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      Protein structure analysis of the interactions between SARS-CoV-2 spike protein and the human ACE2 receptor: from conformational changes to novel neutralizing antibodies

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          Abstract

          The recent severe acute respiratory syndrome, known as Coronavirus Disease 2019 (COVID-19) has spread so much rapidly and severely to induce World Health Organization (WHO) to declare a state of emergency over the new coronavirus SARS-CoV-2 pandemic. While several countries have chosen the almost complete lock-down for slowing down SARS-CoV-2 spread, the scientific community is called to respond to the devastating outbreak by identifying new tools for diagnosis and treatment of the dangerous COVID-19. With this aim, we performed an in silico comparative modeling analysis, which allows gaining new insights into the main conformational changes occurring in the SARS-CoV-2 spike protein, at the level of the receptor-binding domain (RBD), along interactions with human cells angiotensin-converting enzyme 2 (ACE2) receptor, that favor human cell invasion. Furthermore, our analysis provides (1) an ideal pipeline to identify already characterized antibodies that might target SARS-CoV-2 spike RBD, aiming to prevent interactions with the human ACE2, and (2) instructions for building new possible neutralizing antibodies, according to chemical/physical space restraints and complementary determining regions (CDR) mutagenesis of the identified existing antibodies. The proposed antibodies show in silico high affinity for SARS-CoV-2 spike RBD and can be used as reference antibodies also for building new high-affinity antibodies against present and future coronaviruses able to invade human cells through interactions of their spike proteins with the human ACE2. More in general, our analysis provides indications for the set-up of the right biological molecular context for investigating spike RBD–ACE2 interactions for the development of new vaccines, diagnostic kits, and other treatments based on the targeting of SARS-CoV-2 spike protein.

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          The online version of this article (10.1007/s00018-020-03580-1) contains supplementary material, which is available to authorized users.

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)
          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.
          Article 0 comments Cited 9951 times – based on 0 reviews     Review now
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            COVID-19: consider cytokine storm syndromes and immunosuppression

            Puja Mehta, Daniel McAuley, Michael Brown … (2020)
            As of March 12, 2020, coronavirus disease 2019 (COVID-19) has been confirmed in 125 048 people worldwide, carrying a mortality of approximately 3·7%, 1 compared with a mortality rate of less than 1% from influenza. There is an urgent need for effective treatment. Current focus has been on the development of novel therapeutics, including antivirals and vaccines. Accumulating evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. We recommend identification and treatment of hyperinflammation using existing, approved therapies with proven safety profiles to address the immediate need to reduce the rising mortality. Current management of COVID-19 is supportive, and respiratory failure from acute respiratory distress syndrome (ARDS) is the leading cause of mortality. 2 Secondary haemophagocytic lymphohistiocytosis (sHLH) is an under-recognised, hyperinflammatory syndrome characterised by a fulminant and fatal hypercytokinaemia with multiorgan failure. In adults, sHLH is most commonly triggered by viral infections 3 and occurs in 3·7–4·3% of sepsis cases. 4 Cardinal features of sHLH include unremitting fever, cytopenias, and hyperferritinaemia; pulmonary involvement (including ARDS) occurs in approximately 50% of patients. 5 A cytokine profile resembling sHLH is associated with COVID-19 disease severity, characterised by increased interleukin (IL)-2, IL-7, granulocyte-colony stimulating factor, interferon-γ inducible protein 10, monocyte chemoattractant protein 1, macrophage inflammatory protein 1-α, and tumour necrosis factor-α. 6 Predictors of fatality from a recent retrospective, multicentre study of 150 confirmed COVID-19 cases in Wuhan, China, included elevated ferritin (mean 1297·6 ng/ml in non-survivors vs 614·0 ng/ml in survivors; p 39·4°C 49 Organomegaly None 0 Hepatomegaly or splenomegaly 23 Hepatomegaly and splenomegaly 38 Number of cytopenias * One lineage 0 Two lineages 24 Three lineages 34 Triglycerides (mmol/L) 4·0 mmol/L 64 Fibrinogen (g/L) >2·5 g/L 0 ≤2·5 g/L 30 Ferritin ng/ml 6000 ng/ml 50 Serum aspartate aminotransferase <30 IU/L 0 ≥30 IU/L 19 Haemophagocytosis on bone marrow aspirate No 0 Yes 35 Known immunosuppression † No 0 Yes 18 The Hscore 11 generates a probability for the presence of secondary HLH. HScores greater than 169 are 93% sensitive and 86% specific for HLH. Note that bone marrow haemophagocytosis is not mandatory for a diagnosis of HLH. HScores can be calculated using an online HScore calculator. 11 HLH=haemophagocytic lymphohistiocytosis. * Defined as either haemoglobin concentration of 9·2 g/dL or less (≤5·71 mmol/L), a white blood cell count of 5000 white blood cells per mm3 or less, or platelet count of 110 000 platelets per mm3 or less, or all of these criteria combined. † HIV positive or receiving longterm immunosuppressive therapy (ie, glucocorticoids, cyclosporine, azathioprine).
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              Is Open Access

              Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

              Daniel Wrapp, Nianshuang Wang, Kizzmekia S. Corbett … (2020)
              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
              Article 0 comments Cited 4279 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Ciro Leonardo Pierri:
                ORCID: http://orcid.org/0000-0003-1816-548X
                ciro.pierri@uniba.it , ciroleopierri1@gmail.com
                Journal
                Journal ID (nlm-ta): Cell Mol Life Sci
                Journal ID (iso-abbrev): Cell. Mol. Life Sci
                Title: Cellular and Molecular Life Sciences
                Publisher: Springer International Publishing (Cham )
                ISSN (Print): 1420-682X
                ISSN (Electronic): 1420-9071
                Publication date (Electronic): 4 July 2020
                Pages: 1-22
                Affiliations
                [1 ]GRID grid.7644.1, ISNI 0000 0001 0120 3326, Laboratory of Biochemistry, Molecular and Structural Biology, Department of Biosciences, Biotechnologies, Biopharmaceutics, , University of Bari, ; Via E. Orabona, 4, 70125 Bari, Italy
                [2 ]GRID grid.7644.1, ISNI 0000 0001 0120 3326, Department of Soil, Plant and Food Sciences, , University of Bari Aldo Moro, ; Via Amendola 165/A, 70126 Bari, Italy
                [3 ]BROWSer S.r.l. (https://browser-bioinf.com/) c/o Department of Biosciences, Biotechnologies, Biopharmaceutics, University “Aldo Moro” of Bari, Via E. Orabona, 4, 70126 Bari, Italy
                Author information
                http://orcid.org/0000-0001-7273-4263
                http://orcid.org/0000-0003-1816-548X
                Article
                Publisher ID: 3580
                DOI: 10.1007/s00018-020-03580-1
                PMC ID: 7334636
                PubMed ID: 32623480
                SO-VID: 1d7d751a-3e98-43eb-a868-64f7c43913e8
                Copyright © © Springer Nature Switzerland AG 2020
                License:

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                Date received : 16 April 2020
                Date revision received : 10 June 2020
                Date accepted : 22 June 2020
                Categories
                Subject: Original Article

                ScienceOpen disciplines: Molecular biology
                Keywords: sars-cov-2,covid-19,n-cov19,coronavirus,spike,receptor binding domain,neutralizing antibodies,spike post-fusion conformation,ace2 and ace inhibitors,fold recognition tools,comparative modeling
                Data availability:
                ScienceOpen disciplines: Molecular biology
                Keywords: sars-cov-2, covid-19, n-cov19, coronavirus, spike, receptor binding domain, neutralizing antibodies, spike post-fusion conformation, ace2 and ace inhibitors, fold recognition tools, comparative modeling

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