Convergent chemical synthesis of [lysine(24,38,83)] human erythropoietin.
Convergent chemical synthesis of [lysine(24,38,83)] human erythropoietin.
复制标题
DOI：
10.1002/anie.201106060
复制
发表时间：
2012-01-23
影响因子：
16.6
通讯作者：
Kent, Stephen B. H.
中科院分区：
文献类型：
--
作者：
Liu, Suhuai;Pentelute, Brad L.;Kent, Stephen B. H.
关键词：
促红细胞生成素（EPO）是一种糖蛋白激素，在调节红细胞（红细胞）的产生中起重要作用。[1]自1977年首次从尿液中分离纯化人EPO以来，[2] EPO的结构和生理特性已被深入研究。[3]自然界中发现的成熟人EPO由165个氨基酸的多肽链和四个共价连接的寡糖组成，[4]其中一个是在Ser 126处的O-连接寡糖，另外三个是在残基Asn 24，38，83处的N-连接寡糖。[5]EPO用作治疗剂来治疗由慢性肾病引起的贫血。[6]商业EPO是使用重组DNA技术制备的。天然和重组EPO [7]的碳水化合物部分是异质的，并且由在每个糖基化位点具有不同长度和组成的多个聚糖组成。[5a这种异质性使得难以评估碳水化合物对EPO的药代动力学性质的影响，更重要的是，使在分子水平上理解EPO的作用机制变得复杂。因此，开发一种制备均质EPO的替代策略是非常重要的。通过全合成制备均质的糖基化EPO是有机合成界当前的主要目标。[9]蛋白质[10]和糖蛋白[11]的化学合成的最新进展使得通过全合成制备均质EPO原则上成为可能，从而提供了完全控制共价结构以进行系统的结构-活性研究的前景。早期的合成成就是制备了一系列均相聚合物修饰的EPO类似物，具有明确的共价结构和完整的生物活性。[12]这些糖蛋白模拟物含有由EPO基因编码的全长166个残基的多肽链，并且通过使用硫酯介导的天然化学连接顺序组装四个合成肽片段来制备。[13]这种顺序组装多个肽段的线性策略涉及重复连接和纯化，这导致最终产物的产率低。[14]最近的
Erythropoietin (EPO) is a glycoprotein hormone that plays important roles in regulating the production of red blood cells (erythrocytes).[1] Since human EPO was first isolated and purified from urine in 1977,[2] the structure and physiological properties of EPO have been thoroughly studied.[3] Mature human EPO found in nature consists of a polypeptide chain of 165 amino acids with four covalently attached oligosaccharides,[4] one of which is an O-linked oligosaccharide at Ser126, and the other three are N-linked oligosaccharides at residues Asn24, 38, 83.[5] EPO is used as a therapeutic agent to treat anemia caused by chronic kidney disease.[6] Commercial EPO is prepared using recombinant DNA technology. The carbohydrate moieties of both native and recombinant EPO [7] are heterogenerous and composed of multiple glycans with different lengths and composition at each glycosylation site.[5a, 8] This heterogeneity makes it difficult to evaluate the effects of carbohydrate on EPO’s pharmacokinetic properties and, more importantly, complicates the understanding of mechanism of EPO’s action at the molecular level. For these reasons, it is important to develop an alternative strategy to prepare homogeneous EPO.The production of homogeneous, glycosylated EPO by total synthesis is a major current objective of the organic synthesis community.[9] Recent developments in chemical synthesis of proteins [10] and glycoproteins [11] have made it possible in principle to prepare homogeneous EPO by total synthesis, thus offering the prospect of complete control of the covalent structure in order to perform systematic structure-activity studies. An early synthetic achievement was the preparation of a series of homogeneous polymer-modified EPO analogues of defined covalent structure and full biological activity.[12] These glycoprotein mimetics contained the full length 166 residue polypeptide chain encoded by the EPO gene, and were prepared by sequentially assembly of four synthetic peptide segments using thioester-mediated native chemical ligation.[13] This linear strategy of sequentially assembling multiple peptide segments involves repetitive ligation and purification, which results in low yields of final products.[14] More recently, a
登录
查看更多内容
影响因子：
56.9
作者：
DAWSON, PE;MUIR, TW;KENT, SBH
通讯作者：
KENT, SBH
影响因子：
16.6
作者：
Bang, D;Makhatadze, GI;Kent, SB
通讯作者：
Kent, SB
影响因子：
16.6
作者：
Bang, Duhee;Pentelute, Brad L.;Kent, Stephen B. H.
通讯作者：
Kent, Stephen B. H.
影响因子：
6.6
作者：
Kajihara, Yasuhiro;Yamamoto, Naoki;Murase, Takefumi
通讯作者：
Murase, Takefumi
影响因子：
5.8
作者：
Lappin, T
通讯作者：
Lappin, T