Khatri Vinod, Boback Nico, Abdelwahab Hassan, Niemeyer Daniela, Palmer Tahlia M, Sahoo Anil Kumar, Kerkhoff Yannic, Ludwig Kai, Heinze Julian, Balci Dilara, Trimpert Jakob, Haag Rainer, Povolotsky Tatyana L, Netz Roland R, Drosten Christian, Lauster Daniel C, Bhatia Sumati
Freie Universität Berlin, Institute of Chemistry and Biochemistry, Takustr. 3, 14195, Berlin, Germany.
Department of Chemistry, TDL Govt. College for Women Murthal, Sonipat, Haryana, 131027, India.
Small. 2025 Aug;21(34):e2500719. doi: 10.1002/smll.202500719. Epub 2025 Jul 16.
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 dPGSA and dPGSA, with a dissociation constant K of 4.78 nm and 10.85 nm, respectively, bind ≈500 times stronger than the high density polysulfated analog dPGS, to intact SARS-CoV-2 virus particles or isolated spike protein. In fact, the presence of sulfate groups in a heteromultivalent compound dPGSAS 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 dPGSA inhibits SARS-CoV-2 (WT, D614G) replication up to 98.6% at 0.5 µm concentrations.
已知多唾液酸苷和多硫酸盐都能与严重急性呼吸综合征冠状病毒2（SARS-CoV-2）刺突蛋白的受体结合域（RBD）相互作用。然而，尚未对它们的结合亲和力和潜在的协同抗病毒作用进行全面的逐位点分析。在此，我们报告了使用微量热泳技术在溶液中合成与SARS-CoV-2刺突蛋白具有纳摩尔结合亲和力的多唾液酸苷。基于树枝状聚甘油的多唾液酸苷dPGSA和dPGSA，解离常数K分别为4.78纳米和10.85纳米，与完整的SARS-CoV-2病毒颗粒或分离的刺突蛋白结合的强度比高密度多硫酸化类似物dPGS强约500倍。事实上，杂多价化合物dPGSAS中硫酸根的存在会削弱其与刺突蛋白的结合。一种多羧化类似物不与SARS-CoV-2结合，排除了多唾液酸苷的相互作用仅仅由静电驱动的可能性。通过显式溶剂全原子分子动力学模拟和整体对接研究，获得了不同官能团与SARS-CoV-2 RBD相互作用的原子细节。数据支持以下结论：唾液酸苷与SARS-CoV-2的RBD结合时比硫酸盐相互作用更强。值得注意的是，亲和力最高的结合剂dPGSA在浓度为0.5微摩尔时可抑制SARS-CoV-2（野生型、D614G）复制达98.6%。
