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    Exploring the role of glycans in the interaction of SARS-CoV-2 RBD MESHD and human receptor ACE2

    Authors: Kien Nguyen; Srirupa Chakraborty; Rachael Mansbach; Bette Korber; S. Gnanakaran

    doi:10.1101/2021.03.30.437783 Date: 2021-03-31 Source: bioRxiv

    COVID-19 MESHD is a highly infectious respiratory disease MESHD caused by the novel coronavirus SARS-CoV-2. It has become a global pandemic and its frequent mutations may pose new challenges for vaccine design. During viral infection, the Spike RBD of SARS-CoV-2 binds the human host cell receptor ACE2 HGNC, enabling the virus to enter the host cell. Both the Spike and ACE2 HGNC are densely glycosylated, and it is unclear how distinctive glycan types may modulate the interaction of RBD and ACE2 HGNC. Detailed understanding of these determinants is key for the development of novel therapeutic strategies. To this end, we perform extensive all-atom simulations of the (i) RBD- ACE2 HGNC complex without glycans, (ii) RBD- ACE2 HGNC with oligomannose MAN9 HGNC glycans in ACE2 HGNC, and (iii) RBD- ACE2 HGNC with complex FA2 HGNC glycans in ACE2 HGNC. These simulations identify the key residues at the RBD- ACE2 HGNC interface that form contacts with higher probabilities, thus providing a quantitative evaluation that complements recent structural studies. Notably, we find that this RBD- ACE2 HGNC contact signature is not altered by the presence of different glycoforms, suggesting that RBD- ACE2 HGNC interaction is robust. Applying our simulated results, we illustrate how the recently prevalent N501Y mutation may alter specific interactions with host ACE2 HGNC that facilitate the virus-host binding. Furthermore, our simulations reveal how the glycan on Asn90 of ACE2 HGNC can play a distinct role in the binding and unbinding of RBD. Finally, an energetics analysis shows that MAN9 HGNC glycans on ACE2 HGNC decrease RBD- ACE2 HGNC affinity, while FA2 HGNC glycans lead to enhanced binding of the complex. Together, our results provide a more comprehensive picture of the detailed interplay between virus and human receptor, which is much needed for the discovery of effective treatments that aim at modulating the physical-chemical properties of this virus.

    The BioNTech / Pfizer vaccine BNT162b2 induces class-switched SARS-CoV-2-specific plasma cells and potential memory B cells as well as IgG and IgA serum and IgG saliva antibodies upon the first immunization

    Authors: Anne Sophie Lixenfeld; inga Kuensting; Emily L. Martin; Vera von Kopylow; Selina Lehrian; Hanna B. Lunding; Jana Sophia Buhre; Janna L. Quack; Moritz Steinhaus; Tobias Graf; Marc Ehlers; Johann Rahmoeller

    doi:10.1101/2021.03.10.21252001 Date: 2021-03-12 Source: medRxiv

    To treat the SARS-CoV-2 virus MESHD, that enters the body through the respiratory tract, different vaccines in particular against the SARS-CoV-2 spike PROTEIN ( S)-protein PROTEIN have been developed or are in the development process. For the BioNTech / Pfizer mRNA vaccine BNT162b2, which is injected twice, protection against COVID-19 MESHD has been described for the first weeks after the second vaccination. The underlying mechanisms of defense and the long-term effectiveness of this vaccine against COVID-19 MESHD are currently under investigation. In addition to the induction of systemic antibodies (Abs), Ab responses in the respiratory tract would help to form a first line of defense against SARS-CoV-2. Furthermore, protection depends on Fab HGNC-part-dependent neutralizing capacities, however, Fc-part-mediated effector mechanisms might also be important. Long-term defense would be based on the induction of long-lived antibody-producing plasma cells (PCs) and memory B cells. Here, we established different assays to analyze anti-SARS-CoV-2-S IgG and IgA Abs in blood serum and saliva as well as SARS-CoV-2-S1-reactive IgG and IgA PCs MESHD and potential memory B cells in the blood of individuals upon their first immunization with BNT162b2. We show that the vaccine induces in particular anti-SARS-CoV-2-S IgG1 and IgG3 HGNC as well as IgA1 HGNC and in some individuals also IgG2 and IgA2 serum Abs. In the saliva, we found no anti-SARS-CoV-2-S IgA, but instead IgG Abs. Furthermore, we found SARS-CoV-2-S reactive IgG+ blood PCs MESHD and potential memory B cells as well as SARS-CoV-2-S reactive IgA+ PCs and/or potential memory B cells in some individuals. Our data suggest that the vaccine induces a promising CD4+ T cell-dependent systemic IgG1 and IgG3 HGNC Ab response with IgG+ PCs and potential memory B cells. In addition to the systemic IgG response, the systemic IgA and saliva IgG response might help to improve a first line of defense in the respiratory tract against SARS-CoV-2 and its mutants.

    Molecular basis for a germline-biased neutralizing antibody response to SARS-CoV-2

    Authors: Sarah Ashley Clark; Lars Eric Clark; Adrian Coscia; Lindsay G.A. McKay; Sundaresh Shankar; Rebecca I. Johnson; Anthony Griffiths; Jonathan Abraham; Christophe Buyck; Johan Neyts; Marnix Van Loock; Leo James; Jakob luptak; Guinevere L Grice; Soraya Ebrahimi; Xiaoli Xiong; John AG Briggs; Sumita Pai; angalee nadesalingham; Marie-Christine Ouellet; Marc-André Roy; Marie-Christine Saint-Jacques; Claudia Savard

    doi:10.1101/2020.11.13.381533 Date: 2020-11-13 Source: bioRxiv

    The SARS-CoV-2 viral spike (S) protein PROTEIN mediates attachment and entry into host cells and is a major target of vaccine and drug design. Potent SARS-CoV-2 neutralizing antibodies derived from closely related antibody heavy chain genes ( IGHV3-53 HGNC or 3-66) have been isolated from multiple COVID-19 MESHD convalescent individuals. These usually contain minimal somatic mutations and bind the S receptor-binding domain (RBD) to interfere with attachment to the cellular receptor angiotensin-converting enzyme 2 ( ACE2 HGNC). We used antigen-specific single B cell sorting to isolate S-reactive monoclonal antibodies from the blood of a COVID-19 MESHD convalescent individual. The seven most potent neutralizing antibodies were somatic variants of the same IGHV3-53 HGNC-derived antibody and bind the RBD with varying affinity. We report X-ray crystal structures of four Fab HGNC variants bound to the RBD and use the structures to explain the basis for changes in RBD affinity. We show that a germline revertant antibody binds tightly to the SARS-CoV-2 RBD MESHD and neutralizes virus, and that gains in affinity for the RBD do not necessarily correlate with increased neutralization potency, suggesting that somatic mutation is not required to exert robust antiviral effect. Our studies clarify the molecular basis for a heavily germline-biased human antibody response to SARS-CoV-2.

    Structural basis for bivalent binding and inhibition of SARS-CoV-2 infection MESHD by human potent neutralizing antibodies

    Authors: Renhong Yan; Ruoke Wang; Bin Ju; Jinfang Yu; Yuanyuan Zhang; Nan Liu; Jia Wang; Qi Zhang; Peng Chen; Bing Zhou; Yaning Li; Shuyuan Zhang; Long Tian; Xinyue Zhong; Lin Cheng; Xiangyang Ge; Juanjuan Zhao; Hong-wei Wang; Xinquan Wang; Zheng Zhang; Linqi Zhang; Qiang Zhou; Yongzheng Zhang; Qiang Zhou; Jinghe Huang; Auke C Reidinga; Daisy Rusch; Kim CE Sigaloff; Renee A Douma; Lianne de Haan; Egill A Fridgeirsson; Niels C Gritters van de Oever; Roger JMW Rennenberg; Guido van Wingen; Marcel JH Aries; Martijn Beudel; ítalo Karmann Aventurato; Mariana Rabelo de Brito; Marina Koutsodontis Machado Alvim; José Roberto da Silva Junior; Lívia Liviane Damião; Maria Ercilia de Paula Castilho Stefano; Iêda Maria Pereira de Sousa; Elessandra Dias da Rocha; Solange Maria Gonçalves; Luiz Henrique Lopes da Silva; Vanessa Bettini; Brunno Machado de Campos; Guilherme Ludwig; Rosa Maria Mendes Viana; Ronaldo Martins; Andre S. Vieira; José Carlos Alves-Filho; Eurico de Arruda Neto; Adriano Sebollela; Fernando Cendes; Fernando Q Cunha Sr.; André Damásio; Marco Aurélio Ramirez Vinolo; Carolina Demarchi Munhoz; Stevens K Rehen Sr.; Thais Mauad; Amaro Nunes Duarte-Neto; Luiz Fernando Ferraz da Silva; Marisa Dolhnikoff; Paulo Saldiva; Alexandre Todorovic Fabro; Alessandro S Farias; Pedro Manoel M. Moraes-Vieira; José Luiz Proença Módena; Clarissa Lin Yasuda; Marcelo A. Mori; Thiago Mattar Cunha; Daniel Martins-de-Souza

    doi:10.1101/2020.10.13.336800 Date: 2020-10-13 Source: bioRxiv

    Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus virus diseases 2019 ( COVID-19 MESHD). We isolated a large number of nAbs from SARS-CoV-2 infected MESHD individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein PROTEIN and the receptor angiotensin converting enzyme 2 HGNC ( ACE2 HGNC). In order to understand the mechanism of these nAbs on neutralizing SARS-CoV-2 virus infections MESHD, we have performed cryo-EM analysis and here report cryo-EM structures of the ten most potent nAbs in their native full-length IgG or Fab HGNC forms bound to the trimeric S protein PROTEIN of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBD in the "up" conformation than the monovalent binding of Fab HGNC, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit from the S protein PROTEIN. Comparison of large number of nAbs identified common and unique structural features associated with their potent neutralizing activities. This work provides structural basis for further understanding the mechanism of nAbs, especially through revealing the bivalent binding and their correlation with more potent neutralization and the shedding of S1 subunit.

    Cross-neutralization of a SARS-CoV-2 antibody to a functionally conserved site is mediated by avidity

    Authors: Hejun Liu; Nicholas C. Wu; Meng Yuan; Sandhya Bangaru; Jonathan L. Torres; Tom G. Caniels; Jelle van Schooten; Xueyong Zhu; Chang-Chun D. Lee; Philip J.M. Brouwer; Marit J. van Gils; Rogier W. Sanders; Andrew B. Ward; Ian A. Wilson

    doi:10.1101/2020.08.02.233536 Date: 2020-08-03 Source: bioRxiv

    Most antibodies isolated from COVID-19 MESHD patients are specific to SARS-CoV-2. COVA1 HGNC-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV MESHD. Here we determined a crystal structure of COVA1 HGNC-16 Fab HGNC with the SARS-CoV-2 RBD, and a negative-stain EM reconstruction with the spike glycoprotein PROTEIN trimer, to elucidate the structural basis of its cross-reactivity. COVA1 HGNC-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long CDR H3, and competes with ACE2 HGNC binding due to steric hindrance rather than epitope overlap. COVA1 HGNC-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with structural and functional rationale for the epitope conservation, provide a blueprint for development of more universal SARS-like coronavirus vaccines and therapies.

    A glycan cluster on the SARS-CoV-2 spike PROTEIN ectodomain is recognized by Fab HGNC-dimerized glycan-reactive antibodies

    Authors: Priyamvada Acharya; Wilton Williams; Rory Henderson; Katarzyna Janowska; Kartik Manne; Robert Parks; Margaret Deyton; Jordan Sprenz; Victoria Stalls; Megan Kopp; Katayoun Mansouri; Robert J Edwards; Ryan Meyerhoff; Thomas Oguin; Gregory Sempowski; Kevin O Saunders; Barton F Haynes

    doi:10.1101/2020.06.30.178897 Date: 2020-06-30 Source: bioRxiv

    SummaryThe COVID-19 MESHD COVID-19 MESHD pandemic caused by SARS-CoV-2 has escalated into a global crisis. The spike (S) protein PROTEIN that mediates cell entry and membrane fusion is the current focus of vaccine and therapeutic antibody development efforts. The S protein PROTEIN, like many other viral fusion proteins such as HIV-1 envelope (Env) and influenza hemagglutinin, is glycosylated with both complex and high mannose glycans. Here we demonstrate binding to the SARS-CoV-2 S MESHD S protein PROTEIN by a category of Fab HGNC-dimerized glycan-reactive (FDG) HIV-1-induced broadly neutralizing antibodies (bnAbs). A 3.1 Å resolution cryo-EM structure of the S protein PROTEIN ectodomain bound to glycan-dependent HIV-1 bnAb MESHD 2G12 revealed a quaternary glycan epitope on the spike S2 domain involving multiple protomers. These data reveal a new epitope on the SARS-CoV-2 spike PROTEIN that can be targeted for vaccine design.HighlightsFab-dimerized, glycan-reactive (FDG) HIV-1 bnAbs cross-react with SARS-CoV-2 spike PROTEIN SARS-CoV-2 spike MESHD.3.1 Å resolution cryo-EM structure reveals quaternary S2 epitope for HIV-1 bnAb MESHD 2G12.2G12 targets glycans, at positions 709, 717 and 801, in the SARS-CoV-2 spike PROTEIN.Our studies suggest a common epitope for FDG antibodies centered around glycan 709.Competing Interest StatementThe authors have declared no competing interest.View Full Text

    Potent neutralization of SARS-CoV-2 in vitro and in an animal model by a human monoclonal antibody

    Authors: Wei Li; Aleksandra Drelich; David R Martinez; Lisa E Gralinski; Chuan Chen; Zehua Sun; Alexandra Schäfer; Sarah R Leist; Xianglei Liu; Doncho V Zhelev; Liyong Zhang; Eric L Peterson; Alex Conard; John W Mellors; Chien-Te Tseng; Ralph S Baric; Dimiter S Dimitrov

    doi:10.1101/2020.05.13.093088 Date: 2020-05-14 Source: bioRxiv

    Effective therapies are urgently needed for the SARS-CoV-2/ COVID19 MESHD pandemic. We identified panels of fully human monoclonal antibodies (mAbs) from eight large phage-displayed Fab HGNC, scFv and VH libraries by panning against the receptor binding domain (RBD) of the SARS-CoV-2 spike PROTEIN ( S) glycoprotein PROTEIN. One high affinity mAb, IgG1 ab1, specifically neutralized replication competent SARS-CoV-2 with exceptional potency as measured by two different assays. There was no enhancement of pseudovirus infection in cells expressing Fc{gamma} receptors at any concentration. It competed with human angiotensin-converting enzyme 2 HGNC ( hACE2 HGNC) for binding to RBD suggesting a competitive mechanism of virus neutralization. IgG1 ab1 potently neutralized mouse ACE2 adapted SARS-CoV-2 in wild type BALB/c mice and native virus in hACE2 HGNC expressing transgenic mice. The ab1 sequence has relatively low number of somatic mutations indicating that ab1-like antibodies could be quickly elicited during natural SARS-CoV-2 infection MESHD or by RBD-based vaccines. IgG1 ab1 does not have developability liabilities, and thus has potential for therapy and prophylaxis of SARS-CoV-2 infections MESHD. The rapid identification (within 6 days) of potent mAbs shows the value of large antibody libraries for response to public health threats from emerging microbes.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins

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