Förster resonance energy transfer reveals phillygenin and swertiamarin concurrently target AKT on different binding domains to increase the anti-inflammatory effect  

作　　者：Xiaoyao Ma Jinling Zhang Ge Fang He Gao Jie Gao Li Fu Yuanyuan Hou Gang Bai 

机构地区：[1]State Key Laboratory of Medicinal Chemical Biology,College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research,Nankai University,Tianjin 300000,China [2]College of Life Health,Dalian University,Dalian 116622,China [3]Dalian Fusheng Pharmaceutical Co.,Ltd.,Dalian 116000,China

出　　处：《Chinese Chemical Letters》2024年第5期207-212,共6页中国化学快报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.81973449).

摘　　要：The clinical benefit of combination therapy is significant,but it is not easy to define the mechanism of complexity and diversity.Previous studies illustrate that phillygenin(Phi)binds in the allosteric inhibit pocket of protein kinase B(AKT),and swertiamarin(Swe)acts on the pleckstrin homology(PH)domain of AKT.However,the combined synergistic effect of relieving the inflammatory response has yet to be elucidated.Based on high sensitivity,specificity and fast-responsibility fluorescent sensors,the Förster resonance energy transfer(FRET)technique offers a route to provide clear insights into physiological and pathological processes.In the study,molecular docking,the fluorescent probes of Phi and Swe for FRET were designed and synthesized.FRET analysis shown that Swe and Phi concurrently acted on the PH domain and allosterically inhibited pocket of AKT,respectively.The combination of Swe and Phi significantly increased the heat stability of AKT and decreased protease-induced degeneration.In lipopolysaccharides(LPS)-induced mice and cells,the combination arrested AKT activation,nuclear factor kappa-B(NF-κB)phosphorylation,and the expression of tumor necrosis factor-α(TNF-α),interleukin(IL)-6 and IL-8.In conclusion,FRET revealed Phi and Swe concurrently targeted AKT on different domains and the combination of Phi and Swe enhanced the anti-inflammatory effect.

关 键 词：FRET SWERTIAMARIN Phillygenin AKT ANTI-INFLAMMATION Combinatorial drug 

分 类 号：TQ460.1[化学工程—制药化工]