环(L-脯-L-苯丙)二肽——潜在的磷酸二酯酶抑制剂

利用海藻来源的黄曲霉中提取到的次级代谢产物筛选GPR41的激动剂,发现环二肽类化合物环(L-脯-L-苯丙)二肽(17号)可在多种(G41-CHO,G12-CHO,Mock-CHO,SH-sy5y和HEK293)细胞中引起细胞内cAMP水平升高.实验结果表明,17号化合物引起cAMP升高不依赖于GPCR的激活,且腺苷酸环化酶激活剂forskolin与17号化合物共处理组比fsk单独处理组cAMP进一步增加.实验结果提示,17号化合物可能是通过抑制cAMP水解,从而引起cAMP水平的持续升高.17号化合物与已知的PDE抑制剂具有相似的结构特征,可能是潜在的磷酸二酯酶抑制剂.这是首次发现环(L-脯-L-苯丙)二肽具有在多种细胞内提高cAMP浓度的作用.

Cyclo (L-Pro-L-Phe) dipeptide: the potential phosphodiesterase inhibitors

A stable GPR41 receptor cell line was used to screen candidate agonist from the secondary metabolites extracted from gulf seaweed aflatoxin c-f-3 in Putian Fujian. The cAMP results have shown that the No.17 compound Cyclo (L-Pro-L-Phe), belonging to cyclic dipeptide, is able to increase intracellular cAMP in a variety of cells (including G41-CHO, G12-CHO, Mock-CHO, SH-sy5y and HEK293). We have demonstrated that No.17 compound induced cAMP increase in a GPCR-independent manner. Co-adminstration of adenylate cyclase activating agent forskolin and No.17 compound can lead to a further increase in cAMP level compared with those treated with forskolin alone. These results have suggested that No.17 compound may induce a sustained elevation of cAMP levels by inhibiting cAMP hydrolysis. Since No.17 compound shared similar chemical structures with some known PDE inhibitors, which may be a potential of phosphodiesterase inhibitors. This is the first report that Cyclo(L-Pro-L-Phe) could regulate cAMP formation in a variety of cells (G41-CHO, G12-CHO, Mock-CHO, SH-sy5y and HEK293).