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Heparan sulfate SARS-CoV-2 spike S1 Protein Interactions

Author(s)

M. Parafioriti, M. Ni, M. Petitou, C.J. Mycroft-West, T.R. Rudd, N.S. Gandhi, V. Ferro, J.E. Turnbull, M.A. Lima, M.A. Skidmore, D.G. Fernig, E.A. Yates, A. Bisio, M. Guerrini, & S. Elli

Sources

: Evidence for multiple binding modes in the initial contact between SARS-CoV-2 spike S1 protein and cell surface glycans. Chem. Eur. J. 2022, e202202599 https://doi.org/10.1002/chem.202202599

Infection of host cells by SARS-CoV-2 begins with recognition by the virus S (spike) protein of cell surface heparan sulfate, 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 Heparan Sulfate polysaccharide chains.
hs_s1-rbd.png
The evidence for multiple binding modes also suggests that particular inhibitors will not be optimal against protein S. Rather, diverse Heparan Sulfate -based structures, characterized by high affinity and multi-valent compounds, may be required.

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