Parodi Alice, Righetti Giada, Pesce Emanuela, Salis Annalisa, Tomati Valeria, Pastorino Cristina, Tasso Bruno, Benvenuti Mirko, Damonte Gianluca, Pedemonte Nicoletta, Cichero Elena, Millo Enrico
Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV, 1, 16132 Genoa, Italy.
Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
Pharmaceuticals (Basel). 2022 Feb 23;15(3):274. doi: 10.3390/ph15030274.
Cystic fibrosis (CF) is a genetic disease affecting the lungs and pancreas and causing progressive damage. CF is caused by mutations abolishing the function of CFTR, a protein whose role is chloride's mobilization in the epithelial cells of various organs. Recently a therapy focused on small molecules has been chosen as a main approach to contrast CF, designing and synthesizing compounds acting as misfolding (correctors) or defective channel gating (potentiators). Multi-drug therapies have been tested with different combinations of the two series of compounds. Previously, we designed and characterized two series of correctors, namely, hybrids, which were conceived including the aminoarylthiazole (AAT) core, merged with the benzodioxole carboxamide moiety featured by VX-809. In this paper, we herein proceeded with molecular modeling studies guiding the design of a new third series of hybrids, featuring structural variations at the thiazole moiety and modifications on position 4. These derivatives were tested in different assays including a YFP functional assay on models F508del-CFTR CFBE41o-cells, alone and in combination with VX-445, and by using electrophysiological techniques on human primary bronchial epithelia to demonstrate their F508del-CFTR corrector ability. This study is aimed (i) at identifying three molecules ( and ), useful as novel CFTR correctors with a good efficacy in rescuing the defect of F508del-CFTR; and (ii) at providing useful information to complete the structure-activity study within all the three series of hybrids as possible CFTR correctors, supporting the development of pharmacophore modelling studies, taking into account all the three series of hybrids. Finally, in silico evaluation of the hybrids pharmacokinetic (PK) properties contributed to highlight hybrid developability as drug-like correctors.
囊性纤维化（CF）是一种影响肺部和胰腺并导致进行性损害的遗传性疾病。CF 由使 CFTR 功能丧失的突变引起，CFTR 是一种蛋白质，其作用是在各个器官的上皮细胞中转运氯离子。最近，一种专注于小分子的疗法已被选为对抗 CF 的主要方法，即设计和合成可作为错误折叠（校正剂）或缺陷通道门控（增强剂）的化合物。已经对这两类化合物的不同组合进行了多药疗法测试。此前，我们设计并表征了两类校正剂，即杂合物，其设计思路是包含氨基芳基噻唑（AAT）核心，并与 VX - 809 具有的苯并二恶唑甲酰胺部分融合。在本文中，我们进行了分子建模研究，以指导设计新的第三类杂合物，其噻唑部分具有结构变化且 4 位有修饰。这些衍生物在不同实验中进行了测试，包括在 F508del - CFTR CFBE41o - 细胞模型上单独以及与 VX - 445 联合进行的 YFP 功能实验，还通过在人原代支气管上皮细胞上使用电生理技术来证明它们对 F508del - CFTR 的校正能力。本研究旨在：（i）鉴定三种分子（ 和 ），作为新型 CFTR 校正剂，在挽救 F508del - CFTR 缺陷方面具有良好疗效；（ii）提供有用信息，以完成所有三类杂合物作为可能的 CFTR校正剂的构效关系研究，支持药效团建模研究的开展，同时考虑所有三类杂合物。最后，对杂合物药代动力学（PK）性质的计算机模拟评估有助于突出杂合物作为类药物校正剂的可开发性。
