靶向BRISC去泛素化酶复合体抑制NLRP3炎症小体活化及其应用基础研究

NLRP3炎症小体与多种人类重大疾病的发生发展密切相关，目前临床上仍然缺乏有效的针对性治疗药物。我们发现BRISC复合体去泛素化酶活性抑制剂硫藤黄菌素和全霉素可通过抑制NLRP3的去泛素化来有效阻止NLRP3炎症小体活化，其体内外活性高于目前已知最好的NLRP3抑制剂MCC950，初步证明靶向BRISC复合体抑制NLRP3炎症小体活化的可行性。本项目拟在我们前期研究的基础上开展以下工作：1）系统研究硫藤黄菌素和全霉素对NLRP3炎症小体的抑制作用；2）硫藤黄菌素和全霉素治疗NLRP3炎症小体相关疾病小鼠模型；3）硫藤黄菌素和全霉素抑制NLRP3炎症小体的优效性；4）硫藤黄菌素和全霉素抑制NLRP3炎症小体的机制及脱靶效应评估。本项目旨在证明BRISC复合体是抑制NLRP3炎症小体的有效靶点，为研究NLRP3炎症小体提供有效的化学探针，并为NLRP3相关疾病的治疗提供新思路和新的先导化合物。

Inappropriate activation of NLRP3 inflammasome has been linked with various human autoinflammatory and autoimmune diseases. However, there is still a lack of drugs that directly interfere with NLRP3 inflammasome activation in clinical treatment. Here, we find that thiolutin and holomycin, two previously reported inhibitors of BRISC deubiquitinase complex, significantly block NLRP3 inflammasome activation mainly through preventing NLRP3 deubiquitination. Importantly, the invivo and invitro activity of these two inhibitors is higher than MCC950, the most potential NLRP3 specific inhibitor reported previously. Thus, targeted inhibition of the BRISC may be an effective strategy for the treatment of NLRP3-associated inflammatory diseases. Therefore, We intend to focus on the following aspects: 1) thiolutin and holomycin selectively inhibit the activation of NLRP3 inflammasome; 2) thiolutin and holomycin attenuate the NLRP3 inflammasome-associated diseases; 3) the superiority of thiolutin and holomycin over other reported NLRP3 inhibitors for blocking NLRP3 inflammasome activation; 4) the molecular mechanisms of thiolutin and holomycin in the regulation of NLRP3 inflammasome. This study aims to confirm that inhibition of the BRISC deubiquitinase complex is a potential target for the development of NLRP3 antagonists. Moreover, it will provide effective chemical probes for the research of NLRP3 inflammasome, as well as novel strategy and lead compounds in drug discovery for NLRP3-associated inflammatory diseases.