新型胰高血糖素样肽-1类似物的合成及降糖活性

Synthesis and hypoglycemic activity studies of novel glucagon-like peptide-1 analogues

目的合成具有全新肽序的新型胰高血糖素样肽-1(GLP-1)受体激动剂非洲爪蟾GLP-1并对其(XenGLP-1)进行长效化修饰。方法先通过在其C端引入PSSGAPPPS序列以增加其降糖活性,再在XenGLP-1序列上引入半胱氨酸,进一步利用MAL-PEG2 000与其进行缀合。结果合成得到PEG2 000-ZF-1和PEG2 000-ZF-2 2个缀合肽,并对缀合肽进行长效化降糖活性研究。结论 2个PEG化缀合肽具有长效的降糖活性,具有很好的药物开发前景。

A novel glucagon-like peptide-1(G LP-1)receptor agonist,Xenopuslaevis GLP-lwith a novel peptide sequence was synthesized and modified(XenGLP-1)for controlled release.The current work was initiated with the introduction of the C-terminal tail(PSSGAPPPS)of exendin-4 into XenGLP-1 to achieve improved stability and activity.Cysteine was then introduced to XenGLP-1.Maleimide modified polyethylene glycol 2 000(PEG2000)was then straight forward attached to the thiol group of cysteine with high chemical selectivity to obtain PEG2000-Z F-l and PEG2000-ZF-2.The long-acting hypoglycemic effect of PEG2000-ZF-l and PEG2000-ZF-2 was investigated to identify its efficiency for anti-diabetics.The 2 PEG conjugated peptides have long acting hypoglycemic activity and have good prospects for drug development.