Design and synthesis of a hybrid potentiator-corrector agonist of the cystic fibrosis mutant protein ΔF508-CFTR

被引:23
|
作者
Mills, Aaron D. [1 ,2 ,3 ,4 ]
Yoo, Choong [1 ]
Butler, Jeffrey D. [1 ]
Yang, Baoxue [2 ,3 ]
Verkman, A. S. [2 ,3 ]
Kurth, Mark J. [1 ]
机构
[1] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA
[2] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94143 USA
[4] Univ Idaho, Dept Chem, Moscow, ID 83844 USA
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
Cystic fibrosis transmembrane conductance regulator protein (CFTR); Delta F508-CFTR; Potentiators; Correctors; Hybrids; Multi-ligand drug; TRANSMEMBRANE CONDUCTANCE REGULATOR; SMALL-MOLECULE CORRECTORS; CFTR;
D O I
10.1016/j.bmcl.2009.11.020
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A developing therapy of cystic. brosis caused by the Delta F508 mutation in CFTR employs correction of defective CFTR chloride channel gating by a 'potentiator' and of defective CFTR protein folding by a 'corrector'. Based on SAR data for phenylglycine-type potentiators and bithiazole correctors, we designed a hybrid molecule incorporating an enzymatic hydrolysable linker to deliver the potentiator (PG01) fragment 2 and the corrector (Corr-4a) fragment 13. The hybrid molecule 14 contained PG01-OH and Corr-4a-linker-CO2H moieties, linked with an ethylene glycol spacer through an ester bond. The potentiator 2 and corrector 13 fragments (after cleavage) had low micromolar potency for restoration of Delta F508-CFTR channel gating and cellular processing, respectively. Cleavage of hybrid molecule 14 by intestinal enzymes under physiological conditions produced the active potentiator 2 and corrector fragments 13, providing proof-of-concept for small-molecule potentiator-corrector hybrids as a single drug therapy for CF caused by the Delta F508 mutation. (C) 2009 Elsevier Ltd. All rights reserved.
引用
收藏
页码:87 / 91
页数:5
相关论文
共 26 条
  • [21] Design of Crotoxin-Based Peptides with Potentiator Activity Targeting the D-F508NBD1 Cystic Fibrosis Transmem- brane Conductance Regulator
    Ravatin, Marc
    Odolczyk, Norbert
    Servel, Nathalie
    Guijarro, J. Inaki
    Tagat, Eric
    Chevalier, Benoit
    Baatallah, Nesrine
    Corringer, Pierre-Jean
    Lukacs, Gergely L.
    Edelman, Aleksander
    Zielenkiewicz, Piotr
    Chambard, Jean -Marie
    Hinzpeter, Alexandre
    Faure, Grazyna
    JOURNAL OF MOLECULAR BIOLOGY, 2023, 435 (03)
  • [22] Pharmacological chaperone-rescued cystic fibrosis CFTR-F508del mutant overcomes PRAF2-gated access to endoplasmic reticulum exit sites
    Kusumika Saha
    Benoit Chevalier
    Stéphane Doly
    Nesrine Baatallah
    Thomas Guilbert
    Iwona Pranke
    Mark G. H. Scott
    Hervé Enslen
    Chiara Guerrera
    Cérina Chuon
    Aleksander Edelman
    Isabelle Sermet-Gaudelus
    Alexandre Hinzpeter
    Stefano Marullo
    Cellular and Molecular Life Sciences, 2022, 79
  • [23] The L467F-F508del Complex Allele Hampers Pharmacological Rescue of Mutant CFTR by Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients: The Value of the Ex Vivo Nasal Epithelial Model to Address Non-Responders to CFTR-Modulating Drugs
    Sondo, Elvira
    Cresta, Federico
    Pastorino, Cristina
    Tomati, Valeria
    Capurro, Valeria
    Pesce, Emanuela
    Lena, Mariateresa
    Iacomino, Michele
    Baffico, Ave Maria
    Coviello, Domenico
    Bandiera, Tiziano
    Zara, Federico
    Galietta, Luis J., V
    Bocciardi, Renata
    Castellani, Carlo
    Pedemonte, Nicoletta
    INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 2022, 23 (06)
  • [24] Innovative Strategy toward Mutant CFTR Rescue in Cystic Fibrosis: Design and Synthesis of Thiadiazole Inhibitors of the E3 Ligase RNF5
    Brusa, Irene
    Sondo, Elvira
    Pesce, Emanuela
    Tomati, Valeria
    Gioia, Dario
    Falchi, Federico
    Balboni, Beatrice
    Martinez, Jose Antonio Ortega
    Veronesi, Marina
    Romeo, Elisa
    Margaroli, Natasha
    Recanatini, Maurizio
    Girotto, Stefania
    Pedemonte, Nicoletta
    Roberti, Marinella
    Cavalli, Andrea
    JOURNAL OF MEDICINAL CHEMISTRY, 2023, 66 (14) : 9797 - 9822
  • [25] Activation of 3-Phosphoinositide-dependent Kinase 1 (PDK1) and Serum-and Glucocorticoid-induced Protein Kinase 1 (SGK1) by Short-chain Sphingolipid C4-ceramide Rescues the Trafficking Defect of ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator (ΔF508-CFTR)
    Caohuy, Hung
    Yang, Qingfeng
    Eudy, Yvonne
    Ha, Thien-An
    Xu, Andrew E.
    Glover, Matthew
    Frizzell, Raymond A.
    Jozwik, Catherine
    Pollard, Harvey B.
    JOURNAL OF BIOLOGICAL CHEMISTRY, 2014, 289 (52) : 35953 - 35968
  • [26] Reduced expression of Tis7/IFRD1 protein in murine and human cystic fibrosis airway epithelial cell models homozygous for the F508del-CFTR mutation
    Blanchard, Elise
    Marie, Solenne
    Riffault, Laure
    Bonora, Monique
    Tabary, Olivier
    Clement, Annick
    Jacquot, Jacky
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2011, 411 (03) : 471 - 476