结构新型促胰岛素分泌肽的聚乙二醇修饰及生物活性研究  

Study on PEGylation and biological activity of a novel insulinotropic peptide analogue

作　　者：刘东 任崇飞 杨欣茹 李铁健 张贵民 LIU Dong;REN Chong-fei;YANG Xin-ru;LI Tie-jian;ZHANG Gui-min(Shandong Newtime Pharmaceutical Co.,Ltd.,Linyi 273400,China;Lunan Pharmaceutical Group Co.,Ltd.,National Engineering and Technology Research Center of Chirality Pharmaceutical,Linyi 273400,China)

机构地区：[1]山东新时代药业有限公司,山东临沂273400 [2]鲁南制药集团股份有限公司,国家手性制药工程技术研究中心,山东临沂273400

出　　处：《实用药物与临床》2020年第12期1113-1118,共6页Practical Pharmacy and Clinical Remedies

基　　金：2019年山东省重点研发计划(重大科技创新工程)(2019JZZY010516)。

摘　　要：目的研究长效聚乙二醇化修饰的促胰岛素分泌肽。方法设计筛选得到新型GLP-1类似物DT1,进行不同类型和不同分子量的PEG修饰,得到一种长效聚乙二醇化修饰的促胰岛素分泌肽同源二聚体(PEG-Di-DT1),修饰率可达85%,产物纯化后色谱纯度不低于99.0%。结果体内外生物活性测定显示,PEG-Di-DT1体外刺激RIN-m5F细胞释放cAMP的ED 50为14.76 ng/ml(以多肽计,2.74 ng/ml),45μg/kg剂量皮下注射给药对db/db模型小鼠有明显的降血糖作用,维持降血糖时间可达72 h。结论同源双肽的双马来酰亚胺活化PEG修饰,可获得体内外生物活性保留率高的产品。PEG-Di-DT1具有良好的体内外生物活性,有潜力成为治疗人2型糖尿病的长效药物。Objective To study the long-acting glucagon-like peptide with PEGylation.Methods The new GLP-1 analogue DT1 was obtained by different types or weighs of PEG on the new GLP-1 analogue DT1.The modification rate was 85%,and the chromatographic purity by HPLC reached to 99.0%.Results The biological activity of PEG-Di-DT1 in vitro indicated that the ED 50 of cAMP production in RIN-m5F cells stimulated by PEG-Di-DT1 was 14.76 ng/ml(2.74 ng/ml,according to polypeptide).Subcutaneous administration of 45μg/kg could significantly lower the blood glucose in db/db mice models,and the efficacy could maintain for 72 h.Conclusion Homologous dipeptides modified by mal-PEG-mal could obtain the product with high bioactivity retention in vitro and in vivo.PEG-Di-DT1 has good biological activities,and shows potential to be used as long-acting peptide drug for type 2 diabetes.

关 键 词：促胰岛素分泌肽 PEG修饰 同源二聚体 生物活性 长效药物 

分 类 号：R914[医药卫生—药物化学]