Spicer Julie A, Miller Christian K, O'Connor Patrick D, Jose Jiney, Huttunen Kristiina M, Jaiswal Jagdish K, Denny William A, Akhlaghi Hedieh, Browne Kylie A, Trapani Joseph A
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand; Maurice Wilkins Centre for Molecular Biodiscovery, A New Zealand Centre for Research Excellence, Auckland, New Zealand.
Bioorg Med Chem Lett. 2017 Feb 15;27(4):1050-1054. doi: 10.1016/j.bmcl.2016.12.057. Epub 2016 Dec 23.
The pore-forming protein perforin is a key component of mammalian cell-mediated immunity and essential to the pathway that allows elimination of virus-infected and transformed cells. Perforin activity has also been implicated in certain auto-immune conditions and therapy-induced conditions such as allograft rejection and graft versus host disease. An inhibitor of perforin activity could be used as a highly specific immunosuppressive treatment for these conditions, with reduced side-effects compared to currently accepted therapies. Previously identified first-in-class inhibitors based on a 2-thioxoimidazolidin-4-one core show suboptimal physicochemical properties and toxicity toward the natural killer (NK) cells that secrete perforin in vivo. The current benzenesulphonamide-based series delivers a non-toxic bioisosteric replacement possessing improved solubility.
成孔蛋白穿孔素是哺乳动物细胞介导免疫的关键组成部分，对于消除病毒感染细胞和转化细胞的途径至关重要。穿孔素活性还与某些自身免疫性疾病以及治疗诱导的疾病有关，如同种异体移植排斥反应和移植物抗宿主病。穿孔素活性抑制剂可作为这些疾病的高度特异性免疫抑制治疗药物，与目前公认的疗法相比，副作用更小。先前鉴定的基于2-硫代咪唑烷-4-酮核心的一流抑制剂显示出不理想的物理化学性质以及对体内分泌穿孔素的自然杀伤（NK）细胞的毒性。当前基于苯磺酰胺的系列提供了一种无毒的生物电子等排体替代物，其溶解性有所改善。
