Design, Synthesis, and Bioevaluation of Novel NLRP3 Inhibitor with IBD Immunotherapy from the Virtual Screen,Journal of Medicinal Chemistry

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Design, Synthesis, and Bioevaluation of Novel NLRP3 Inhibitor with IBD Immunotherapy from the Virtual Screen
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-13 , DOI: 10.1021/acs.jmedchem.4c01445
Ziwen Zhang ₁ , Hongyu Wu ₁ , Kai Yin ₁ , Xinru Zheng ₁ , Zhonglian Cao ₂ , Wei Guo ₃ , Chunchang Zhao ₄ , Xianfeng Gu ₁

Affiliation

NLRP3, a crucial member of the NLRP family, plays a pivotal role in immune regulation and inflammatory modulation. Here, we report a potent and specific NLRP3 inhibitor Z48 obtained though docking-based virtual screening and structure–activity relationship studies with an IC₅₀ of 0.26 μM in THP-1 cells and 0.21 μM in mouse bone marrow-derived macrophages. Mechanistic studies indicated that Z48 could bind directly to the NLRP3 protein (K_D = 1.05 μM), effectively blocking the assembly and activation of the NLRP3 inflammasome, consequently manifesting anti-inflammatory properties. Crucially, with acceptable mouse pharmacokinetic profiles, Z48 demonstrated notable therapeutic efficacy in a mouse model of DSS-induced ulcerative colitis, while displaying no significant therapeutic impact on NLRP3^KO mice. In conclusion, this study provided a promising NLRP3 inflammasome inhibitor with novel molecular scaffold, poised for further development as a therapeutic candidate in the treatment of inflammatory bowel disease.

中文翻译：

虚拟筛选中新型 NLRP3 抑制剂与 IBD 免疫疗法的设计、合成和生物评价

NLRP3 是 NLRP 家族的重要成员，在免疫调节和炎症调节中起关键作用。在这里，我们报道了一种通过基于对接的虚拟筛选和结构-活性关系研究获得的有效和特异性 NLRP3 抑制剂 Z48，在 THP-1 细胞中 IC₅₀ 为 0.26 μM，在小鼠骨髓来源的巨噬细胞中为 0.21 μM。机制研究表明，Z48 可以直接与 NLRP3 蛋白结合（K_D = 1.05 μM），有效阻断 NLRP3 炎性小体的组装和激活，从而表现出抗炎特性。至关重要的是，Z48 具有可接受的小鼠药代动力学特征，在 DSS 诱导的溃疡性结肠炎小鼠模型中表现出显着的治疗效果，同时对 NLRP3^KO 小鼠没有显着的治疗作用。总之，本研究提供了一种有前途的 NLRP3 炎性小体抑制剂，具有新型分子支架，有望进一步开发为治疗炎症性肠病的治疗候选药物。

更新日期：2024-09-13

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