Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides That Restore Trafficking and Activity of ΔF508-CFTR
Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides That Restore Trafficking and Activity of ΔF508-CFTR
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DOI：
10.1021/ml200136e
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发表时间：
2011-09-01
影响因子：
4.2
通讯作者：
Ghadiri, M. Reza
中科院分区：
文献类型：
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作者：
Hutt, Darren M.;Olsen, Christian A.;Ghadiri, M. Reza
囊性纤维化（CF）是一种功能丧失性疾病，由CF跨膜传导调节因子（CFTR）蛋白突变引起，CFTR是一种定位于上皮细胞顶端质膜的氯离子通道。该疾病的最常见形式由苯丙氨酸-508（Delta F508）的缺失引起，导致CFTR在内质网中的积累，伴随着氯通量的损失。我们发现环状四肽，如11、14和15，能够纠正运输缺陷并恢复Delta F508-CFTR的细胞表面活性。尽管已知这类环状四肽含有某些组蛋白脱乙酰酶（HDAC）同种型的抑制剂，但它们的HDAC抑制效力与它们拯救Delta F508-CFTR的能力不直接相关。在完整的HDAC分析中，15强烈抑制HDAC 1、2、3、10和11，但不抑制HDAC 4-9。尽管15在HDAC谱中具有比参考试剂伏立诺他（2）更低的有效IC 50值，但其在拯救Delta F508-CFTR方面明显比2更有效。我们表明特异性HDAC可以对校正Delta F508-CFTR具有不同的影响，这可以反映脱乙酰酶和蛋白质支架作用。
Cystic fibrosis (CF) is a loss-of-function disease caused by mutations in the CF transmembrane conductance regulator (CFTR) protein, a chloride ion channel that localizes to the apical plasma membrane of epithelial cells. The most common form of the disease results from the deletion of phenylalanine-508 (Delta F508), leading to the accumulation of CFTR in the endoplasmic reticulum with a concomitant loss of chloride flux. We discovered that cyclic tetrapeptides, such as 11, 14, and 15, are able to correct the trafficking defect and restore the cell surface activity of Delta F508-CFTR. Although this class of cyclic tetrapeptides is known to contain inhibitors of certain histone deacetylase (HDAC) isoforms, their HDAC inhibitory potencies did not directly correlate with their ability to rescue Delta F508-CFTR. In full HDAC profiling, 15 strongly inhibited HDACs 1, 2, 3, 10, and 11 but not HDACs 4-9. Although 15 had less potent IC50 values than reference agent vorinostat (2) in HDAC profiling, it was markedly more potent than 2 in rescuing Delta F508-CFTR We suggest that specific HDACs can have a differential influence on correcting Delta F508-CFTR, which may reflect both deacetylase and protein scaffolding actions.