Structure-guided combination therapy to potently improve the function of mutant CFTRs.
Structure-guided combination therapy to potently improve the function of mutant CFTRs.
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DOI：
10.1038/s41591-018-0200-x
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发表时间：
2018-11
期刊：
影响因子：
82.9
通讯作者：
Lukacs GL
中科院分区：
文献类型：
--
作者：
Veit G;Xu H;Dreano E;Avramescu RG;Bagdany M;Beitel LK;Roldan A;Hancock MA;Lay C;Li W;Morin K;Gao S;Mak PA;Ainscow E;Orth AP;McNamara P;Edelman A;Frenkiel S;Matouk E;Sermet-Gaudelus I;Barnes WG;Lukacs GL
现有的药物不能有效地挽救体外折叠缺陷和改善囊性纤维化（CF）的临床表型，所述囊性纤维化是由F508缺失（ΔF508或F508 del）和CF跨膜传导调节因子（CFTR）（质膜（PM）阴离子通道）中的一些点突变引起的。为了克服校正剂功效上限，在这里，我们表明靶向CFTR的不同结构缺陷的化合物可以协同地拯救突变体在PM的表达和功能。基于细胞的高通量筛选和机制分析鉴定了三个小分子系列，其靶向核苷酸结合结构域（NBD 1）、NBD 2及其跨膜结构域（MSD）界面处的缺陷。虽然这些化合物单独地略微改善ΔF508-CFTR折叠效率、功能和稳定性，但它们的组合导致永生化和原代人气道上皮和小鼠鼻上皮中约50-100%的野生型水平校正。同样地，校正剂组合对各种CFTR结构域中的罕见错义突变有效，可能通过结构变构起作用，表明其广泛应用的机制框架。
Available drugs are unable to effectively rescue the folding defects in vitro and ameliorate the clinical-phenotype of cystic fibrosis (CF), caused by deletion of F508 (ΔF508 or F508del) and some point mutations in the CF transmembrane conductance regulator (CFTR), a plasma membrane (PM) anion channel. To overcome the corrector efficacy ceiling, here we show that compounds targeting distinct structural defects of CFTR can synergistically rescue mutants expression and function at the PM. High throughput cell-based screens and mechanistic analysis identified three small-molecule series that target defects at the nucleotide binding domain (NBD1), NBD2 and their membrane spanning domains (MSDs) interfaces. While individually these compounds marginally improve ΔF508-CFTR folding efficiency, function, and stability, their combinations lead to ~50–100% of wild type-level correction in immortalized and primary human airway epithelia, and in mouse nasal epithelia. Likewise, corrector combinations were effective for rare missense mutations in various CFTR domains, probably acting via structural allostery, suggesting a mechanistic framework for their broad application.
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伴侣在单分子和细胞中拯救了突变CFTR的能量景观。
影响因子：
16.6
作者：
Bagdany M;Veit G;Fukuda R;Avramescu RG;Okiyoneda T;Baaklini I;Singh J;Sovak G;Xu H;Apaja PM;Sattin S;Beitel LK;Roldan A;Colombo G;Balch W;Young JC;Lukacs GL
通讯作者：
Lukacs GL
影响因子：
5.6
作者：
Cui, Liying;Aleksandrov, Luba;Riordan, John R.
通讯作者：
Riordan, John R.
影响因子：
3.3
作者：
Apaja PM;Foo B;Okiyoneda T;Valinsky WC;Barriere H;Atanasiu R;Ficker E;Lukacs GL;Shrier A
通讯作者：
Shrier A
影响因子：
3.5
作者：
Aleksandrov, AA;Riordan, JR
通讯作者：
Riordan, JR
影响因子：
14.8
作者：
Calamini, Barbara;Silva, Maria Catarina;Madoux, Franck;Hutt, Darren M.;Khanna, Shilpi;Chalfant, Monica A.;Saldanha, S. Adrian;Hodder, Peter;Tait, Bradley D.;Garza, Dan;Balch, William E.;Morimoto, Richard I.
通讯作者：
Morimoto, Richard I.