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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\u2010CoV\u20102 in solution using microscale thermophoresis. The dendritic polyglycerol based polysialosides dPG<jats:sub>500<\/jats:sub>SA<jats:sub>0.55<\/jats:sub> and dPG<jats:sub>500<\/jats:sub>SA<jats:sub>0.25<\/jats:sub>, with a dissociation constant <jats:italic>K<\/jats:italic><jats:sub>d<\/jats:sub> of 4.78 n<jats:sc>m<\/jats:sc> and 10.85 n<jats:sc>m<\/jats:sc>, respectively, bind \u2248500 times stronger than the high density polysulfated analog dPG<jats:sub>500<\/jats:sub>S<jats:sub>0.55<\/jats:sub>, to intact SARS\u2010CoV\u20102 virus particles or isolated spike protein. In fact, the presence of sulfate groups in a heteromultivalent compound dPG<jats:sub>500<\/jats:sub>SA<jats:sub>0.20<\/jats:sub>S<jats:sub>0.20<\/jats:sub> weakens the binding to spike proteins. A polycarboxylated analog does not bind to SARS\u2010CoV\u20102, ruling out that the interaction of polysialoside is simply driven by electrostatics. Using explicit\u2010solvent all\u2010atom molecular dynamics simulations and ensemble docking studies, atomistic details are obtained on the interaction of different functional groups with the SARS\u2010CoV\u20102 RBD. The data support the conclusion that sialosides interact stronger than sulfates for their binding with RBD of SARS\u2010CoV\u20102. Notably, the most affine binder dPG<jats:sub>500<\/jats:sub>SA<jats:sub>0.55<\/jats:sub> inhibits SARS\u2010CoV\u20102 (WT, D614G) replication up to 98.6% at 0.5 \u00b5<jats:sc>m<\/jats:sc> concentrations.<\/jats:p>","DOI":"10.1002\/smll.202500719","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T04:49:46Z","timestamp":1752727786000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Polysialosides Outperform Sulfated Analogs for Binding with SARS\u2010CoV\u20102"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7777-1984","authenticated-orcid":false,"given":"Vinod","family":"Khatri","sequence":"first","affiliation":[{"name":"Freie Universit\u00e4t Berlin Institute of Chemistry and Biochemistry  Takustr. 3 14195 Berlin Germany"},{"name":"Department of Chemistry TDL Govt. 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