Matsuda M, Nishimura S, Nakajima F, Nishimura T
Division of Immunoregulation, Research Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
J Med Chem. 2001 Mar 1;44(5):715-24. doi: 10.1021/jm000295r.
An efficient and practical synthesis of cell adhesive glycopeptides exhibiting unique properties as a novel type of modulator of cellular recognition is described. A nonnatural glycopeptide 1 composed of sialyl Lewis x and Lys-Gly-Arg-Gly-Asp-Ser that interacts with both selectins and integrins has been systematically synthesized by combined chemical and enzymatic strategy. It is suggested that glycopeptide 1 showed much higher affinity with P-selectin (K(a) = 6.6 x 10(7) M(-1)) and E-selectin (K(a) = 4.5 x 10(5) M(-1)) than sialyl Lewis x. This compound also inhibited a specific interaction between human integrin beta(1) and its monoclonal antibody more effectively than the tetrapeptide Arg-Gly-Asp-Ser. Interestingly, it was demonstrated by surface plasmon resonance analysis that this heterobifunctional glycopeptide exhibited a capacity to form stable complexes with P-selectin and integrin beta(1) concurrently. It is also suggested that this activity can be used for the inhibition of integrin-mediated adhesion of activated helper T cells onto collagen-coated plates as a cell migration model. These results indicate that the chemoenzymatic hybridization strategy of different biological functions of carbohydrates and peptides is a new concept for designing potent glycoconjugates as antiinflammatory and anticancer metastasis reagents.
本文描述了一种高效实用的细胞黏附糖肽的合成方法，该糖肽作为一种新型细胞识别调节剂具有独特性质。通过化学和酶促相结合的策略，系统地合成了一种由唾液酸化路易斯x和Lys-Gly-Arg-Gly-Asp-Ser组成的非天然糖肽1，它能与选择素和整合素相互作用。结果表明，糖肽1与P-选择素（K(a)=6.6×10(7) M(-1)）和E-选择素（K(a)=4.5×10(5) M(-1)）的亲和力比唾液酸化路易斯x高得多。该化合物比四肽Arg-Gly-Asp-Ser更有效地抑制了人整合素β(1)与其单克隆抗体之间的特异性相互作用。有趣的是，表面等离子体共振分析表明，这种异双功能糖肽能够同时与P-选择素和整合素β(1)形成稳定的复合物。研究还表明，作为细胞迁移模型，这种活性可用于抑制整合素介导的活化辅助性T细胞黏附到胶原包被的平板上。这些结果表明，碳水化合物和肽的不同生物学功能的化学酶促杂交策略是设计强效糖缀合物作为抗炎和抗癌转移试剂的一个新概念。
