TY - JOUR
T1 - Evidence for Multiple Binding Modes in the Initial Contact Between SARS-CoV-2 Spike S1 Protein and Cell Surface Glycans**
AU - Parafioriti, Michela
AU - Ni, Minghong
AU - Petitou, Maurice
AU - Mycroft-West, Courtney J.
AU - Rudd, Timothy R.
AU - Gandhi, Neha S.
AU - Ferro, Vito
AU - Turnbull, Jeremy E.
AU - Lima, Marcelo A.
AU - Skidmore, Mark A.
AU - Fernig, David G.
AU - Yates, Edwin A.
AU - Bisio, Antonella
AU - Guerrini, Marco
AU - Elli, Stefano
N1 - Publisher Copyright:
© 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.
PY - 2023/1/2
Y1 - 2023/1/2
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85141499954
UR - https://www.scopus.com/inward/citedby.url?scp=85141499954&partnerID=8YFLogxK
U2 - 10.1002/chem.202202599
DO - 10.1002/chem.202202599
M3 - Article
C2 - 36134621
AN - SCOPUS:85141499954
SN - 0947-6539
VL - 29
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
IS - 1
M1 - e202202599
ER -