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

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

  • Eur J Med Chem. 2023 Jan 5;245(Pt 2):114919. doi: 10.1016/j.ejmech.2022.114919.
Lei Pang 1,  Hongmei Liu 2,  Hongyu Quan 2,  Hehuan Sui 3,  Yi Jia 4
Affiliations

Affiliations

  • 1 Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing, 400038, China; The Second Clinical Medical College of North Sichuan Medical College·Department of Pharmacy, Nanchong Central Hospital·Nanchong Key Laboratory of Individualized Drug Therapy, Nanchong, Sichuan, 637000, China.
  • 2 Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing, 400038, China.
  • 3 The Second Clinical Medical College of North Sichuan Medical College·Department of Pharmacy, Nanchong Central Hospital·Nanchong Key Laboratory of Individualized Drug Therapy, Nanchong, Sichuan, 637000, China. Electronic address: suihehuan0327@126.com.
  • 4 Institute of Materia Medica and Department of Pharmaceutics, College of Pharmacy, Third Military Medical University, ChongQing, 400038, China. Electronic address: jy@tmmu.edu.cn.
PMID: 36399877 DOI: 10.1016/j.ejmech.2022.114919
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.

Keywords

GSDMD; Inflammatory bowel disease; Interleukin-1β; NLRP3 inflammasome; Oridonin; Pyroptosis.

Figures
Products