Lakka Achillia, Tsakalof Andreas
Faculty of Medicine, University of Thessaly, Biopolis, 41110 Larisa (Greece).
Laboratory of Chemistry, Faculty of Medicine, University of Thessaly, Biopolis, 41110 Larisa (Greece), Fax: (+30) 2410-685545.
Chempluschem. 2013 Aug;78(8):808-815. doi: 10.1002/cplu.201300101. Epub 2013 Jun 11.
A number of diseases, including cancer, diabetes, and inflammation, are linked to deregulation of cell signaling pathways controlled by protein kinases. Inhibition of the kinases involved can interrupt aberrant signaling and have a specific therapeutic effect. Protein kinases are recognized as validated therapeutic targets for the treatment of a number of diseases and there are considerable efforts to discover new kinase inhibitors suitable for drug development. The main goal of this study was to fabricate the synthetic imitations of the adenosine triphosphate (ATP) binding cleft in protein kinases and thus produce polymers suitable for screening and isolation of new protein kinase ATP-mimetic inhibitors from different sources. Such polymers were created by the imprinting of tri-O-acetyladenosine in acrylic polymer matrix with the use of methacrylic acid (MAA) or 3-vinylbenzoic acid (VBA) as a functional monomer and ethylene glycol dimethacrylate as a cross-linking agent. The imprints prepared with the use of VBA demonstrate substantially better binding efficiency than that with MAA and particularly high affinity to the initial template (K as low as 1.2 μM), sufficient concentration of binding sites N (up to 32 μmol g ), and pronounced specificity (imprinting factor up to 11). Under flow conditions, the fabricated polymers also demonstrate high capacity and template affinity. The produced imprints reproduce spatially noncovalent interactions present in the ATP binding site of protein kinases and can be anticipated as approximate synthetic imitations of the binding cleft.
包括癌症、糖尿病和炎症在内的许多疾病都与蛋白激酶所控制的细胞信号通路失调有关。抑制相关激酶可中断异常信号传导并产生特定的治疗效果。蛋白激酶被认为是治疗多种疾病的有效治疗靶点，人们正在付出巨大努力来发现适合药物开发的新型激酶抑制剂。本研究的主要目标是制造蛋白激酶中三磷酸腺苷（ATP）结合裂隙的合成模拟物，从而制备出适合从不同来源筛选和分离新型蛋白激酶ATP模拟抑制剂的聚合物。通过在丙烯酸聚合物基质中用甲基丙烯酸（MAA）或3-乙烯基苯甲酸（VBA）作为功能单体以及乙二醇二甲基丙烯酸酯作为交联剂对三-O-乙酰腺苷进行印迹来制备此类聚合物。用VBA制备的印迹显示出比用MAA制备的印迹更好的结合效率，对初始模板具有特别高的亲和力（K低至1.2 μM）、足够的结合位点浓度N（高达32 μmol g）以及显著的特异性（印迹因子高达11）。在流动条件下，所制备的聚合物也显示出高容量和模板亲和力。所产生的印迹再现了蛋白激酶ATP结合位点中存在的空间非共价相互作用，并且可以预期为结合裂隙的近似合成模拟物。
