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      A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

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          Abstract

          A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.

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          Most cited references81

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          Cytoscape: a software environment for integrated models of biomolecular interaction networks.

          Cytoscape is an open source software project for integrating biomolecular interaction networks with high-throughput expression data and other molecular states into a unified conceptual framework. Although applicable to any system of molecular components and interactions, Cytoscape is most powerful when used in conjunction with large databases of protein-protein, protein-DNA, and genetic interactions that are increasingly available for humans and model organisms. Cytoscape's software Core provides basic functionality to layout and query the network; to visually integrate the network with expression profiles, phenotypes, and other molecular states; and to link the network to databases of functional annotations. The Core is extensible through a straightforward plug-in architecture, allowing rapid development of additional computational analyses and features. Several case studies of Cytoscape plug-ins are surveyed, including a search for interaction pathways correlating with changes in gene expression, a study of protein complexes involved in cellular recovery to DNA damage, inference of a combined physical/functional interaction network for Halobacterium, and an interface to detailed stochastic/kinetic gene regulatory models.
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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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              Is Open Access

              A new coronavirus associated with human respiratory disease in China

              Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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                Author and article information

                Journal
                Nature
                Nature
                Springer Science and Business Media LLC
                1476-4687
                0028-0836
                Jul 2020
                : 583
                : 7816
                Affiliations
                [1 ] QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.
                [2 ] Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA.
                [3 ] J. David Gladstone Institutes, San Francisco, CA, USA.
                [4 ] Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
                [5 ] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [6 ] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
                [7 ] Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
                [8 ] Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, Paris, France.
                [9 ] Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA.
                [10 ] Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA.
                [11 ] European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Genome Campus, Cambridge, UK.
                [12 ] Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
                [13 ] The UC Berkeley-UCSF Graduate Program in Bioengineering, University of California San Francisco, San Francisco, CA, USA.
                [14 ] Center for Computational Biology and Bioinformatics, Department of Medicine, University of California San Diego, San Diego, CA, USA.
                [15 ] Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, USA.
                [16 ] Department of Pharmacology, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA.
                [17 ] Biophysics Graduate Program, University of California San Francisco, San Francisco, CA, USA.
                [18 ] Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
                [19 ] Zoic Labs, Culver City, CA, USA.
                [20 ] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
                [21 ] Department of Urology, University of California San Francisco, San Francisco, CA, USA.
                [22 ] Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.
                [23 ] Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
                [24 ] George William Hooper Foundation, Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.
                [25 ] Medical Scientist Training Program, University of California San Francisco, San Francisco, CA, USA.
                [26 ] Virus and Immunity Unit, Institut Pasteur, Paris, France.
                [27 ] Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
                [28 ] Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
                [29 ] Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA.
                [30 ] Buck Institute for Research on Aging, Novato, CA, USA.
                [31 ] Direction Scientifique, Institut Pasteur, Paris, France.
                [32 ] Division of Genetics, Department of Medicine, University of California San Diego, San Diego, CA, USA.
                [33 ] Viral Populations and Pathogenesis Unit, CNRS UMR 3569, Institut Pasteur, Paris, France. marco.vignuzzi@pasteur.fr.
                [34 ] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Adolfo.Garcia-Sastre@mssm.edu.
                [35 ] Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Adolfo.Garcia-Sastre@mssm.edu.
                [36 ] Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Adolfo.Garcia-Sastre@mssm.edu.
                [37 ] The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Adolfo.Garcia-Sastre@mssm.edu.
                [38 ] QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA. Kevan.Shokat@ucsf.edu.
                [39 ] Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA. Kevan.Shokat@ucsf.edu.
                [40 ] Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. Kevan.Shokat@ucsf.edu.
                [41 ] Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA. Kevan.Shokat@ucsf.edu.
                [42 ] QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA. shoichet@cgl.ucsf.edu.
                [43 ] Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA. shoichet@cgl.ucsf.edu.
                [44 ] Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, USA. shoichet@cgl.ucsf.edu.
                [45 ] QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA. nevan.krogan@ucsf.edu.
                [46 ] Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, USA. nevan.krogan@ucsf.edu.
                [47 ] J. David Gladstone Institutes, San Francisco, CA, USA. nevan.krogan@ucsf.edu.
                [48 ] Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA. nevan.krogan@ucsf.edu.
                [49 ] Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. nevan.krogan@ucsf.edu.
                Article
                NIHMS1587111 10.1038/s41586-020-2286-9
                10.1038/s41586-020-2286-9
                7431030
                32353859
                9e3a182c-8fb9-422f-8ad2-2d06f2a7b974
                History

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