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      Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance

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          Abstract

          The ongoing COVID‐19 pandemic represents an unprecedented global health crisis. Here, we report the identification of a synthetic nanobody (sybody) pair, Sb#15 and Sb#68, that can bind simultaneously to the SARS‐CoV‐2 spike RBD and efficiently neutralize pseudotyped and live viruses by interfering with ACE2 interaction. Cryo‐EM confirms that Sb#15 and Sb#68 engage two spatially discrete epitopes, influencing rational design of bispecific and tri‐bispecific fusion constructs that exhibit up to 100‐ and 1,000‐fold increase in neutralization potency, respectively. Cryo‐EM of the sybody‐spike complex additionally reveals a novel up‐out RBD conformation. While resistant viruses emerge rapidly in the presence of single binders, no escape variants are observed in the presence of the bispecific sybody. The multivalent bispecific constructs further increase the neutralization potency against globally circulating SARS‐CoV‐2 variants of concern. Our study illustrates the power of multivalency and biparatopic nanobody fusions for the potential development of therapeutic strategies that mitigate the emergence of new SARS‐CoV‐2 escape mutants.

          Abstract

          Sybodies Sb#15 and Sb#68 inhibit SARS‐CoV‐2 infectivity by targeting non‐overlapping epitopes on the spike glycoprotein. Covalent sybody fusion and valency engineering enhances neutralization potency against variants and impedes emergence of escape mutants.

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          Most cited references75

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          Trimmomatic: a flexible trimmer for Illumina sequence data

          Motivation: Although many next-generation sequencing (NGS) read preprocessing tools already existed, we could not find any tool or combination of tools that met our requirements in terms of flexibility, correct handling of paired-end data and high performance. We have developed Trimmomatic as a more flexible and efficient preprocessing tool, which could correctly handle paired-end data. Results: The value of NGS read preprocessing is demonstrated for both reference-based and reference-free tasks. Trimmomatic is shown to produce output that is at least competitive with, and in many cases superior to, that produced by other tools, in all scenarios tested. Availability and implementation: Trimmomatic is licensed under GPL V3. It is cross-platform (Java 1.5+ required) and available at http://www.usadellab.org/cms/index.php?page=trimmomatic Contact: usadel@bio1.rwth-aachen.de Supplementary information: Supplementary data are available at Bioinformatics online.
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            The Sequence Alignment/Map format and SAMtools

            Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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              Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

              Structure of the nCoV trimeric spike The World Health Organization has declared the outbreak of a novel coronavirus (2019-nCoV) to be a public health emergency of international concern. The virus binds to host cells through its trimeric spike glycoprotein, making this protein a key target for potential therapies and diagnostics. Wrapp et al. determined a 3.5-angstrom-resolution structure of the 2019-nCoV trimeric spike protein by cryo–electron microscopy. Using biophysical assays, the authors show that this protein binds at least 10 times more tightly than the corresponding spike protein of severe acute respiratory syndrome (SARS)–CoV to their common host cell receptor. They also tested three antibodies known to bind to the SARS-CoV spike protein but did not detect binding to the 2019-nCoV spike protein. These studies provide valuable information to guide the development of medical counter-measures for 2019-nCoV. Science, this issue p. 1260
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                Author and article information

                Contributors
                c.paulino@rug.nl
                philippe.plattet@vetsuisse.unibe.ch
                m.seeger@imm.uzh.ch
                Journal
                EMBO Rep
                EMBO Rep
                10.1002/(ISSN)1469-3178
                EMBR
                embor
                EMBO Reports
                John Wiley and Sons Inc. (Hoboken )
                1469-221X
                1469-3178
                07 March 2022
                April 2022
                07 March 2022
                : 23
                : 4 ( doiID: 10.1002/embr.v23.4 )
                : e54199
                Affiliations
                [ 1 ] Institute of Medical Microbiology University of Zurich Zurich Switzerland
                [ 2 ] Division of Neurological Sciences Vetsuisse Faculty University of Bern Bern Switzerland
                [ 3 ] Department of Membrane Enzymology at the Groningen Biomolecular Sciences and Biotechnology Institute University of Groningen Groningen The Netherlands
                [ 4 ] Linkster Therapeutics AG Zurich Switzerland
                [ 5 ] Department of Structural Biology at the Groningen Biomolecular Sciences and Biotechnology Institute University of Groningen Groningen The Netherlands
                [ 6 ] Institute of Virology and Immunology Bern & Mittelhäusern Switzerland
                [ 7 ] Department of Infectious Diseases and Pathobiology Vetsuisse Faculty University of Bern Bern Switzerland
                [ 8 ] Interfaculty Bioinformatics Unit and Swiss Institute of Bioinformatics University of Bern Bern Switzerland
                Author notes
                [*] [* ] Corresponding author. Tel: +31 50 363 34 02; E‐mail: c.paulino@ 123456rug.nl

                Corresponding author. Tel: +41 31 631 23 70; E‐mail: philippe.plattet@ 123456vetsuisse.unibe.ch

                Corresponding author. Tel: +41 44 634 53 96; E‐mail: m.seeger@ 123456imm.uzh.ch

                [ † ]

                These authors contributed equally to this work

                Author information
                https://orcid.org/0000-0002-1492-3055
                https://orcid.org/0000-0001-5554-9664
                https://orcid.org/0000-0002-8920-3343
                https://orcid.org/0000-0002-7394-8981
                https://orcid.org/0000-0003-3476-4749
                https://orcid.org/0000-0002-2292-3282
                https://orcid.org/0000-0002-9901-2065
                https://orcid.org/0000-0002-6852-6119
                https://orcid.org/0000-0003-3944-4533
                https://orcid.org/0000-0001-8948-3704
                https://orcid.org/0000-0001-8480-197X
                https://orcid.org/0000-0001-9907-7830
                https://orcid.org/0000-0001-9951-181X
                https://orcid.org/0000-0002-4455-430X
                https://orcid.org/0000-0001-5204-4556
                https://orcid.org/0000-0002-3957-2298
                https://orcid.org/0000-0002-1561-078X
                https://orcid.org/0000-0001-5629-6363
                https://orcid.org/0000-0002-2708-2507
                https://orcid.org/0000-0002-5804-9689
                https://orcid.org/0000-0001-7017-109X
                https://orcid.org/0000-0003-3313-2598
                https://orcid.org/0000-0003-1761-8571
                Article
                EMBR202154199
                10.15252/embr.202154199
                8982573
                35253970
                33d78fef-d99f-4468-aaaa-9967354f1875
                © 2022 The Authors. Published under the terms of the CC BY 4.0 license

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 January 2022
                : 21 October 2021
                : 31 January 2022
                Page count
                Figures: 13, Tables: 3, Pages: 19, Words: 15223
                Funding
                Funded by: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (SNF) , doi 10.13039/501100001711;
                Award ID: 4078P0_198314
                Funded by: Universitat Zurich
                Categories
                Article
                Articles
                Custom metadata
                2.0
                05 April 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.3 mode:remove_FC converted:05.04.2022

                Molecular biology
                escape mutants,sars‐cov‐2,sybodies,synthetic nanobodies,variants of concern,immunology,microbiology, virology & host pathogen interaction,structural biology

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