A Probe for NLRP3 Inflammasome Inhibitor MCC950 Identifies Carbonic Anhydrase 2 as a Novel Target.
A Probe for NLRP3 Inflammasome Inhibitor MCC950 Identifies Carbonic Anhydrase 2 as a Novel Target.
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DOI：
10.1021/acschembio.1c00218
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发表时间：
2021-06-18
影响因子：
4
通讯作者：
Tate EW
中科院分区：
文献类型：
--
作者：
Kennedy CR;Goya Grocin A;Kovačič T;Singh R;Ward JA;Shenoy AR;Tate EW
抑制炎性小体和焦萎途径是临床治疗自身免疫性和炎性疾病的有前途的策略。MCC 950是一种NLR家族炎性体pyrin结构域3（NLRP 3）蛋白的有效抑制剂，在一系列疾病的动物模型中显示出令人鼓舞的结果;然而，到目前为止，尚未发现脱靶。在此，我们报告了一种新的光亲和炔标记的探针MCC 950（IMP 2070）的设计，合成和应用，该探针与NLRP 3直接接合，并抑制巨噬细胞中的炎性小体激活。活巨噬细胞中基于亲和力的化学蛋白质组学鉴定了几种潜在的脱靶，包括碳酸酐酶2（CA 2）作为IMP 2070的特异性靶标，并且独立的细胞热蛋白质组学分析揭示了MCC 950对CA 2的稳定性。MCC 950显示出对CA 2活性的非竞争性抑制，证实碳酸酐酶是该化合物的脱靶类别。这些数据突出了MCC 950及其衍生物在临床前或临床研究中可能表现出脱靶效应的潜在生物学机制。
Inhibition of inflammasome and pyroptotic pathways are promising strategies for clinical treatment of autoimmune and inflammatory disorders. MCC950, a potent inhibitor of the NLR-family inflammasome pyrin domain-containing 3 (NLRP3) protein, has shown encouraging results in animal models for a range of conditions; however, until now, no off-targets have been identified. Herein, we report the design, synthesis, and application of a novel photoaffinity alkyne-tagged probe for MCC950 (IMP2070) which shows direct engagement with NLRP3 and inhibition of inflammasome activation in macrophages. Affinity-based chemical proteomics in live macrophages identified several potential off-targets, including carbonic anhydrase 2 (CA2) as a specific target of IMP2070, and independent cellular thermal proteomic profiling revealed stabilization of CA2 by MCC950. MCC950 displayed noncompetitive inhibition of CA2 activity, confirming carbonic anhydrase as an off-target class for this compound. These data highlight potential biological mechanisms through which MCC950 and derivatives may exhibit off-target effects in preclinical or clinical studies.
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