Targeting cancer-specific glycans by cyclic peptide lectinomimics.
Targeting cancer-specific glycans by cyclic peptide lectinomimics.
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通过环肽凝集素靶向癌症特异性聚糖。
DOI：
10.1007/s00726-017-2485-3
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发表时间：
2017
期刊：
影响因子：
3.5
通讯作者：
Cudic,Predrag
中科院分区：
文献类型：
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作者：
Rodriguez,MariaC;Yongye,AustinB;Cudic,Mihael;MartinezMayorga,Karina;Liu,Enbo;Mueller,BarbaraM;Ainsley,Jon;Karabencheva-Christova,Tatyana;Christov,ChristoZ;Cudic,Mare;Cudic,Predrag
人类癌症从正常表型向恶性表型的转变与细胞表面糖基化异常有关。因此，针对癌症中的糖基化变化不仅可以更好地了解碳水化合物在生物系统中的作用，而且还有助于开发用于生物分析和生物医学应用的新的分子探针。在已报道的研究中，我们合成了基于odorranalectin1的凝集素模拟物，odorranalectin1是从青蛙Odorrana grahamiskin中分离出来的最小的凝集素样环肽，并在分子和细胞水平上评估了这些肽与特定碳水化合物结合的能力。此外，我们还证明了1中的二硫键可以被内酰胺桥取代。然而，内酰胺桥2和3的方向影响了环肽的构象，从而影响了这些多肽与碳水化合物的结合能力。在水中采用相似构象的天然化合物1及其类似物3优先与烯丙基岩藻糖结合，并与较低程度的半乳糖和N-乙酰-D-半乳糖胺结合，通常存在于粘蛋白O-葡聚糖核心结构中。在基于细胞的分析中，肽1和3显示出与Aleuria aurantialectin相似的结合特征，并且这两个肽在Transwell实验中抑制转移性乳腺癌细胞系的迁移。综上所述，报道的数据证明了设计基于环肽的凝集素组学的可行性。
The transformation from normal to malignant phenotype in human cancers is associated with aberrant cell-surface glycosylation. Thus, targeting glycosylation changes in cancer is likely to provide not only better insight into the roles of carbohydrates in biological systems, but also facilitate the development of new molecular probes for bioanalytical and biomedical applications. In the reported study, we have synthesized lectinomimics based on odorranalectin1; the smallest lectin-like cyclic peptide isolated from the frogOdorrana grahamiskin, and assessed the ability of these peptides to bind specific carbohydrates on molecular and cellular levels. In addition, we have shown that the disulfide bond found in1can be replaced with a lactam bridge. However, the orientation of the lactam bridge, peptides2and3, influenced cyclic peptide‘s conformation and thus these peptides’ ability to bind carbohydrates. Naturally occurring1and its analog3that adopt similar conformation in water bind preferentiallyl-fucose, and to a lesser degreed-galactose andN-acetyl-d-galactosamine, typically found within the mucinO-glycan core structures. In cell-based assays, peptides1and3showed a similar binding profile toAleuria aurantialectin and these two peptides inhibited the migration of metastatic breast cancer cell lines in a Transwell assay. Altogether, the reported data demonstrate the feasibility of designing lectinomimics based on cyclic peptides.