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      A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2

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          Abstract

          Neutralizing antibodies could be antivirals against COVID-19 pandemics. Here, we report isolation of four human-origin monoclonal antibodies from a convalescent patient, all of which display neutralization abilities. B38 and H4 block the binding between virus S-protein RBD and cellular receptor ACE2. A competition assay indicates their different epitopes on the RBD, making them a potential virus-targeting MAb-pair to avoid immune escape in future clinical applications. Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity. Our results highlight the promise of antibody-based therapeutics and provide a structural basis for rational vaccine design.

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          Most cited references16

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            A pneumonia outbreak associated with a new coronavirus of probable bat origin

            Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats 1–4 . Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans 5–7 . Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV.
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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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                Author and article information

                Journal
                Science
                Science
                SCIENCE
                Science (New York, N.y.)
                American Association for the Advancement of Science
                0036-8075
                1095-9203
                13 May 2020
                : eabc2241
                Affiliations
                [1 ]Department of Pathogen Microbiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
                [2 ]Research Network of Immunity and Health (RNIH), Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.
                [3 ]CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing, China.
                [4 ]School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
                [5 ]Shenzhen Key Laboratory of Pathogen and Immunity, Shenzhen Third People’s Hospital, Shenzhen, China.
                [6 ]College of Veterinary Medicine, China Agricultural University, Beijing, China.
                [7 ]Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences (CAS), Tianjin, China.
                [8 ]Shanxi Academy of Advanced Research and Innovation, Taiyuan, China.
                [9 ]University of Chinese Academy of Sciences, Beijing, China.
                [10 ]Center for Influenza Research and Early Warning, Chinese Academy of Sciences (CASCIRE), Beijing, China.
                [11 ]NHC Key Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
                [12 ]Laboratory Animal Center, Chinese Center for Disease Control and Prevention, Beijing, China.
                [13 ]Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, China.
                Author notes
                [*]

                These authors contributed equally to this work.

                []Corresponding author. Email: wuy@ 123456biols.ac.cn (Y.W.); gaofeng@ 123456tib.cas.cn (F.G.); gaof@ 123456im.ac.cn (G.F.G.); liulei3322@ 123456aliyun.com (L.L.)
                Author information
                https://orcid.org/0000-0003-2734-0673
                https://orcid.org/0000-0003-4568-9158
                https://orcid.org/0000-0001-8607-3750
                https://orcid.org/0000-0001-7069-9556
                https://orcid.org/0000-0002-7967-1581
                https://orcid.org/0000-0001-9800-9107
                https://orcid.org/0000-0003-4286-7772
                https://orcid.org/0000-0003-3608-4106
                https://orcid.org/0000-0002-5595-363X
                https://orcid.org/0000-0003-2778-4290
                https://orcid.org/0000-0002-5963-1136
                https://orcid.org/0000-0001-5556-2025
                https://orcid.org/0000-0002-3869-615X
                https://orcid.org/0000-0002-0670-010X
                https://orcid.org/0000-0001-9612-6844
                Article
                abc2241
                10.1126/science.abc2241
                7223722
                32404477
                2a97d9cd-6a3e-4667-bf17-4e036f612aae
                Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                : 13 April 2020
                : 05 May 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100007225, Ministry of Science and Technology;
                Award ID: 2018ZX10733403
                Funded by: doi http://dx.doi.org/10.13039/100007225, Ministry of Science and Technology;
                Award ID: 2016YFD0500304
                Funded by: doi http://dx.doi.org/10.13039/100007225, Ministry of Science and Technology;
                Award ID: 2017ZX10304402
                Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81902058
                Funded by: doi http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 31872745
                Funded by: doi http://dx.doi.org/10.13039/501100004835, Zhejiang University;
                Award ID: 2020XGZX019
                Funded by: the National Key R&D Program of China;
                Award ID: 2018YFC1200603
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