Arya P, Kutterer K M, Qin H, Roby J, Barnes M L, Lin S, Lingwood C A, Peter M G
Chemical Biology Program, Steacie Institute for Molecular Sciences, National Research Council of Canada, Ottawa, ON.
Bioorg Med Chem. 1999 Dec;7(12):2823-33. doi: 10.1016/s0968-0896(99)00226-6.
Solution and solid phase strategies for the synthesis of alpha-galactose based neoglycopeptide derivatives 2-13 were developed. Neoglycopeptides generated were tested for the inhibition of verotoxin binding to globotriosylceramide (Gb3) using ELISA. Among all of the compounds tested, only the lipid derivatives of neoglycopeptides, 11, 12 and 13 were found to be inhibitors, IC50 = 2.0 mM (11b and 12c) and 0.2 mM (11c and 13c). All of the inhibitors (11b, 11c, 12c and 13c) have a similar branching of the two alpha-galactosyl units at the N-terminal glycine residue of a short peptide and a lipid moiety attached at the C-terminal site. Both of these factors seem to be crucial for the inhibition. It is interesting to note that the inhibitors have only a portion of the natural trisaccharide ligand. The secondary groups either may contribute in sub-site oriented interactions with the protein receptors or may mimic the internal sugar units of the cell-surface ligand, Gb3.
开发了用于合成基于α-半乳糖的新糖肽衍生物2-13的溶液和固相策略。使用酶联免疫吸附测定（ELISA）测试生成的新糖肽对志贺毒素与球三糖神经酰胺（Gb3）结合的抑制作用。在所有测试的化合物中，仅发现新糖肽的脂质衍生物11、12和13是抑制剂，IC50 = 2.0 mM（11b和12c）以及0.2 mM（11c和13c）。所有抑制剂（11b、11c、12c和13c）在短肽的N端甘氨酸残基处具有两个α-半乳糖基单元的相似分支，并且在C端位点连接有脂质部分。这两个因素似乎对抑制作用至关重要。值得注意的是，抑制剂仅具有天然三糖配体的一部分。二级基团可能要么在与蛋白质受体的亚位点定向相互作用中起作用，要么可能模拟细胞表面配体Gb3的内部糖单元。
