Zhang Wenjing, Jin Weihua, Pomin Vitor H, Zhang Fuming, Linhardt Robert J
Department of Endocrinology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, United States.
Front Mol Biosci. 2022 Sep 19;9:954752. doi: 10.3389/fmolb.2022.954752. eCollection 2022.
The molecular interactions of sulfated glycans, such as heparin, with antithrombin (AT) and platelet factor 4 (PF4) are essential for certain biological events such as anticoagulation and heparin induced thrombocytopenia (HIT). In this study, a library including 84 sulfated glycans (polymers and oligomers) extracted from marine algae along with several animal-originated polysaccharides were subjected to a structure-activity relationship (SAR) study regarding their specific molecular interactions with AT and PF4 using surface plasmon resonance. In this SAR study, multiple characteristics were considered including different algal species, different methods of extraction, molecular weight, monosaccharide composition, sulfate content and pattern and branching vs. linear chains. These factors were found to influence the binding affinity of the studied glycans with AT. Many polysaccharides showed stronger binding than the low molecular weight heparin (e.g., enoxaparin). Fourteen polysaccharides with strong AT-binding affinities were selected to further investigate their binding affinity with PF4. Eleven of these polysaccharides showed strong binding to PF4. It was observed that the types of monosaccharides, molecular weight and branching are not very essential particularly when these polysaccharides are oversulfated. The sulfation levels and sulfation patterns are, on the other hand, the primary contribution to strong AT and PF4 interaction.
硫酸化聚糖（如肝素）与抗凝血酶（AT）和血小板因子4（PF4）的分子相互作用对于某些生物事件（如抗凝和肝素诱导的血小板减少症（HIT））至关重要。在本研究中，一个包含从海藻中提取的84种硫酸化聚糖（聚合物和低聚物）以及几种动物源多糖的文库，使用表面等离子体共振对它们与AT和PF4的特定分子相互作用进行了构效关系（SAR）研究。在这项SAR研究中，考虑了多个特征，包括不同的藻类物种、不同的提取方法、分子量、单糖组成、硫酸盐含量和模式以及支链与直链。发现这些因素会影响所研究聚糖与AT的结合亲和力。许多多糖表现出比低分子量肝素（如依诺肝素）更强的结合力。选择了14种具有强AT结合亲和力的多糖，进一步研究它们与PF4的结合亲和力。其中11种多糖表现出与PF4的强结合。观察到单糖类型、分子量和支链不是非常关键，特别是当这些多糖过度硫酸化时。另一方面，硫酸化水平和硫酸化模式是与AT和PF4强相互作用的主要贡献因素。
