Ginsenosides as selective glucocorticoid drugs

Glucocorticoids are potent anti-inflammatory drugs widely used clinically to treat various inflammatory and immune conditions. However, two main clinical problems limit their use. GCs trigger severe side effects and they induce acquired glucocorticoid resistance, especially during chronic systemic treatment [6-11]. Therefore, developing novel strategies to improve the treatment inflammatory and immune conditions becomes urgent. Here, we present evidence that ginsenosides act as selective GR agonists, antagonists, and prodrugs. Moreover, our data illustrate that the number and positions of glucose groups bound to the steroid backbone of ginsenosides and different chemical structures are essential factors underlying the differential mechanistic effects of ginsenosides. Understanding the molecular mechanisms and the effects of natural compound (ginsenosides) opens a novel road towards developing improved anti-inflammatory GCs. Attaching one glucose group to classical GCs produced selective Gr agonists, such as GDex and GPdn, which exert anti-inflammatory effects without triggering side effects due to the absence of GR transactivation activities. Attaching two glucose groups to classical GCs resulted in the creation of GC prodrugs, such as GbPdn, which mediates its action locally at the site of inflammation, dependent on GBA2 activity, without triggering side effects.