Intramolecularly lactam stapled oxyntomodulin analogues inhibit cancer cell proliferation in vitro  

作　　者：Junli Wang Cen Liu Hongliu Yang Tao Ma Yonggang Liu Fener Chen 

机构地区：[1]Engineering Center of Catalysis and Synthesis for Chiral Molecules,Department of Chemistry,Fudan University,Shanghai 200433,China [2]Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China [3]School of Chinese Materia Medica,Beijing University of Chinese Medicine,Liangxiang Campus,Beijing 102488,China

出　　处：《Chinese Chemical Letters》2023年第4期222-225,共4页中国化学快报（英文版）

摘　　要：As a glucagon(GCG) receptor(GCGR) and glucagon-like peptide 1(GLP-1) receptor(GLP-1R) dual agonist, oxyntomodulin(OXM) has been attracting scientific attentions due to its efficacies of suppressing appetite, increasing energy expenditure, and inducing body weight loss in obese humans. Based on the scaffold of native OXM, specific helix-favoring amino acids substitutions and the consequent salt bridge formations were believed to offer enhanced and balanced GCGR/GLP-1R activations through increasing α-helical conformation. Novel OXM analogues are obtained by intramolecular lactam stapling of positions[Glu16 & Lys20] or [Lys17 & Glu21] to further strengthen conformationally constrained stabilization. Even though the lactam staple does not provide additional dual GCGR/GLP-1R activations in vitro, the stapled OXM analogues are firstly reported to have higher or lower anti-PANC-1 cell proliferation activity, meanwhile which has no obvious inhibitory effect on the proliferation of He La cells. Therefore, it is speculated that the stapled analogues may have the potential to inhibit the proliferation of specific cancer cell types.Among the stapled peptides as well as their precursors, analogue 6 has the most prominent anti-PANC-1 proliferation activity with the IC50value of 115.1 μmol/L. Its mechanism of actions including effective signal pathways should be worth further investigations in future.

关 键 词：Oxyntomodulin analogues Intramolecular lactam Dual GCGR/GLP-1R activations Anti-PANC-1 proliferation 

分 类 号：R730.5[医药卫生—肿瘤]