Pesce Emanuela, Bellotti Marta, Liessi Nara, Guariento Sara, Damonte Gianluca, Cichero Elena, Galatini Andrea, Salis Annalisa, Gianotti Ambra, Pedemonte Nicoletta, Zegarra-Moran Olga, Fossa Paola, Galietta Luis J V, Millo Enrico
Istituto Giannina Gaslini, via Gerolamo Gaslini 5, 16147 Genoa, Italy.
Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV 5, 16132 Genoa, Italy.
Eur J Med Chem. 2015 Jun 24;99:14-35. doi: 10.1016/j.ejmech.2015.05.030. Epub 2015 May 28.
The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel present in the membrane of epithelial cells. Mutations affecting the CFTR gene cause cystic fibrosis (CF), a multi-organ severe disease. The most common CF mutation, F508del, impairs the processing and activity (gating) of CFTR protein. Other mutations, like G551D, only cause a gating defect. Processing and gating defects can be targeted by small molecules called generically correctors and potentiators, respectively. Aminoarylthiazoles (AATs) represent an interesting class of compounds that includes molecules with dual activity, as correctors and potentiators. With the aim to improve the activity profile of AATs, we have now designed and synthesized a library of novel compounds in order to establish an initial SAR that may provide indications about the chemical groups that are beneficial or detrimental for rescue activity. The new compounds were tested as correctors and potentiators in CFBE41o-expressing F508del-CFTR using a functional assay. A dual active compound, AAT-4a, characterized by improved efficacy and marked synergy when combined with the corrector VX-809 has been identified. Moreover, by computational methods, a possible binding site for AATs in nucleotide binding domain NBD1 has been detected. These results will direct the synthesis of new analogues with possibly improved activity.
囊性纤维化跨膜传导调节因子（CFTR）是一种存在于上皮细胞膜中的氯离子通道。影响CFTR基因的突变会导致囊性纤维化（CF），这是一种多器官严重疾病。最常见的CF突变F508del会损害CFTR蛋白的加工和活性（门控）。其他突变，如G551D，仅导致门控缺陷。加工缺陷和门控缺陷可分别由一类称为校正剂和增强剂的小分子靶向。氨基芳基噻唑（AATs）是一类有趣的化合物，包括具有双重活性的分子，即校正剂和增强剂。为了改善AATs的活性谱，我们现在设计并合成了一个新型化合物库，以建立初步的构效关系，这可能为对挽救活性有益或有害的化学基团提供线索。使用功能测定法在表达F508del-CFTR的CFBE41o细胞中测试新化合物作为校正剂和增强剂的活性。已鉴定出一种双重活性化合物AAT-4a，其与校正剂VX-809联合使用时具有更高的疗效和显著的协同作用。此外，通过计算方法，在核苷酸结合结构域NBD1中检测到AATs可能的结合位点。这些结果将指导合成可能具有更高活性的新类似物。
