Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolising enzyme, is known as a tumour cell survival factor that causes immune escape in several types of cancer. Flavonoids of Sophora flavescens have a variety of biological benefits for humans; however, cancer immunotherapy effect has not been fully investigated. The flavonoids (1–6) isolated from S. flavescens showed IDO1 inhibitory activities (IC50 4.3–31.4 µM). The representative flavonoids (4–6) of S. flavescens were determined to be non-competitive inhibitors of IDO1 by kinetic analyses. Their binding affinity to IDO1 was confirmed using thermal stability and surface plasmon resonance (SPR) assays. The molecular docking analysis and mutagenesis assay revealed the structural details of the interactions between the flavonoids (1–6) and IDO1. These results suggest that the flavonoids (1–6) of S. flavescens, especially kushenol E (6), as IDO1 inhibitors might be useful in the development of immunotherapeutic agents against cancers.
Highlights
Sophora flavescens has been used traditionally to treat skin diseases, viral hepatitis, and cancer owing to the presence of medicinal components such as alkaloids and flavonoids[1,2,3]
All of the flavonoids (1–6) isolated from S. flavescens were tested for IDO1 inhibitory activity (Figure 1)
The representative flavonoids (4–6) were identified as noncompetitive IDO1 inhibitors through kinetic analyses, and the direct interactions with IDO1 were confirmed by thermal stability assay and surface plasmon resonance (SPR) assay
Summary
Sophora flavescens has been used traditionally to treat skin diseases, viral hepatitis, and cancer owing to the presence of medicinal components such as alkaloids and flavonoids[1,2,3]. Many studies have focused on the medicinal properties of alkaloids than those of flavonoids, some studies have evaluated flavonoids and their bioactive mechanisms of action. The polyphenol structure of flavonoids is responsible for their various pharmacological activities, which are elicited by chelating metal ions or scavenging free radicals[4,5,6,7,8]. It has been proved that the existence of prenyl and lavandulyl residue could intensify the pharmacological activity of the flavonoids[9]. Because prenylation and lavandulylation increase lipophilicity, which results in an increased membrane-binding affinity and a stronger interaction with the target proteins[10,11].
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