微波促进固相合成胰高血糖素样肽-1类似物及其降血糖活性

Solid phase synthesis of glucagon-like peptide-1 analogues under microwave irradiation and their hypoglycemic activities

目的:提高胰高血糖素样肽-1(GLP-1)对二肽激肽酶(DPPⅣ)的稳定性。方法:以Rink Amide-MBHA树脂为载体,采用Fmoc/t-Bu正交保护固相合成策略,运用微波照射促进合成GLP-1类似物,最后经过反相制备高效液相色谱纯化得到目标多肽纯品。结果:所合成的GLP-1及其类似物的相对分子质量和纯度均经过电喷雾质谱和高效液相色谱确证。降血糖活性研究结果显示,改造后的GLP-1类似物有很好的降血糖活性且作用时间较长。结论:修饰后的GLP-1类似物在保留降糖活性的同时延长了作用时间,这为开发新型抗糖尿病药物提供了基础。

Aim： To improve the stability of glucagon-like peptide-1 （GLP-1） to the degradation by dipeptidyl peptidase IV （ DPP IV）. Methods： A rapid and efficient microwave irradiation solid phase synthesis method was implemented in the preparation of the GLP-1 analogues on Rink Amide-MBHA resin by an Fmoc/t-Bu orthogonal protection strategy. The crude peptides were purified by preparative RP-HPLC. Results： The molecular weight and purity of GLP-1 analogues have been confirmed by the electrospray mass spectrometry analysis and the HPLC method. The study of the biological activity showed GLP-1 analogues decreased the blood glucose prominently. Conclusion： The modified GLP-1 analogues have prolonged glucose-lowering activity, which might be on the pipeline of novel antidiabetic candidates.