Tjin Caroline Chandra, Wissner Rebecca F, Jamali Haya, Schepartz Alanna, Ellman Jonathan A
Department of Chemistry and Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, Connecticut 06520, United States.
ACS Med Chem Lett. 2018 Sep 14;9(10):1013-1018. doi: 10.1021/acsmedchemlett.8b00283. eCollection 2018 Oct 11.
Protein arginine deiminase 4 (PAD4) is a calcium-dependent enzyme that catalyzes the conversion of arginine to citrulline within target proteins. Dysregulation of PAD4 has been implicated in a number of human diseases, including rheumatoid arthritis and other inflammatory diseases as well as cancer. In this study, we report on the design, synthesis, and evaluation of a new class of haloacetamidine-based compounds as potential PAD4 inhibitors. Specifically, we describe the identification of 4,5,6-trichloroindazole as a highly potent PAD4 inhibitor that displays >10-fold selectivity for PAD4 over PAD3 and >50-fold over PAD1 and PAD2. The efficacy of this compound in cells was determined by measuring the inhibition of PAD4-mediated H4 citrullination in HL-60 granulocytes.
蛋白精氨酸脱亚氨酶4（PAD4）是一种钙依赖性酶，可催化靶蛋白中精氨酸向瓜氨酸的转化。PAD4的失调与多种人类疾病有关，包括类风湿性关节炎和其他炎症性疾病以及癌症。在本研究中，我们报告了一类新型基于卤代脒的化合物作为潜在PAD4抑制剂的设计、合成和评估。具体而言，我们描述了4,5,6-三氯吲唑作为一种高效PAD4抑制剂的鉴定，该抑制剂对PAD4的选择性比对PAD3高10倍以上，对PAD1和PAD2高50倍以上。通过测量HL-60粒细胞中PAD4介导的H4瓜氨酸化抑制作用来确定该化合物在细胞中的功效。
