Synthesis and immunological evaluation of the unnatural β-linked mucin-1 Thomsen-Friedenreich conjugate.
Synthesis and immunological evaluation of the unnatural β-linked mucin-1 Thomsen-Friedenreich conjugate.
复制标题
DOI：
10.1039/d1ob00007a
复制
发表时间：
2021-03-21
影响因子：
3.2
通讯作者：
Huang X
中科院分区：
文献类型：
--
作者：
Wu X;McFall-Boegeman H;Rashidijahanabad Z;Liu K;Pett C;Yu J;Schorlemer M;Ramadan S;Behren S;Westerlind U;Huang X
MUC1 糖肽是抗癌疫苗开发中有吸引力的抗原。使用天然 MUC1 糖肽进行疫苗设计的一个潜在缺点是聚糖和肽主链与糖苷酶之间的 O-糖基连接不稳定。为了克服这一挑战，我们合成了一种 MUC1 糖肽模拟物，其中半乳糖-半乳糖胺二糖通过非天然 β-糖基键与苏氨酸（Thomsen-Friedenreich 或 Tf 抗原）连接。所得的 MUC1-β-Tf 对糖苷酶具有大大增强的稳定性，该糖苷酶能够通过天然 α-Tf 连接从相应的 MUC1 糖肽中裂解聚糖。 MUC1-β-Tf 随后与强大的载体噬菌体 Qβ 缀合。该缀合物在临床相关的人MUC1转基因小鼠中诱导高水平的IgG抗体，该小鼠不仅交叉识别天然MUC1-α-Tf糖肽，而且还交叉识别表达MUC1的肿瘤细胞，这支持了聚糖/肽连接的立体化学的简单转换可以成为糖肽抗癌疫苗表位设计策略的观点。合成了在聚糖和肽主链之间带有非天然 β-糖基键的 MUC1 糖肽。该模拟物可以诱导高水平的 IgG 抗体交叉识别表达天然 MUC1 糖蛋白的癌细胞。
MUC1 glycopeptides are attractive antigens for anti-cancer vaccine development. One potential drawback in using the native MUC1 glycopeptide for vaccine design is the instability of the O-glycosyl linkage between the glycan and the peptide backbone to glycosidase. To overcome this challenge, a MUC1 glycopeptide mimic has been synthesized with the galactose-galactosamine disaccharide linked with threonine (Thomsen-Friedenreich or Tf antigen) through an unnatural β-glycosyl bond. The resulting MUC1-β-Tf had a much-enhanced stability toward a glycosidase capable of cleaving the glycan from the corresponding MUC1 glycopeptide with the natural α-Tf linkage. The MUC1-β-Tf was subsequently conjugated with a powerful carrier bacteriophage Qβ. The conjugate induced high levels of IgG antibodies in clinically relevant human MUC1 transgenic mice, which cross-recognized not only the natural MUC1-α-Tf glycopeptide but also MUC1 expressing tumor cells, supporting the notion that a simple switch of the stereochemistry of the glycan/peptide linkage can be a strategy for anti-cancer vaccine epitope design for glycopeptides. A MUC1 glycopeptide bearing an unnatural β-glycosyl bond between the glycan and the peptide backbone was synthesized. The mimic can induce high levels of IgG antibodies cross-recognizing cancer cells expressing the native MUC1 glycoprotein.
登录
查看更多内容
影响因子：
3.1
作者：
Ellervik, U;Magnusson, G
通讯作者：
Magnusson, G
影响因子：
4.3
作者：
Awad, Loay;Madani, Rime;Vogel, Pierre
通讯作者：
Vogel, Pierre
影响因子：
4.6
作者：
Nilsson, Jonas;Brinkmalm, Gunnar;Larson, Goran
通讯作者：
Larson, Goran
影响因子：
3.5
作者：
Miyazaki, Takatsugu;Park, Enoch Y.
通讯作者：
Park, Enoch Y.
影响因子：
4.7
作者：
Geraci, Corrada;Consoli, Grazia M. L.;Spadaro, Angelo
通讯作者：
Spadaro, Angelo