Synthesis and immunostimulating activity of a thioglycolipopeptide glycomimetic as a potential anticancer vaccine derived from Tn antigen
Synthesis and immunostimulating activity of a thioglycolipopeptide glycomimetic as a potential anticancer vaccine derived from Tn antigen
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DOI：
10.1080/07328300008544097
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发表时间：
2000-01-01
影响因子：
1
通讯作者：
Ronsisvalle, G
中科院分区：
文献类型：
--
作者：
Bousquet, E;Spadaro, A;Ronsisvalle, G
Tn表位是肿瘤相关的O-连接细胞表面糖肽之一。它在超过70%的人类上皮癌如肺癌、结肠癌、胃癌和乳腺癌中表达。Tn抗原的N-乙酰半乳糖胺和丝氨酸或苏氨酸之间的糖苷键可以在糖苷酶存在下化学或酶促裂解。后一种情况在体内尤其是个问题。因此，获得Tn抗原的代谢稳定的类似物将是非常有意义的，所述类似物保持或改善Tn抗原的免疫原性活性。本工作的目的是使用Tn抗原的化学和代谢稳定的糖模拟物合成完全合成的疫苗，其中糖苷间氧被硫原子（S-Tn）取代。将S-Tn硫代糖肽与P3 CS免疫佐剂连接，制备S-Tn疫苗。此外，我们合成了天然Tn抗原，并将其类似地衍生化以获得Tn疫苗。最后，我们使用培养的小鼠脾细胞评价了两种合成的潜在疫苗的体外免疫刺激活性。S-Tn构建体显示出与Tn类似物在最大反应方面相当的免疫刺激活性。此外，由于其更高的稳定性，与Tn类似物相比，S-Tn构建体在更低的剂量下达到其最大效果。
The Tn epitope is one of the tumor associated O-linked cell surface glycopeptides. It is expressed in over 70% of human epithelial cancers such as lung, colon, stomach and breast carcinomas. The glycosidic linkage of the Tn antigen, between N-acetylgalactosamine and serine or threonine, can be cleaved either chemically or enzymatically in the presence of glycosidases. The latter case is particularly a problem in vivo. Therefore, it would be of great interest to obtain a metabolically stable analogue of the Tn antigen that maintains or improves the immunogenic activity of the latter. The purpose of this work was to synthesize a, totally synthetic vaccine using a chemically and metabolically stable glycomimetic of the Tn antigen in which the interglycosidic oxygen was replaced by a sulphur atom (S-Tn). The S-Tn thioglycopeptide was linked to the P3CS immunoadjuvant to obtain the potential S-Tn vaccine. Moreover, we synthesized the natural Tn antigen and derivatized it similarly to obtain the Tn vaccine. Last, we evaluated the immunostimulating activity of the two synthetic potential vaccines in vitro using cultured mouse splenocytes. The S-Tn construct showed immunostimulating activity comparable, in terms of maximal response, to the Tn analogue. Moreover, due to its higher stability the S-Tn construct reached its maximal effect at lower doses compared to the Tn analogue.