2. Academic Validation
  3. Identification of D359-0396 as a novel inhibitor of the activation of NLRP3 inflammasome

Identification of D359-0396 as a novel inhibitor of the activation of NLRP3 inflammasome

  • Neurochem Int. 2023 Oct:169:105565. doi: 10.1016/j.neuint.2023.105565.
Zihao Li 1,  Senlin Ji 1,  Chuyu Wu 2,  Jiayong Wu 3,  Runjing Cao 1,  Yunshu Wang 1,  Yun Xu 3,  Jingwei Li 4,  Cun-Jin Zhang 5
Affiliations

Affiliations

  • 1 Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, Jiangsu 210008, China.
  • 2 State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Screening, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
  • 3 Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, Jiangsu 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, Jiangsu 210008, China.
  • 4 Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, Jiangsu 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, Jiangsu 210008, China. Electronic address: [email protected].
  • 5 Department of Neurology of Nanjing Drum Tower Hospital, Medical School and the State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Key Laboratory of Molecular Medicine, Translational Medicine Institute of Brain Disorders, Nanjing University, Nanjing, Jiangsu 210008, China; Institute of Brain Sciences, Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Key Laboratory for Molecular Medicine, Medical School of Nanjing University, Nanjing, Jiangsu 210008, China; Jiangsu Province Stroke Center for Diagnosis and Therapy, Nanjing, Jiangsu 210008, China; Nanjing Neuropsychiatry Clinic Medical Center, Nanjing, Jiangsu 210008, China. Electronic address: [email protected].
PMID: 37385448 DOI: 10.1016/j.neuint.2023.105565
Abstract

Aims: Pyroptosis is a unique pro-inflammatory form of programmed cell death which plays a critical role in promoting the pathogenesis of multiple inflammatory and autoimmune diseases. However, the current drug that is capable of inhibition Pyroptosis has not been translated successfully in the clinic, suggesting a requirement for drug screening in depth.

Methods: We screened more than 20,000 small molecules and found D359-0396 demonstrates a potent anti-pyroptosis and anti-inflammation effect in both mouse and human macrophage. In vivo, EAE (a mouse model of MS) and septic shock mouse model was used to investigate the protective effect of D359-0396. In vitro experiments we used LPS plus ATP/nigericin/MSU to induce Pyroptosis in both mouse and human macrophage, and finally the anti-pyroptosis function of D359-0396 was assessed.

Results: Our findings show that D359-0396 is well-tolerated without remarkable disruption of homeostasis. Mechanistically, while D359-0396 is capable of inhibiting Pyroptosis and IL-1β release in macrophages, this process depends on the NLRP3-Casp1-GSDMD pathway rather than NF-κB, AIM2 or NLRC4 inflammasome signaling. Consistently, D359-0396 significantly suppresses the oligomerization of NLRP3, ASC, and the cleavage of GSDMD. In vivo, D359-0396 not only ameliorates the severity of EAE (a mouse model of MS), but also exhibits a better therapeutic effect than teriflunomide, the first-line drug of MS. Similarly, D359-0396 treatment also significantly protects mice from septic shock.

Conclusion: Our study identified D359-0396 as a novel small-molecule with potential application in NLRP3-associated diseases.

Keywords

D359-0396; Inflammation; Multiple sclerosis; Pyroptosis; Sepsis.

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