Cyclic Peptidyl Inhibitors against CAL/CFTR Interaction for Treatment of Cystic Fibrosis.
Cyclic Peptidyl Inhibitors against CAL/CFTR Interaction for Treatment of Cystic Fibrosis.
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用于治疗囊性纤维化的针对CAL/CFTR相互作用的环肽基抑制剂。
DOI：
10.1021/acs.jmedchem.0c01528
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发表时间：
2020-12-24
影响因子：
7.3
通讯作者：
Pei D
中科院分区：
文献类型：
--
作者：
Dougherty PG;Wellmerling JH;Koley A;Lukowski JK;Hummon AB;Cormet-Boyaka E;Pei D
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, encoding for a chloride ion channel. Membrane expression of CFTR is negatively regulated by CFTR-associated ligand (CAL). We previously showed that inhibition of the CFTR/CAL interaction with a cell-permeable peptide improves function of rescued F508del-CFTR. In this study, optimization of the peptidyl inhibitor yielded PGD97, which exhibits a KD value of 6 nM for the CAL PDZ domain, ≥ 130-fold selectivity over closely related PDZ domains, and a serum t1/2 of >24 h. In patient-derived F508del homozygous cells, PGD97 (100 nM) increased short-circuit currents by ~3-fold and further potentiated the therapeutic effects of small-molecule correctors (e.g., VX-661) by ~2-fold (with an EC50 of ~10 nM). Our results suggest that PGD97 may be used as a novel treatment for CF, either as a single agent or in combination with small-molecule correctors/potentiators.
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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：
16.6
作者：
Qian, Ziqing;Xu, Xiaohua;Amacher, Jeanine F.;Madden, Dean R.;Cormet-Boyaka, Estelle;Pei, Dehua
通讯作者：
Pei, Dehua
影响因子：
3.7
作者：
Amacher, Jeanine F.;Zhao, Ruizhi;Madden, Dean R.
通讯作者：
Madden, Dean R.
影响因子：
16.6
作者：
Cushing, Patrick R.;Vouilleme, Lars;Madden, Dean R.
通讯作者：
Madden, Dean R.
影响因子：
5.7
作者：
Amacher, Jeanine F.;Cushing, Patrick R.;Madden, Dean R.
通讯作者：
Madden, Dean R.