【摘要】 GLP-1类似物是治疗II型糖尿病和肥胖症方面最具潜力的一类药物,但采用注射给药方式,患者接受度较差.因此,开发口服长效的GLP-1类似物一直是研究的热点.然而多肽类药物易经过胃肠道被水解,从而丧失生理活性,同时由于脂溶性差,难以实现肠道吸收.本文设计了3个GLP-1类似物,并比较了添加石胆酸和商业化辅助渗透剂SNAC抵抗胰蛋白酶、糜蛋白酶和胃蛋白酶的水解效果.结果表明,类似物1在石胆酸存在情况下,可显著抵抗胰蛋白酶和糜蛋白酶的水解作用,有望制成肠溶剂实现多肽类药物的口服给药.更多还原

【Abstract】 GLP-1 analogues are the most promising class of drugs in the treatment of type II diabetes and obesity, and are poorly accepted by patients when administered by injection. Therefore, the development of oral long-lasting GLP-1 analogues has always been the focus of research. However, peptide drugs are easily hydrolyzed through the gastrointestinal tract, resulting in loss of physiological activity. Meanwhile, due to poor lipid solubility, it is difficult to realize intestinal absorption. In this paper, three GLP-1 analogues were designed, and the anti-hydrolysis effects of gallstone acid and commercial auxiliary penetrant SNAC on trypsin, chymotrypsin and pepsin were compared. The results showed that analogue 1 could significantly resist the hydrolysis of trypsin and chymotrypsin in the presence of lithocholic acid, and is expected to be used as intestinal solvent for oral administration of peptide drug.更多还原