahi A
      • Kelvin DJ
      Molecular mechanisms responsible for SARS-CoV-2 antibody waning and vaccine escape in Omicron sublineages BA.4 and BA.5.
      ,
      • Cao Y
      • Yisimayi A
      • Jian F
      • Song W
      • Xiao T
      • Wang L
      • Du S
      • Wang J
      • Li Q
      • Chen X
      • Yu Y
      • Wang P
      • Zhang Z
      • Liu P
      • An R
      • Hao X
      • Wang Y
      • Wang J
      • Feng R
      • Sun H
      • Zhao L
      • Zhang W
      • Zhao D
      • Zheng J
      • Yu L
      • Li C
      • Zhang N
      • Wang R
      • Niu X
      • Yang S
      • Song X
      • Chai Y
      • Hu Y
      • Shi Y
      • Zheng L
      • Li Z
      • Gu Q
      • Shao F
      • Huang W
      • Jin R
      • Shen Z
      • Wang Y
      • Wang X
      • Xiao J
      • Xie XS
      BA.2.12.1, BA.4 and BA.5 escape antibodies elicited by Omicron infection.
      ,
      • Yao L
      • Zhu KL
      • Jiang XL
      • Wang XJ
      • Zhan BD
      • Gao HX
      • Geng XY
      • Duan LJ
      • Dai EH
      • Ma MJ.
      Omicron subvariants escape antibodies elicited by vaccination and BA.2.2 infection.
      ]. 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 [
      • Kliker L
      • Zuckerman N
      • Atari N
      • Barda N
      • Gilboa M
      • Nemet I
      • Abd Elkader B
      • Fratty IS
      • Jaber H
      • Mendelson E
      • Alroy-Preis S
      • Kreiss Y
      • Regev-Yochay G
      • Mandelboim M
      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 [
      • Kliker L
      • Zuckerman N
      • Atari N
      • Barda N
      • Gilboa M
      • Nemet I
      • Abd Elkader B
      • Fratty IS
      • Jaber H
      • Mendelson E
      • Alroy-Preis S
      • Kreiss Y
      • Regev-Yochay G
      • Mandelboim M
      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.
      ]. Notably, the fourth dose of vaccine did not further improve the neutralising efficiency over the third dose against all Omicron variants [
      • Kliker L
      • Zuckerman N
      • Atari N
      • Barda N
      • Gilboa M
      • Nemet I
      • Abd Elkader B
      • Fratty IS
      • Jaber H
      • Mendelson E
      • Alroy-Preis S
      • Kreiss Y
      • Regev-Yochay G
      • Mandelboim M
      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.
      ].

      Declaration of Competing Interest

      None of the authors of this study has financial or other reasons that could lead to a conflict of interest.

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