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SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2.
Cell. 2020 11 12; 183(4):1043-1057.e15.Cell

Abstract

We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities.

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Authors+Show Affiliations

Clausen TM
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Infectious Disease, Copenhagen University Hospital, 2200 Copenhagen, Denmark. Electronic address: tmandelclausen@health.ucsd.edu.
Sandoval DR
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Spliid CB
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Infectious Disease, Copenhagen University Hospital, 2200 Copenhagen, Denmark.
Pihl J
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department for Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Infectious Disease, Copenhagen University Hospital, 2200 Copenhagen, Denmark.
Perrett HR
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Painter CD
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA.
Narayanan A
Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Majowicz SA
Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Kwong EM
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
McVicar RN
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Thacker BE
TEGA Therapeutics, Inc., 3550 General Atomics Court, G02-102, San Diego, CA 92121, USA.
Glass CA
TEGA Therapeutics, Inc., 3550 General Atomics Court, G02-102, San Diego, CA 92121, USA.
Yang Z
Copenhagen Center for Glycomics, Department of Molecular and Cellular Medicine, University of Copenhagen, 2200 Copenhagen, Denmark.
Torres JL
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Golden GJ
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California, USA.
Bartels PL
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA.
Porell RN
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Garretson AF
Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
Laubach L
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Feldman J
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
Yin X
Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Pu Y
Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Hauser BM
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
Caradonna TM
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA.
Kellman BP
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA 92093, USA.
Martino C
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Gordts PLSM
Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA.
Chanda SK
Immunity and Pathogenesis Program, Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Schmidt AG
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA 02139, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
Godula K
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA.
Leibel SL
Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA.
Jose J
Department of Biochemistry and Molecular Biology, The Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA 16802, USA.
Corbett KD
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Ward AB
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Carlin AF
Department of Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
Esko JD
Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: jesko@health.ucsd.edu.

MeSH

Amino Acid SequenceAngiotensin-Converting Enzyme 2BetacoronavirusBinding SitesCOVID-19Cell LineCoronavirus InfectionsHeparinHeparitin SulfateHumansKidneyLungMolecular Dynamics SimulationPandemicsPeptidyl-Dipeptidase APneumonia, ViralProtein BindingProtein DomainsRecombinant ProteinsSARS-CoV-2Spike Glycoprotein, CoronavirusVirus Internalization

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32970989

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Citation

Clausen, Thomas Mandel, et al. "SARS-CoV-2 Infection Depends On Cellular Heparan Sulfate and ACE2." Cell, vol. 183, no. 4, 2020, pp. 1043-1057.e15.
Clausen TM, Sandoval DR, Spliid CB, et al. SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Cell. 2020;183(4):1043-1057.e15.
Clausen, T. M., Sandoval, D. R., Spliid, C. B., Pihl, J., Perrett, H. R., Painter, C. D., Narayanan, A., Majowicz, S. A., Kwong, E. M., McVicar, R. N., Thacker, B. E., Glass, C. A., Yang, Z., Torres, J. L., Golden, G. J., Bartels, P. L., Porell, R. N., Garretson, A. F., Laubach, L., ... Esko, J. D. (2020). SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. Cell, 183(4), 1043-e15. https://doi.org/10.1016/j.cell.2020.09.033
Clausen TM, et al. SARS-CoV-2 Infection Depends On Cellular Heparan Sulfate and ACE2. Cell. 2020 11 12;183(4):1043-1057.e15. PubMed PMID: 32970989.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2. AU - Clausen,Thomas Mandel, AU - Sandoval,Daniel R, AU - Spliid,Charlotte B, AU - Pihl,Jessica, AU - Perrett,Hailee R, AU - Painter,Chelsea D, AU - Narayanan,Anoop, AU - Majowicz,Sydney A, AU - Kwong,Elizabeth M, AU - McVicar,Rachael N, AU - Thacker,Bryan E, AU - Glass,Charles A, AU - Yang,Zhang, AU - Torres,Jonathan L, AU - Golden,Gregory J, AU - Bartels,Phillip L, AU - Porell,Ryan N, AU - Garretson,Aaron F, AU - Laubach,Logan, AU - Feldman,Jared, AU - Yin,Xin, AU - Pu,Yuan, AU - Hauser,Blake M, AU - Caradonna,Timothy M, AU - Kellman,Benjamin P, AU - Martino,Cameron, AU - Gordts,Philip L S M, AU - Chanda,Sumit K, AU - Schmidt,Aaron G, AU - Godula,Kamil, AU - Leibel,Sandra L, AU - Jose,Joyce, AU - Corbett,Kevin D, AU - Ward,Andrew B, AU - Carlin,Aaron F, AU - Esko,Jeffrey D, Y1 - 2020/09/14/ PY - 2020/07/13/received PY - 2020/08/16/revised PY - 2020/09/10/accepted PY - 2020/9/25/pubmed PY - 2020/11/26/medline PY - 2020/9/24/entrez KW - COVID-19 KW - SARS-CoV-2 KW - coronavirus KW - heparan sulfate KW - heparan sulfate-binding proteins KW - heparin KW - lung epithelial cells KW - pseudotyped virus KW - spike proteins SP - 1043 EP - 1057.e15 JF - Cell JO - Cell VL - 183 IS - 4 N2 - We show that SARS-CoV-2 spike protein interacts with both cellular heparan sulfate and angiotensin-converting enzyme 2 (ACE2) through its receptor-binding domain (RBD). Docking studies suggest a heparin/heparan sulfate-binding site adjacent to the ACE2-binding site. Both ACE2 and heparin can bind independently to spike protein in vitro, and a ternary complex can be generated using heparin as a scaffold. Electron micrographs of spike protein suggests that heparin enhances the open conformation of the RBD that binds ACE2. On cells, spike protein binding depends on both heparan sulfate and ACE2. Unfractionated heparin, non-anticoagulant heparin, heparin lyases, and lung heparan sulfate potently block spike protein binding and/or infection by pseudotyped virus and authentic SARS-CoV-2 virus. We suggest a model in which viral attachment and infection involves heparan sulfate-dependent enhancement of binding to ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin presents new therapeutic opportunities. SN - 1097-4172 UR - https://www.unboundmedicine.com/medline/citation/32970989/SARS_CoV_2_Infection_Depends_on_Cellular_Heparan_Sulfate_and_ACE2_ DB - PRIME DP - Unbound Medicine ER -