CN114558008A - 一种nlrp3抑制剂 - Google Patents

一种nlrp3抑制剂 Download PDF

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CN114558008A
CN114558008A CN202210168597.5A CN202210168597A CN114558008A CN 114558008 A CN114558008 A CN 114558008A CN 202210168597 A CN202210168597 A CN 202210168597A CN 114558008 A CN114558008 A CN 114558008A
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nlrp3
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王飞龙
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Abstract

本发明涉及一种NLRP3抑制剂，所述抑制剂有效成分为小分子化合物UK5099。本发明通过体内、体外实验证明了UK5099可特异性抑制NLRP3炎症小体激活，为临床治疗NLRP3相关的疾病提供新的方法。

Description

一种NLRP3抑制剂
技术领域
本发明属于小分子药物领域，特别涉及一种NLRP3抑制剂。
背景技术
NLRP3炎症小体是由感受器分子NLRP3、衔接蛋白ASC和效应蛋白前体procaspase-1三个部分组成一种蛋白复合物体，其可感受机体内各种危险信号而被激活，进而剪切细胞因子IL-1β和IL-18，以及打孔蛋白Gasdermin D，促进炎症反应和引起细胞凋亡。自从于2002年被发现以来，大量研究表明NLPR3炎症小体与阿尔茨海默病、帕金森、动脉粥样硬化、痛风、风湿性疾病、感染性疾病、哮喘等多种疾病有着密切的关系。因此，研发能够特异性抑制NLRP3的药物有望为治疗这些疾病提供新的手段，也是全球各大制药公司竞争的焦点。尽管目前已经报道了一些NLRP3的小分子抑制剂，但是目前均停留在基础研究或临床1/2期研究中，尚无药物用到临床，这些小分子的效果亦不明。因此，研发新的、能够特异性抑制NLRP3的小分子抑制剂有着重要的科学意义和临床应用价值。
发明内容
本发明所要解决的技术问题是提供一种NLRP3抑制剂，通过体内、体外实验证明了UK5099可特异性抑制NLRP3炎症小体激活，为临床治疗NLRP3相关的疾病提供新的方法。
本发明提供了一种NLRP3抑制剂，所述抑制剂有效成分为小分子化合物UK5099。
所述UK5099的结构式为：
Figure BDA0003516516630000011
所述UK5099对NLRP3的抑制作用独立于其对线粒体丙酮酸转运体(MPC)的效应。
所述UK5099以NLRP3为靶点，制备治疗阿尔茨海默病、帕金森、动脉粥样硬化、痛风、风湿性疾病、感染性疾病或哮喘或其他与NLRP3炎症小体相关疾病的药物。
所述药物配以药学上可接受的辅料或辅助性成分制备成制剂使用。
所述制剂选自片剂、粉剂、颗粒剂、胶囊、口服液、缓释剂中的一种。
有益效果
本发明通过体内、体外实验证明了UK5099可特异性抑制NLRP3炎症小体激活，为临床治疗NLRP3相关的疾病提供新的方法。
附图说明
图1为UK5099抑制促炎细胞因子IL-1β和TNF-α分泌的浓度梯度试验；
图2为UK5099对NLRP3、Csaspase-1和Gasdermin D的作用图；
图3为UK5099对野生型和缺失MPC表达BMDMs分泌IL-1β的抑制作用图；
图4为UK5099对野生型和缺失MPC表达BMDMs中的NLRP3、Csaspase-1和GasderminD的作用图；
图5为UK5099降低内毒素诱导的脓毒症小鼠模型体内细胞因子水平，并改善其生存率。
具体实施方式
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。此外应理解，在阅读了本发明讲授的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。
实施例1
以下实施案例中的实验方法，如无特殊说明，均为常规实验方法。实验中所用试剂和耗材如无特殊说明，均来自于Sigma、Invivogene、R&D、Corning、Biolegend等本研究领域的主流供应商。
1.小鼠骨髓来源的巨噬细胞(BMDMs)的获取
使用6-8周龄的小鼠提取骨髓细胞，在含有10ng/ml的M-CSF培养液中培养7天，其中第四天加入一半的新鲜培养液，得到BMDMs。收集BMDMs并重新种在细胞培养板中(1*106/ml)过夜，进行下一阶段的实验。
2.炎症小体的激活
(1)NLRP3炎症小体的激活：使用LPS预处理BMDMs三小时，然后将原培养液替换为不含血清的培养液，并加入不同浓度的UK5099 30分钟，再使用ATP或Nigericin刺激30和60分钟，收集上清液和蛋白，用于之后的ELISA和Western Blot实验。
(2)NLRC4炎症小体的激活：使用LPS预处理BMDMs三小时，然后将原培养液替换为不含血清的培养液，并加入不同浓度的UK509930分钟，再使用Flagellin+Lipo2000刺激6小时，收集上清液和蛋白，用于之后的ELISA和Western Blot实验。
(3)AIM2炎症小体的激活：使用LPS预处理BMDMs三小时，然后将原培养液替换为不含血清的培养液，并加入不同浓度的UK509930分钟，再使用dsDNA+Lipo2000刺激6小时，收集上清液和蛋白，用于之后的ELISA和Western Blot实验。
3.小鼠体内实验(脓毒症模型)
使用UK5099(50mg/kg)腹腔注射预处理小鼠1小时，然后使用LPS(15mg/kg)腹腔注射造成脓毒症模型，一批小鼠于6小时后处死并提取血清用于细胞因子检测，另一批小鼠用于观察生存率。
由图1所示，使用小鼠骨髓来源的巨噬细胞(BMDMs)作为研究对象，采用LPS+ATP诱导NLRP3炎症小体激活模型，UK5099可显著抑制IL-1β的产生，并呈剂量依赖型，其IC50＝4.852μM。UK5099对TNF-α的抑制作用不明显，说明其可特异性抑制NLRP3炎症小体激活。UK5099同样可以抑制其它激活剂(LPS+Nigericin)诱导的NLRP3炎症小体激活。
由图2所示，Western blot显示UK5099不影响pro-IL-1β的表达，但可以抑制NLRP3下游Caspase-1和Gasdermin D的剪切，说明UK5099的作用靶点在NLRP3。
由图3所示，UK5099数十年来一直被认为是线粒体丙酮酸转运体(MPC)的特异性抑制剂，但是本发明发现其不但可以在野生型BMDMs抑制IL-1β的产生，在缺乏MPC表达的BMDMs同样存在这样的作用，说明其对NLRP3的抑制作用独立于MPC，NLRP3是其作用新靶点。
由图4所示，UK5099在对照和缺失MPC表达的BMDMs上均可抑制NLRP3下游Caspase-1和Gasdermin D的剪切，说明UK5099的作用于NLRP3而抑制NLRP3炎症小体的激活，这一效应与MPC无关。
由图5所示，使用UK5099预处理小鼠后通过内毒素腹腔内注射诱导脓毒症模型，UK5099可以显著降低小鼠血清IL-1β、TNF-α、IL-6和IL-12的水平，并大幅提高小鼠的生存率，说明UK5099在体内亦存在显著的抑制NLRP3的作用，可以作为一种潜在的药物来治疗脓毒症等炎症性疾病。

Claims (6)

1.一种NLRP3抑制剂，其特征在于：所述抑制剂有效成分为小分子化合物UK5099。
2.根据权利要求1所述的抑制剂，其特征在于：所述UK5099的结构式为：
Figure FDA0003516516620000011
3.根据权利要求1所述的抑制剂，其特征在于：所述UK5099对NLRP3的抑制作用独立于其对线粒体丙酮酸转运体的效应。
4.根据权利要求1所述的抑制剂，其特征在于：所述UK5099以NLRP3为靶点，制备治疗阿尔茨海默病、帕金森、动脉粥样硬化、痛风、风湿性疾病、感染性疾病或哮喘或其他与NLRP3炎症小体相关疾病的药物。
5.根据权利要求1所述的抑制剂，其特征在于：所述药物配以药学上可接受的辅料或辅助性成分制备成制剂使用。
6.根据权利要求5所述的抑制剂，其特征在于：所述制剂选自片剂、粉剂、颗粒剂、胶囊、口服液、缓释剂中的一种。
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160250249A1 (en) * 2013-10-03 2016-09-01 Inserm ( Institute National De Lasanté Et De La Re Cherche Médicale) Methods and pharmaceutical compositions for modulating autophagy in a subject in need thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160250249A1 (en) * 2013-10-03 2016-09-01 Inserm ( Institute National De Lasanté Et De La Re Cherche Médicale) Methods and pharmaceutical compositions for modulating autophagy in a subject in need thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DAVID G. PERREGAUX等: "Tenidap and other anion transport inhibitors disrupt cytolytic T lymphocyte-mediated IL-1β post-translational processing" *
阴弯弯等: "高氧抑制LPS/ATP诱导的骨髓源性巨噬细胞的焦亡" *

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