Structural insight into SARS-CoV-2 neutralizing antibodies and modulation of syncytia.

Autor:	Asarnow D; Department of Biochemistry and Biophysics, University of California, San Francisco (UCSF) School of Medicine, San Francisco, CA, USA; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA., Wang B; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Lee WH; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Hu Y; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Huang CW; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Faust B; Department of Biochemistry and Biophysics, University of California, San Francisco (UCSF) School of Medicine, San Francisco, CA, USA; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA., Ng PML; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Ngoh EZX; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Bohn M; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA, USA., Bulkley D; Department of Biochemistry and Biophysics, University of California, San Francisco (UCSF) School of Medicine, San Francisco, CA, USA; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA., Pizzorno A; CIRI, Centre International de Recherche en Infectiologie (Team VirPath), Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France., Ary B; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA, USA., Tan HC; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Lee CY; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Minhat RA; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Terrier O; CIRI, Centre International de Recherche en Infectiologie (Team VirPath), Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France., Soh MK; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Teo FJ; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Yeap YYC; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Seah SGK; Biological Defence Program, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore., Chan CEZ; Biological Defence Program, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore., Connelly E; Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA, USA., Young NJ; Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA, USA., Maurer-Stroh S; Bioinformatics Institute, Agency for Science, Technology and Research (A(∗)STAR), 30 Biopolis Street, Matrix, Singapore 138671, Singapore; Infectious Diseases Laboratories (ID Labs), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore; Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore 117558, Singapore., Renia L; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore; Infectious Diseases Laboratories (ID Labs), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore., Hanson BJ; Biological Defence Program, DSO National Laboratories, 27 Medical Drive, Singapore 117510, Singapore., Rosa-Calatrava M; CIRI, Centre International de Recherche en Infectiologie (Team VirPath), Université de Lyon, INSERM U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, 69007 Lyon, France; VirNext, Faculté de Médecine RTH Laennec, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France., Manglik A; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA, USA; Department of Anesthesia and Perioperative Care, UCSF, San Francisco, CA, USA. Electronic address: aashish.manglik@ucsf.edu., Cheng Y; Department of Biochemistry and Biophysics, University of California, San Francisco (UCSF) School of Medicine, San Francisco, CA, USA; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA; Howard Hughes Medical Institute, UCSF, San Francisco, CA, USA. Electronic address: ycheng@ucsf.edu., Craik CS; QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco (UCSF), San Francisco, CA, USA. Electronic address: charles.craik@ucsf.edu., Wang CI; Singapore Immunology Network, Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore. Electronic address: wang_chengi@immunol.a-star.edu.sg.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2021 Jun 10; Vol. 184 (12), pp. 3192-3204.e16. Date of Electronic Publication: 2021 Apr 24.
DOI:	10.1016/j.cell.2021.04.033
Abstrakt:	Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is initiated by binding of the viral Spike protein to host receptor angiotensin-converting enzyme 2 (ACE2), followed by fusion of viral and host membranes. Although antibodies that block this interaction are in emergency use as early coronavirus disease 2019 (COVID-19) therapies, the precise determinants of neutralization potency remain unknown. We discovered a series of antibodies that potently block ACE2 binding but exhibit divergent neutralization efficacy against the live virus. Strikingly, these neutralizing antibodies can inhibit or enhance Spike-mediated membrane fusion and formation of syncytia, which are associated with chronic tissue damage in individuals with COVID-19. As revealed by cryoelectron microscopy, multiple structures of Spike-antibody complexes have distinct binding modes that not only block ACE2 binding but also alter the Spike protein conformational cycle triggered by ACE2 binding. We show that stabilization of different Spike conformations leads to modulation of Spike-mediated membrane fusion with profound implications for COVID-19 pathology and immunity. Competing Interests: Declaration of interests B.W., W.-H.L., C.-W.H., Y.H., P.M.L.N., E.Z.X.N., H.C.T., C.Y.L., R.A.M., M.K.S., F.J.T., Y.Y.C.Y., and C.-I.W. are listed as inventors of a filed patent for all 27 monoclonal antibodies mentioned in this manuscript. (Copyright © 2021 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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