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      Omicron BA.2 (B.1.1.529.2): High Potential for Becoming the Next Dominant Variant

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      The Journal of Physical Chemistry Letters
      American Chemical Society

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          Abstract

          The Omicron variant has three subvariants: BA.1 (B.1.1.529.1), BA.2 (B.1.1.529.2), and BA.3 (B.1.1.529.3). BA.2 is found to be able to alarmingly reinfect patients originally infected by Omicron BA.1. An important question is whether BA.2 or BA.3 will become a new dominating “variant of concern”. Currently, no experimental data has been reported about BA.2 and BA.3. We construct a novel algebraic topology-based deep learning model to systematically evaluate BA.2’s and BA.3’s infectivity, vaccine breakthrough capability, and antibody resistance. Our comparative analysis of all main variants, namely, Alpha, Beta, Gamma, Delta, Lambda, Mu, BA.1, BA.2, and BA.3, unveils that BA.2 is about 1.5 and 4.2 times as contagious as BA.1 and Delta, respectively. It is also 30% and 17-fold more capable than BA.1 and Delta, respectively, to escape current vaccines. Therefore, we project that Omicron BA.2 is on a path to becoming the next dominant variant. We forecast that like Omicron BA.1, BA.2 will also seriously compromise most existing monoclonal antibodies. All key predictions have been nearly perfectly confirmed before the official publication of this work.

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          Most cited references45

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

            Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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              Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding

              Summary The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD’s surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.
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                Author and article information

                Journal
                J Phys Chem Lett
                J Phys Chem Lett
                jz
                jpclcd
                The Journal of Physical Chemistry Letters
                American Chemical Society
                1948-7185
                25 April 2022
                05 May 2022
                : 13
                : 17
                : 3840-3849
                Affiliations
                []Department of Mathematics, Michigan State University , East Lansing, Michigan 48824, United States
                []Department of Electrical and Computer Engineering, Michigan State University , East Lansing, Michigan 48824, United States
                [§ ]Department of Biochemistry and Molecular Biology, Michigan State University , East Lansing, Michigan 48824, United States
                Author notes
                Author information
                https://orcid.org/0000-0001-5416-6231
                https://orcid.org/0000-0002-5781-2937
                Article
                10.1021/acs.jpclett.2c00469
                9063109
                35467344
                534371b4-5aec-4925-9399-6d0be962aa2f
                © 2022 American Chemical Society

                This article is made available via the PMC Open Access Subset for unrestricted RESEARCH re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 16 February 2022
                : 19 April 2022
                Funding
                Funded by: National Institute of General Medical Sciences, doi 10.13039/100000057;
                Award ID: GM126189
                Funded by: Michigan State University Foundation, doi 10.13039/100016254;
                Award ID: NA
                Funded by: Michigan Economic Development Corporation, doi 10.13039/100004948;
                Award ID: NA
                Funded by: Pfizer, doi 10.13039/100004319;
                Award ID: NA
                Funded by: Bristol-Myers Squibb, doi 10.13039/100002491;
                Award ID: NA
                Funded by: Division of Information and Intelligent Systems, doi 10.13039/100000145;
                Award ID: IIS1900473
                Funded by: Division of Mathematical Sciences, doi 10.13039/100000121;
                Award ID: DMS-2052983
                Funded by: Division of Mathematical Sciences, doi 10.13039/100000121;
                Award ID: DMS-1761320
                Funded by: National Aeronautics and Space Administration, doi 10.13039/100000104;
                Award ID: 80NSSC21M0023
                Categories
                Letter
                Custom metadata
                jz2c00469
                jz2c00469

                Physical chemistry
                Physical chemistry

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