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Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2
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Nico Boback ,
Hassan Abdelwahab ,
Daniela Niemeyer ,
Tahlia M. Palmer ,
Anil Kumar Sahoo,
Yannic Kerkhoff ,
Kai Ludwig ,
Julian Heinze,
Dilara Balci,
Jakob Trimpert,
Rainer Haag ,
Tatyana L. Povolotsky ,
Roland R. Netz ,
Christian Drosten,
Daniel C. Lauster ,
Sumati Bhatia
Small, Volume: 21, Issue: 34, Start page: 2500719
Swansea University Author:
Sumati Bhatia
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DOI (Published version): 10.1002/smll.202500719
Abstract
Both polysialosides and polysulfates are known to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. However, a comprehensive site by site analysis of their binding affinities and potential synergistic antiviral effects have not been performed. Here, we report on the sy...
| Published in: | Small |
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| ISSN: | 1613-6810 1613-6829 |
| Published: |
Wiley
2025
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa69958 |
| Abstract: |
Both polysialosides and polysulfates are known to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. However, a comprehensive site by site analysis of their binding affinities and potential synergistic antiviral effects have not been performed. Here, we report on the synthesis of polysialosides with nanomolar binding affinities to spike proteins of SARS-CoV-2 in solution using microscale thermophoresis. The dendritic polyglycerol based polysialosides dPG500SA0.55 and dPG500SA0.25, with a dissociation constant Kd of 4.78 nm and 10.85 nm, respectively, bind ≈500 times stronger than the high density polysulfated analog dPG500S0.55, to intact SARS-CoV-2 virus particles or isolated spike protein. In fact, the presence of sulfate groups in a heteromultivalent compound dPG500SA0.20S0.20 weakens the binding to spike proteins. A polycarboxylated analog does not bind to SARS-CoV-2, ruling out that the interaction of polysialoside is simply driven by electrostatics. Using explicit-solvent all-atom molecular dynamics simulations and ensemble docking studies, atomistic details are obtained on the interaction of different functional groups with the SARS-CoV-2 RBD. The data support the conclusion that sialosides interact stronger than sulfates for their binding with RBD of SARS-CoV-2. Notably, the most affine binder dPG500SA0.55 inhibits SARS-CoV-2 (WT, D614G) replication up to 98.6% at 0.5 µm concentrations. |
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| Keywords: |
MD simulations; polysialosides; SARS-CoV-2; virus binding |
| College: |
Faculty of Science and Engineering |
| Funders: |
SupraFAB (BioSexSurf); Federal Ministry of Education and Research (13XP511); Berlin University Alliance (CoronaVirusPre-ExplorationProject); Royal Society of Chemistry (RG∖R1∖241050); Deutsche Forschungsgemeinschaft (458564133, 431232613–SFB1449/INF, 434130070-IRTG2662); Novo Nordisk Foundation (NNF23SA0088060). |
| Issue: |
34 |
| Start Page: |
2500719 |