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Evidence for multiple binding modes in the initial contact between SARS-CoV-2 spike S1 protein and cell surface glycans.

Parafioriti, Michela; Ni, Minghong; Petitou, Maurice; Mycroft‐West, Courtney J.; Rudd, Timothy R.; Gandhi, Neha S.; Ferro, Vito; Turnbull, Jeremy E.; Andrade De Lima, Marcelo A.; Skidmore, Mark A.; Fernig, David G.; Bisio, Antonella; Guerrini, Marco; Yates, Edwin A.; Elli, Stefano

Evidence for multiple binding modes in the initial contact between SARS-CoV-2 spike S1 protein and cell surface glycans. Thumbnail


Authors

Michela Parafioriti

Minghong Ni

Maurice Petitou

Courtney J. Mycroft‐West

Timothy R. Rudd

Neha S. Gandhi

Vito Ferro

David G. Fernig

Antonella Bisio

Marco Guerrini

Edwin A. Yates

Stefano Elli



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 evidence for multiple binding modes also suggest 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.

Journal Article Type Article
Acceptance Date Sep 22, 2022
Online Publication Date Sep 22, 2022
Publication Date Jan 2, 2023
Publicly Available Date Mar 28, 2024
Journal Chemistry
Print ISSN 0947-6539
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 29
Issue 1
DOI https://doi.org/10.1002/chem.202202599
Keywords SARS-CoV-2; protein S spike; heparan sulfate; NMR spectroscopy; MD simulation
Publisher URL https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.202202599

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