Development of novel oridonin analogs as specifically targeted NLRP3 inflammasome inhibitors for the treatment of dextran sulfate sodium-induced colitis.

Abstract

Abnormal activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome is closely associated with a variety of inflammatory diseases. Herein, we describe the discovery and optimization of a series of NLRP3 inflammasome inhibitors based on the oridonin skeleton. These inhibitors exhibited moderate to potent inhibitory activity against interleukin 1β (IL-1β) release. Compound E6 showed the strongest inhibitory activity and better safety range against IL-1β (IC50 = 0.45 ± 0.02 μM, selectivity index = 36.49). Compared with oridonin, the activity and selectivity index of compound E6 increased 11.5 and 7.2 times, respectively. Compound E6 also exhibited broad-spectrum activity and specificity. Compound E6 mainly reduced the release of IL-1β by targeting the NLRP3 protein, thereby inhibiting the NLRP3-caspase 1-gasdermin D (GSDMD), as well as inhibiting the caspase 4-GSDMD signaling pathway. Further studies revealed an important therapeutic effect of E6 on dextran sulfate sodium-induced colitis. Compound E6 may be promising for the treatment of NLRP3-related diseases including inflammatory bowel disease.

• Authors: Lei Pang, Hongmei Liu, Hongyu Quan, Hehuan Sui, Yi Jia
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 245 Issue Pt 2 Pg. 114919 (Jan 05 2023) ISSN: 1768-3254 [Electronic] France
• PMID: 36399877 (Publication Type: Journal Article)
• Copyright: Copyright © 2022 Elsevier Masson SAS. All rights reserved.

Chemical References

• Inflammasomes
• oridonin
• NLR Family, Pyrin Domain-Containing 3 Protein
• Dextran Sulfate

Topics

• Humans
• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Dextran Sulfate
• Colitis (chemically induced, drug therapy)