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Identification of Toll-like receptor signaling inhibitors based on selective activation of hierarchically acting signaling proteins.
Science Signaling ( IF 7.3 ) Pub Date : 2018-08-14 , DOI: 10.1126/scisignal.aaq1077
Sirish K Ippagunta 1 , Julie A Pollock 2 , Naina Sharma 2 , Wenwei Lin 3 , Taosheng Chen 3 , Kazuki Tawaratsumida 1 , Anthony A High 4 , Jaeki Min 3 , Yizhe Chen 3 , R Kiplin Guy 3 , Vanessa Redecke 1 , John A Katzenellenbogen 2 , Hans Häcker 1
Affiliation  

Toll-like receptors (TLRs) recognize various pathogen- and host tissue-derived molecules and initiate inflammatory immune responses. Exaggerated or prolonged TLR activation, however, can lead to etiologically diverse diseases, such as bacterial sepsis, metabolic and autoimmune diseases, or stroke. Despite the apparent medical need, no small-molecule drugs against TLR pathways are clinically available. This may be because of the complex signaling mechanisms of TLRs, which are governed by a series of protein-protein interactions initiated by Toll/interleukin-1 receptor homology domains (TIR) found in TLRs and the cytoplasmic adaptor proteins TIRAP and MyD88. Oligomerization of TLRs with MyD88 or TIRAP leads to the recruitment of members of the IRAK family of kinases and the E3 ubiquitin ligase TRAF6. We developed a phenotypic drug screening system based on the inducible homodimerization of either TIRAP, MyD88, or TRAF6, that ranked hits according to their hierarchy of action. From a bioactive compound library, we identified methyl-piperidino-pyrazole (MPP) as a TLR-specific inhibitor. Structure-activity relationship analysis, quantitative proteomics, protein-protein interaction assays, and cellular thermal shift assays suggested that MPP targets the TIR domain of MyD88. Chemical evolution of the original MPP scaffold generated compounds with selectivity for distinct TLRs that interfered with specific TIR interactions. Administration of an MPP analog to mice protected them from TLR4-dependent inflammation. These results validate this phenotypic screening approach and suggest that the MPP scaffold could serve as a starting point for the development of anti-inflammatory drugs.

中文翻译:

基于选择性激活分层作用的信号蛋白,鉴定Toll样受体信号抑制剂。

Toll样受体(TLR)识别各种病原体和宿主组织衍生的分子,并引发炎症性免疫反应。但是,夸大或延长的TLR激活可能导致病因多样化的疾病,例如细菌性败血症,代谢性疾病和自身免疫性疾病或中风。尽管有明显的医学需要,但临床上尚无针对TLR途径的小分子药物。这可能是由于TLR复杂的信号传导机制所决定的,而TLR的复杂信号传导机制由TLR和细胞质衔接蛋白TIRAP和MyD88中的Toll /白介素1受体同源域(TIR)引发的一系列蛋白质-蛋白质相互作用所控制。用MyD88或TIRAP对TLR进行寡聚可导致IRAK激酶家族成员和E3泛素连接酶TRAF6募集。我们基于TIRAP,MyD88或TRAF6的诱导型同二聚化开发了一种表型药物筛选系统,该系统根据其作用等级对命中进行排序。从生物活性化合物库中,我们确定了甲基哌啶子基吡唑(MPP)作为TLR特异性抑制剂。结构-活性关系分析,定量蛋白质组学,蛋白质-蛋白质相互作用测定和细胞热位移测定表明,MPP靶向MyD88的TIR结构域。最初的MPP支架的化学演化生成了对干扰特定TIR相互作用的独特TLR具有选择性的化合物。向小鼠施用MPP类似物可保护它们免受TLR4依赖性炎症的影响。
更新日期:2018-08-15
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