A natural AKT inhibitor swertiamarin targets AKT-PH domain, inhibits downstream signaling, and alleviates inflammation.

Abstract

Swertiamarin (SW), a representative component in Flos Lonicerae Japonicae, has been reported to exert significant activity in preventing infections. In this research, we aim to clarify the details of SW and its target to explore SW's underlying anti-inflammatory mechanisms. An azide labeled SW probe was synthesized for protein target fishing, and the results demonstrated that AKT could be captured specifically. Immunofluorescence colocalization with AKT was implemented by a click reaction of the SW probe and alkynyl CY5. The result showed that AKT was one of the targets of SW. Then, a competitive combination experiment using a set of AKT inhibitors and a membrane translocation experiment confirmed that SW might target the pleckstrin homology (PH) domain of AKT. This specific binding directly deactivated the phosphorylation of AKT on both Ser473 and Thr308, which induced the dephosphorylation of IKK and NF-κB. Finally, proinflammatory cytokines (TNF-α, IL-6, and IL-8) were suppressed both in cells and in acute lung injury animal model by targeting AKT-PH domain. This study demonstrated that SW functions as a natural AKT inhibitor and presents significant anti-inflammatory activity by directly regulating the AKT-PH domain and inhibiting downstream inflammatory molecules.

• Authors: Man Zhang, Xiaoyao Ma, Honglei Xu, Wenbo Wu, Xin He, Xiaoying Wang, Min Jiang, Yuanyuan Hou, Gang Bai
• Journal: The FEBS journal (FEBS J) Vol. 287 Issue 9 Pg. 1816-1829 (05 2020) ISSN: 1742-4658 [Electronic] England
• PMID: 31665825 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Federation of European Biochemical Societies.

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Blood Proteins
• Iridoid Glucosides
• Phosphoproteins
• Protein Kinase Inhibitors
• Pyrones
• platelet protein P47
• swertiamarin
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (chemistry, pharmacology)
• Blood Proteins (antagonists & inhibitors, metabolism)
• Cells, Cultured
• HEK293 Cells
• Humans
• Inflammation (drug therapy, metabolism)
• Iridoid Glucosides (chemistry, pharmacology)
• Lonicera (chemistry)
• Mice
• Molecular Structure
• Phosphoproteins (antagonists & inhibitors, metabolism)
• Plants, Medicinal (chemistry)
• Protein Kinase Inhibitors (chemistry, pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Pyrones (chemistry, pharmacology)
• RAW 264.7 Cells
• Signal Transduction (drug effects)