Citation: Xiaoyao Ma, Jinling Zhang, Ge Fang, He Gao, Jie Gao, Li Fu, Yuanyuan Hou, Gang Bai. Förster resonance energy transfer reveals phillygenin and swertiamarin concurrently target AKT on different binding domains to increase the anti-inflammatory effect[J]. Chinese Chemical Letters, ;2024, 35(5): 108823. doi: 10.1016/j.cclet.2023.108823 shu

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

Xiaoyao Ma ^{a, b, 1} ,
Jinling Zhang ^{a, 1} ,
Ge Fang ^a ,
He Gao ^a ,
Jie Gao ^{a, *,} ,
Li Fu ^{c, *,} ,
Yuanyuan Hou ^{a, *,} ,
Gang Bai ^a

a.
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300000, China
b.
College of Life Health, Dalian University, Dalian 116622, China
c.
Dalian Fusheng Pharmaceutical Co., Ltd., Dalian 116000, China

gaojie@nankai.edu.cn

2295957379@qq.com

houyy@nankai.edu.cn

Received Date: 26 April 2023
Revised Date: 11 July 2023
Accepted Date: 18 July 2023
Available Online: 21 July 2023

Figures(6)

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.
- FRET,
- Swertiamarin,
- Phillygenin,
- AKT,
- Anti-inflammation,
- Combinatorial drug
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