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Rigshospitalet - a part of Copenhagen University Hospital
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SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2

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  • Thomas Mandel Clausen
  • Daniel R Sandoval
  • Charlotte B Spliid
  • Jessica Pihl
  • Hailee R Perrett
  • Chelsea D Painter
  • Anoop Narayanan
  • Sydney A Majowicz
  • Elizabeth M Kwong
  • Rachael N McVicar
  • Bryan E Thacker
  • Charles A Glass
  • Zhang Yang
  • Jonathan L Torres
  • Gregory J Golden
  • Phillip L Bartels
  • Ryan N Porell
  • Aaron F Garretson
  • Logan Laubach
  • Jared Feldman
  • Xin Yin
  • Yuan Pu
  • Blake M Hauser
  • Timothy M Caradonna
  • Benjamin P Kellman
  • Cameron Martino
  • Philip L S M Gordts
  • Sumit K Chanda
  • Aaron G Schmidt
  • Kamil Godula
  • Sandra L Leibel
  • Joyce Jose
  • Kevin D Corbett
  • Andrew B Ward
  • Aaron F Carlin
  • Jeffrey D Esko
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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.

Original languageEnglish
JournalCell
Volume183
Issue number4
Pages (from-to)1043-1057.e15
ISSN0092-8674
DOIs
Publication statusPublished - 12 Nov 2020

    Research areas

  • Amino Acid Sequence, Angiotensin-Converting Enzyme 2, Betacoronavirus/isolation & purification, Binding Sites, COVID-19, Cell Line, Coronavirus Infections/pathology, Heparin/chemistry, Heparitin Sulfate/chemistry, Humans, Kidney/metabolism, Lung/metabolism, Molecular Dynamics Simulation, Pandemics, Peptidyl-Dipeptidase A/chemistry, Pneumonia, Viral/pathology, Protein Binding, Protein Domains, Recombinant Proteins/biosynthesis, SARS-CoV-2, Spike Glycoprotein, Coronavirus/chemistry, Virus Internalization

ID: 62341262