@article{6146791d247a4cae903d2397f883f71a,
title = "SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2",
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.",
author = "Clausen, {Thomas Mandel} and Sandoval, {Daniel R.} and Spliid, {Charlotte B.} and Jessica Pihl and Perrett, {Hailee R.} and Painter, {Chelsea D.} and Anoop Narayanan and Majowicz, {Sydney A.} and Kwong, {Elizabeth M.} and McVicar, {Rachael N.} and Thacker, {Bryan E.} and Glass, {Charles A.} and Zhang Yang and Torres, {Jonathan L.} and Golden, {Gregory J.} and Bartels, {Phillip L.} and Porell, {Ryan N.} and Garretson, {Aaron F.} and Logan Laubach and Jared Feldman and Xin Yin and Yuan Pu and Hauser, {Blake M.} and Caradonna, {Timothy M.} and Kellman, {Benjamin P.} and Cameron Martino and Gordts, {Philip L.S.M.} and Chanda, {Sumit K.} and Schmidt, {Aaron G.} and Kamil Godula and Leibel, {Sandra L.} and Joyce Jose and Corbett, {Kevin D.} and Ward, {Andrew B.} and Carlin, {Aaron F.} and Esko, {Jeffrey D.}",
note = "Funding Information: We thank Scott Selleck (Pennsylvania State University), Eugene Yeo (UC San Diego), John Guatelli (UC San Diego), Mark Fuster (UC San Diego), and Stephen Schoenberger (La Jolla Institute for Immunology) for many helpful discussions, and Annamaria Naggi and Giangiacomo Torri from the Ronzoni Institute for generously providing split-glycol heparin. This work was supported by RAPID grant 2031989 from the National Science Foundation and Project 3 of NIH P01 HL131474 to J.D.E. the Alfred Benzon Foundation to T.M. Clausen, NIH R01 AI146779 and a Massachusetts Consortium on Pathogen Readiness (MassCPR) grant to A.G.S. DOD grant W81XWH-20-1-0270 and Fluomics/NOSI U19 AI135972 to S.K.C. a Career Award for Medical Scientists from the Burroughs Wellcome Fund to A.F.C. Bill and Melinda Gates Foundation grant OPP1170236 to A.B.W. COVID-19 seed funding from the Huck Institutes of the Life Sciences and Penn State start-up funds to J.J. funding for Z.Y. from grant DNRF107 from the Danish National Research Foundation, and T32 training grants GM007753 to B.M.H. and T.M. Caradonna and AI007245 for J.F. J.P. received funding from Innovation Fund Denmark and VAR2 Pharmaceuticals. T.M. Clausen, D.R.S. and J.D.E. conceived, initiated, and coordinated the project. T.M. Clausen, D.R.S. C.B.S. J.P. H.R.P. C.D.P. A.N. S.A.M. E.M.K. R.N.M. J.L.T. B.E.T. C.A.G. G.J.G. A.F.G. S.L.L. and A.F.C. designed and performed the experimental work. Z.Y. R.N.P. L.L. J.F. X.Y. Y.P. B.M.H. T.M. Caradonna, S.K.C. K.G. A.B.W. A.G.S. and K.G. supplied reagents. P.L.B. B.P.K. C.M. J.J. K.D.C. and P.L.S.M.G. provided essential discussion and advice. T.M. Clausen, D.R.S. and J.D.E. performed the main fundraising. T.M. Clausen, D.R.S. and J.D.E. wrote the manuscript. All authors discussed the experiments and results and read and approved the manuscript. J.D.E. is a co-founder of TEGA Therapeutics. J.D.E. and the Regents of the University of California have licensed a University invention to and have an equity interest in TEGA Therapeutics. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies. C.A.G. and B.E.T. are employees of TEGA Therapeutics. Funding Information: We thank Scott Selleck (Pennsylvania State University), Eugene Yeo (UC San Diego), John Guatelli (UC San Diego), Mark Fuster (UC San Diego), and Stephen Schoenberger (La Jolla Institute for Immunology) for many helpful discussions, and Annamaria Naggi and Giangiacomo Torri from the Ronzoni Institute for generously providing split-glycol heparin. This work was supported by RAPID grant 2031989 from the National Science Foundation and Project 3 of NIH P01 HL131474 to J.D.E., the Alfred Benzon Foundation to T.M. Clausen, NIH R01 AI146779 and a Massachusetts Consortium on Pathogen Readiness ( MassCPR ) grant to A.G.S., DOD grant W81XWH-20-1-0270 and Fluomics/NOSI U19 AI135972 to S.K.C., a Career Award for Medical Scientists from the Burroughs Wellcome Fund to A.F.C., Bill and Melinda Gates Foundation grant OPP1170236 to A.B.W., COVID-19 seed funding from the Huck Institutes of the Life Sciences and Penn State start-up funds to J.J., funding for Z.Y. from grant DNRF107 from the Danish National Research Foundation, and T32 training grants GM007753 to B.M.H. and T.M. Caradonna and AI007245 for J.F. J.P. received funding from Innovation Fund Denmark and VAR2 Pharmaceuticals . ",
year = "2020",
month = nov,
day = "12",
doi = "10.1016/j.cell.2020.09.033",
language = "English (US)",
volume = "183",
pages = "1043--1057.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}