Towards a Fully Synthetic MUC1-Based Anticancer Vaccine: Efficient Conjugation of Glycopeptides with Mono-, Di-, and Tetravalent Lipopeptides Using Click Chemistry
Towards a Fully Synthetic MUC1-Based Anticancer Vaccine: Efficient Conjugation of Glycopeptides with Mono-, Di-, and Tetravalent Lipopeptides Using Click Chemistry
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DOI：
10.1002/chem.201100217
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发表时间：
2011-05-01
影响因子：
4.3
通讯作者：
Li, Yan-Mei
中科院分区：
文献类型：
--
作者：
Cai, Hui;Huang, Zhi-Hua;Li, Yan-Mei
与正常细胞相比，膜结合的肿瘤相关糖蛋白MUC 1在癌细胞中异常糖基化，因此被认为是癌症免疫治疗的有吸引力的靶点。然而，来自MUC 1的肿瘤相关糖肽不能引起足够强的免疫应答。因此，开发了由作为B表位的MUC 1糖肽和免疫刺激性toll样受体2（TLR 2）脂肽配体组成的抗肿瘤疫苗。这些完全合成的候选疫苗通过MUC 1糖肽的固相合成制备。Pam（3）Cys脂肽也是在固相上合成的，其C末端偶联至寡价赖氨酸核心，该核心的N末端包含O-炔丙基寡乙二醇酰基侧链。然后通过点击化学将MUC 1糖肽和脂肽赖氨酸构建体缀合以得到寡价合成疫苗。寡价糖肽-脂肽缀合物被认为比其单价类似物更具免疫原性。
The membrane-bound tumor-associated glycoprotein MUC1 is aberrantly glycosylated in cancer cells compared with normal cells, and is therefore considered an attractive target for cancer immunotherapy. However, tumor-associated glycopeptides from MUC1 do not elicit a sufficiently robust immune response. Therefore, antitumor vaccines were developed, which consist of MUC1 glycopeptides as the B epitopes and immune-stimulating toll-like receptor2 (TLR2) lipopeptide ligands. These fully synthetic vaccine candidates were prepared by solid-phase synthesis of the MUC1 glycopeptides. The Pam(3)Cys lipopeptide, also synthesized on solid-phase, was C-terminally coupled to oligovalent lysine cores, which N-terminally incorporate O-propargyl oligoethylene glycol acyl side chains. The MUC1 glycopeptides and lipopeptide lysine constructs were then conjugated by click chemistry to give oligovalent synthetic vaccines. Oligovalent glycopeptide-lipopeptide conjugates are considered more immunogenic than their monovalent analogues.