Biological and Medicinal Chemistry

Initial contact between SARS-CoV-2 spike S1 protein and cell surface glycans involves multiple binding modes

Authors

  • Michela Parafioriti Istituto di Ricerche Chimiche e Biochimiche ‘G. Ronzoni’, via Giuseppe Colombo 81, 20133 Milano, Italy ,
  • Minghong Ni Istituto di Ricerche Chimiche e Biochimiche ‘G. Ronzoni’, via Giuseppe Colombo 81, 20133 Milano, Italy ,
  • Maurice Petitou Istituto di Ricerche Chimiche e Biochimiche ‘G. Ronzoni’, via Giuseppe Colombo 81, 20133 Milano, Italy ,
  • Courtney J. Mycroft-West Rosalind Franklin Institute, Harwell Campus, Didcot, OX11 0QX United Kingdom ,
  • Timothy R. Rudd Analytical and Biological Sciences Division, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom & Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB United Kingdom ,
  • Neha S. Gandhi School of Chemistry and Physics, Queensland University of Technology, 2 George St, Brisbane, QLD-4000, Australia & Centre for Genomics and Personalised Health, Queensland University of Technology, Brisbane, Australia ,
  • Vito Ferro School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Australia & Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Australia ,
  • Jeremy E. Turnbull Molecular and Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, United Kingdom & Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB United Kingdom ,
  • Marcelo A. Lima Molecular and Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, United Kingdom ,
  • Mark A. Skidmore Molecular and Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, United Kingdom & Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB United Kingdom ,
  • David G. Fernig Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB United Kingdom ,
  • Edwin A. Yates Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, L69 7ZB United Kingdom & Molecular and Structural Biosciences, School of Life Sciences, Keele University, Newcastle-Under-Lyme, Staffordshire, United Kingdom ,
  • Antonella Bisio Istituto di Ricerche Chimiche e Biochimiche ‘G. Ronzoni’, via Giuseppe Colombo 81, 20133 Milano, Italy ,
  • Marco Guerrini Istituto di Ricerche Chimiche e Biochimiche ‘G. Ronzoni’, via Giuseppe Colombo 81, 20133 Milano, Italy ,
  • Stefano Elli Istituto di Ricerche Chimiche e Biochimiche ‘G. Ronzoni’, via Giuseppe Colombo 81, 20133 Milano, Italy

Abstract

Infection of host cells by SARS-CoV-2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate (HS), tethering the virus to the extracellular matrix environment, and causing the subunit S1-RBD to undergo a conformational change into the ‘open’ conformation. These two events promote the binding of S1-RBD to the angiotensin converting enzyme 2 (ACE2) receptor, a preliminary step toward viral-cell membrane fusion. Combining ligand-based NMR spectroscopy with molecular dynamics, oligosaccharide analogues were used to explore the interactions between S1-RBD of SARS CoV-2 and HS, revealing several low-specificity binding modes and previously unidentified potential sites for the binding of extended HS polysaccharide chains. The evident multiplicity of binding modes also suggests that highly specific inhibitors will not be optimal against protein S but, rather, diverse HS-based structures, characterized by high affinity and including multi-valent compounds, may be required

Content

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Supplementary material

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Initial contact between SARS-CoV-2 spike S1 protein and cell surface glycans involves multiple binding modes
Infection of host cells by SARS-CoV-2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate (HS), tethering the virus to the extracellular matrix environment, and causing the subunit S1-RBD to undergo a conformational change into the ‘open’ conformation. These two events promote the binding of S1-RBD to the angiotensin converting enzyme 2 (ACE2) receptor, a preliminary step toward viral-cell membrane fusion. Combining ligand-based NMR spectroscopy with molecular dynamics, oligosaccharide analogues were used to explore the interactions between S1-RBD of SARS CoV-2 and HS, revealing several low-specificity binding modes and previously unidentified potential sites for the binding of extended HS polysaccharide chains. The evident multiplicity of binding modes also suggests that highly specific inhibitors will not be optimal against protein S but, rather, diverse HS-based structures, characterized by high affinity and including multi-valent compounds, may be required.