The Development of Benzimidazole-Based Clickable Probes for the Efficient Labeling of Cellular Protein Arginine Deiminases (PADs).
The Development of Benzimidazole-Based Clickable Probes for the Efficient Labeling of Cellular Protein Arginine Deiminases (PADs).
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DOI：
10.1021/acschembio.7b00957
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发表时间：
2018-03-16
影响因子：
4
通讯作者：
Thompson PR
中科院分区：
文献类型：
--
作者：
Nemmara VV;Subramanian V;Muth A;Mondal S;Salinger AJ;Maurais AJ;Tilvawala R;Weerapana E;Thompson PR
瓜氨酸是肽基精氨酸翻译后水解形成肽基瓜氨酸，这是一种由蛋白质精氨酸脱亚胺酶（PAD）（钙调节酶家族）催化的反应。异常增加的瓜氨酸蛋白与一系列自身免疫性疾病有关（例如，类风湿性关节炎（RA）、多发性硬化症、狼疮和溃疡性结肠炎）和某些癌症。鉴于PAD活性增加与人类疾病之间的明确联系，PAD是治疗相关的靶标。在此，我们报告了下一代细胞可渗透和“点击”探针（BB-Cl-Yne和BB-F-Yne）的开发，用于在体外和基于细胞的系统中共价标记PAD。使用先进的化学蛋白质组学技术，我们还报告了BB-Cl-Yne和BB-F-Yne的脱靶。探针对PAD具有高度特异性，脱靶相对较少，特别是BB-F-Yne，表明氟乙脒弹头在下一代不可逆PAD抑制剂中的优先使用。值得注意的是，这些化合物可以以多种方式使用，包括鉴定母体化合物的脱靶和在靶标接合测定中作为ABPP以证明PAD抑制剂的功效。
Citrullination is the post-translational hydrolysis of peptidyl-arginines to form peptidyl-citrulline, a reaction that is catalyzed by the protein arginine deiminases (PADs), a family of calcium-regulated enzymes. Aberrantly increased protein citrullination is associated with a slew of autoimmune diseases (e.g., rheumatoid arthritis (RA), multiple sclerosis, lupus, and ulcerative colitis) and certain cancers. Given the clear link between increased PAD activity and human disease, the PADs are therapeutically relevant targets. Herein, we report the development of next generation cell permeable and “Clickable” probes (BB-Cl-Yne and BB-F-Yne) for covalent labeling of the PADs both in vitro and in cell-based systems. Using advanced chemoproteomic technologies, we also report the off targets of both BB-Cl-Yne and BB-F-Yne. The probes are highly specific for the PADs, with relatively few off targets, especially BB-F-Yne, suggesting the preferential use of the fluoroacetamidine warhead in next generation irreversible PAD inhibitors. Notably, these compounds can be used in a variety of modalities, including the identification of off-targets of the parent compounds and as ABPPs in target engagement assays to demonstrate the efficacy of PAD inhibitors.
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DOI：
10.1084/jem.20100239
发表时间：
2010-08-30
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Li P;Li M;Lindberg MR;Kennett MJ;Xiong N;Wang Y
通讯作者：
Wang Y
影响因子：
13.6
作者：
Ghari F;Quirke AM;Munro S;Kawalkowska J;Picaud S;McGouran J;Subramanian V;Muth A;Williams R;Kessler B;Thompson PR;Fillipakopoulos P;Knapp S;Venables PJ;La Thangue NB
通讯作者：
La Thangue NB
影响因子：
4.6
作者：
Burska AN;Hunt L;Boissinot M;Strollo R;Ryan BJ;Vital E;Nissim A;Winyard PG;Emery P;Ponchel F
通讯作者：
Ponchel F
影响因子：
2.9
作者：
Bicker, Kevin L.;Thompson, Paul R.
通讯作者：
Thompson, Paul R.
影响因子：
27.4
作者：
Knight JS;Subramanian V;O'Dell AA;Yalavarthi S;Zhao W;Smith CK;Hodgin JB;Thompson PR;Kaplan MJ
通讯作者：
Kaplan MJ