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Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2

Vinod Khatri Orcid Logo, Nico Boback Orcid Logo, Hassan Abdelwahab Orcid Logo, Daniela Niemeyer Orcid Logo, Tahlia M. Palmer Orcid Logo, Anil Kumar Sahoo, Yannic Kerkhoff Orcid Logo, Kai Ludwig Orcid Logo, Julian Heinze, Dilara Balci, Jakob Trimpert, Rainer Haag Orcid Logo, Tatyana L. Povolotsky Orcid Logo, Roland R. Netz Orcid Logo, Christian Drosten, Daniel C. Lauster Orcid Logo, Sumati Bhatia Orcid Logo

Small, Volume: 21, Issue: 34, Start page: 2500719

Swansea University Author: Sumati Bhatia Orcid Logo

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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...

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ISSN: 1613-6810 1613-6829
Published: Wiley 2025
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spelling 2025-09-04T10:28:42.0260595 v2 69958 2025-07-14 Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2 a6b1181ebdbe42bd03b24cbdb559d082 0000-0002-5123-4937 Sumati Bhatia Sumati Bhatia true false 2025-07-14 EAAS 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. Journal Article Small 21 34 2500719 Wiley 1613-6810 1613-6829 MD simulations; polysialosides; SARS-CoV-2; virus binding 28 8 2025 2025-08-28 10.1002/smll.202500719 COLLEGE NANME Engineering and Applied Sciences School COLLEGE CODE EAAS Swansea University SU Library paid the OA fee (TA Institutional Deal) 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). 2025-09-04T10:28:42.0260595 2025-07-14T12:41:02.5236069 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Vinod Khatri 0000-0002-7777-1984 1 Nico Boback 0009-0003-5261-7168 2 Hassan Abdelwahab 0009-0000-2282-1748 3 Daniela Niemeyer 0000-0002-1897-6365 4 Tahlia M. Palmer 0009-0001-2783-0149 5 Anil Kumar Sahoo 6 Yannic Kerkhoff 0000-0002-8126-2082 7 Kai Ludwig 0000-0001-6808-8107 8 Julian Heinze 9 Dilara Balci 10 Jakob Trimpert 11 Rainer Haag 0000-0003-3840-162x 12 Tatyana L. Povolotsky 0000-0001-5987-777x 13 Roland R. Netz 0000-0003-0147-0162 14 Christian Drosten 15 Daniel C. Lauster 0000-0003-2009-633x 16 Sumati Bhatia 0000-0002-5123-4937 17 69958__34876__f5d42b8258d34825890c9c28564cf66c.pdf 69958.VoR.pdf 2025-07-31T11:08:33.0233018 Output 2142764 application/pdf Version of Record true © 2025 The Author(s). This is an open access article under the terms of the Creative Commons Attribution License. true eng http://creativecommons.org/licenses/by/4.0/
title Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2
spellingShingle Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2
Sumati Bhatia
title_short Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2
title_full Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2
title_fullStr Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2
title_full_unstemmed Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2
title_sort Polysialosides Outperform Sulfated Analogs for Binding with SARS‐CoV‐2
author_id_str_mv a6b1181ebdbe42bd03b24cbdb559d082
author_id_fullname_str_mv a6b1181ebdbe42bd03b24cbdb559d082_***_Sumati Bhatia
author Sumati Bhatia
author2 Vinod Khatri
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
format Journal article
container_title Small
container_volume 21
container_issue 34
container_start_page 2500719
publishDate 2025
institution Swansea University
issn 1613-6810
1613-6829
doi_str_mv 10.1002/smll.202500719
publisher Wiley
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 1
active_str 0
description 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.
published_date 2025-08-28T05:29:34Z
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