Total synthesis of the glycopeptide recognition domain of the P-selectin glycoprotein ligand 1
Total synthesis of the glycopeptide recognition domain of the P-selectin glycoprotein ligand 1
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DOI：
10.1002/anie.200705762
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发表时间：
2008-01-01
影响因子：
16.6
通讯作者：
Kunz, Horst
中科院分区：
文献类型：
--
作者：
Baumann, Katharina;Kowalczyk, Danuta;Kunz, Horst
在急性和慢性炎症过程中，白细胞募集到炎症组织中，暴露在活化内皮上的碳水化合物识别受体P-和E-选择素以及白细胞上的L-选择素发挥着最重要的作用。 [1]肿瘤细胞的转移也存在类似的情况。[2]与 E-选择素配体相比，P-选择素配体更容易影响恶性 T 细胞侵入皮肤。因此，在这种情况下，P-选择素的抑制提供了更有前景的抗肿瘤策略。 [3]与 E-选择素的天然配体相反，[4] 众所周知，P-选择素糖蛋白配体 1 (PSGL-1) 除了必需的四糖唾液酸 Lewisx 之外，N 端肽序列对识别表位也有显着贡献。 [5]在 PSGL-1 中，已通过生化和分子生物学方法鉴定了与 P-选择素结合的结合位点（图 1）。它位于 N 末端部分，在信号肽裂解后，从 Gln42 开始。酪氨酸残基 Tyr46、Tyr48 和 Tyr51 中至少之一应被 O-硫酸化。 57位的苏氨酸携带O-聚糖侧链，其由唾液酸Lewisx配体和O-糖蛋白（粘蛋白）的核心2结构的组合组成。 PSGL-1 的部分序列 [6] 和整个结合位点 [7] 的化学酶合成已有描述。黄等人[6]合成了糖肽 Tyr51-Glu58，其在 Thr57 处用二糖 GlcNAcb-(1-6)-aGalNAc 进行 O-糖基化。酪氨酸化学硫酸化后，在 GlcNAc 残基处组装唾液酸化 Lewisx 结构
During the recruitment of leukocytes into inflamed tissues in acute and chronical inflammatory processes, the carbohydrate-recognizing receptors P-and E-selectin exposed on the activated endothelium and L-selectin on the leukocytes play most important roles.[1] A similar situation holds true for the metastasis of tumor cells.[2] The intrusion of malign T cells into the skin could be more readily influenced through ligands of P-selectin than ligands of E-selectin. Therefore, in this case the inhibition of P-selectin provided the more promising antitumor strategy.[3] In contrast to the natural ligands of E-selectin,[4] it is known for the P-selectin glycoprotein ligand 1 (PSGL-1) that in addition to the essential tetrasaccharide sialyl Lewisx the N-terminal peptide sequence significantly contributes to the recognition epitope.[5] Within the PSGL-1 the binding site for binding to P-selectin has been identified by biochemical and molecular biological methods (Figure 1).It is located in the N-terminal portion, which, after cleavage of a signal peptide, begins with Gln42. At least one of the tyrosine residues Tyr46, Tyr48, and Tyr51 should be O-sulfated. The threonine in position 57 carries the O-glycan side chain, which consists of a combination of a sialyl Lewisx ligand and the core 2 structure of O-glycoproteins (mucins). Chemoenzymatic syntheses of partial sequences [6] and of the entire binding site of PSGL-1 [7] have been described. Wong et al.[6] synthesized the glycopeptide Tyr51–Glu58 which was O-glycosylated at Thr57 with the disaccharide GlcNAcb-(1–6)-aGalNAc. After chemical sulfation of the tyrosine, the sialyl Lewisx structure was assembled at the GlcNAc residue