Synthesis of tetravalent LacNAc-glycoclusters as high-affinity cross-linker against Erythrina cristagalli agglutinin

详细信息    查看全文

• 作者：Makoto Ogata^a ; ^{ogata@fukushima-nct.ac.jp" class="auth_mail" title="E-mail the corresponding author} ; Yasushi Chuma^b ; Yoshinori Yasumoto^b ; Takashi Onoda^a ; Myco Umemura^c ; Taichi Usui^d ; Enoch Y. Park^b ; ^d ; ^e ; ^{park.enoch@shizuoka.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Carbohydrates ; Cluster effect ; Lectins ; Multivalency
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 January 2016
• 年：2016
• 卷：24
• 期：1
• 页码：1-11
• 全文大小：2262 K

文摘

Four kinds of tetravalent double-headed glycoclusters [(LacNAc)₄-DHGs] were designed with linkers of varying lengths consisting of alkanedioic carboxyamido groups (C₆, C₁₂, C₁₈ and C₂₄) between two bi-antennary LacNAc-glycosides. These glycoclusters served as high-affinity cross-linking ligands for the LacNAc-binding lectin Erythrina cristagalli agglutinin (ECA). The binding activity and cross-linking between each ligand and ECA were characterized by a hemagglutination inhibition (HI) assay, isothermal titration calorimetry (ITC), a quantitative precipitation assay and dynamic light scattering (DLS). For the precipitation assay and DLS measurement, the synthesized (LacNAc)₄-DHGs were found to be capable of binding and precipitating the ECA as multivalent ligands. ITC analysis indicated the binding of (LacNAc)₄-DHGs was driven by a favorable enthalpy change. Furthermore, the entropy penalty from binding (LacNAc)₄-DHGs clearly decreased in a spacer length-dependent manner. The binding affinities of flexible (LacNAc)₄-DHGs (C₁₈ and C₂₄) with long spacers were found to be more favorable than those of the clusters having short spacers (C₆ and C₁₂). These results were supported by molecular dynamics simulations with explicit water molecules for the tetravalent glycoclusters with ECA. We concluded that the subtle modification in the epitope-presenting scaffolds exerts the significant effect in the recognition efficiency involved in the LacNAc moieties by ECA.