Design, synthesis, and biological evaluation of oridonin derivatives as novel NLRP3 inflammasome inhibitors for the treatment of acute lung injury

Abstract

Acute lung injury (ALI) is a severe respiratory disorder closely associated with the excessive activation of the NLRP3 inflammasome. Oridonin (Ori), a natural diterpenoid compound, had been confirmed as a specific covalent NLRP3 inflammasome inhibitor, which was completely different from that of MCC950. However, the further clinical application of Ori was limited by its weak inhibitory activity against NLRP3 inflammasome (IC50 = 1240.67 nM). Fortunately, through systematic structure-optimization of Ori, D6 demonstrated the enhancement of IL-1β inhibitory activity (IC50 = 41.79 nM), which was better than the parent compound Ori. Then, by using SPR, molecular docking and MD simulation, D6 was verified to directly interact with NLRP3 via covalent and non-covalent interaction. The further anti-inflammatory mechanism studies were revealed that D6 could inhibit the activation of NLRP3 inflammasome without affecting the initiation phase of NLRP3 inflammasome activation, and D6 was a broad-spectrum and selective NLRP3 inflammasome inhibitor. Finally, D6 demonstrated a favorable therapeutic effect on LPS-induced ALI in mice model, and the potent pharmacodynamic effect of D6 was correlated with the specific inhibition of NLRP3 inflammasome activation in vivo. Thus, D6 is proved as a potent NLRP3 inhibitor, and has the potential to develop as a novel anti-ALI agent.