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高等学校化学研究 ›› 2004, Vol. 20 ›› Issue (6): 743-746.

• Articles • 上一篇    下一篇

A Class of High-affinity Bicyclooctane G551D-CFTR Activators Identified by High Throughput Screening

HE Cheng-yan1, ZHAO Lu3, LIU Yan-li2, XU Li-na2, SHANG De-jing4, YANG Hong4   

  1. 1. China-Japan Union Hospital, Jilin University, Changchun 130033, P. R. China;
    2. Membrane Channel Research Laboratory, Northeast Normal University, Changchun 130024, P. R. China;
    3. College of Traditional Chinese Medicine Material, Jilin Agricultural University, Changchun 130118, P. R. China;
    4. Faculty of Life Sciences, Liaoning Normal University, Dalian 116029, P. R. China
  • 收稿日期:2004-05-05 出版日期:2004-12-24 发布日期:2011-08-06
  • 基金资助:

    Supported by the Start-up Fund for Returned Overseas Scholars from Northeast Normal University, National Science Fund for Distinguished Young Scholars(No.30325011), Distinguished Young Scholars Fund of Jilin Province(No.20030112), Excellent Young Teachers Program of MOE, P. China and the National Science Foundation of Jilin Proving (No.20010548 and 20030708).

A Class of High-affinity Bicyclooctane G551D-CFTR Activators Identified by High Throughput Screening

HE Cheng-yan1, ZHAO Lu3, LIU Yan-li2, XU Li-na2, SHANG De-jing4, YANG Hong4   

  1. 1. China-Japan Union Hospital, Jilin University, Changchun 130033, P. R. China;
    2. Membrane Channel Research Laboratory, Northeast Normal University, Changchun 130024, P. R. China;
    3. College of Traditional Chinese Medicine Material, Jilin Agricultural University, Changchun 130118, P. R. China;
    4. Faculty of Life Sciences, Liaoning Normal University, Dalian 116029, P. R. China
  • Received:2004-05-05 Online:2004-12-24 Published:2011-08-06
  • Supported by:

    Supported by the Start-up Fund for Returned Overseas Scholars from Northeast Normal University, National Science Fund for Distinguished Young Scholars(No.30325011), Distinguished Young Scholars Fund of Jilin Province(No.20030112), Excellent Young Teachers Program of MOE, P. China and the National Science Foundation of Jilin Proving (No.20010548 and 20030708).

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被引次数

5

摘要： The glycine-to-aspartic acid missense mutation at the codon 551(G551D) of the cystic fibrosis transmembrane conductance regulator(CFTR) is one of the five most frequent cystic fibrosis(CF) mutations associated with a severe CF phenotype. To explore the feasibility of pharmacological correction of disrupted activation of CFTR chloride channel caused by G551D mutation, we developed a halide-sensitive fluorescence miniassay for G551D-CFTR in Fisher rat thyroid(FRT) epithelial cells for the discovery of novel activators of G551D-CFTR. A class of bicyclooctane small molecule compounds that efficiently stimulate G551D-CFTR chloride channel activity was identified by high throughput screening via the FRT cell-based assay. This class of compounds selectively activates G551D-CFTR with a high affinity, whereas little effect of the compounds on wildtype CFTR can be seen. The discovery of a class of bicyclooctane G551D-CFTR activators will permit the analysis of structure-activity relationship of the compounds to identify ideal leads for in vivo therapeutic studies.

关键词: Cystic fibrosis, G551D-CFTR, Activators, Cell-based assay, Small molecule, High throughput screening

Abstract: The glycine-to-aspartic acid missense mutation at the codon 551(G551D) of the cystic fibrosis transmembrane conductance regulator(CFTR) is one of the five most frequent cystic fibrosis(CF) mutations associated with a severe CF phenotype. To explore the feasibility of pharmacological correction of disrupted activation of CFTR chloride channel caused by G551D mutation, we developed a halide-sensitive fluorescence miniassay for G551D-CFTR in Fisher rat thyroid(FRT) epithelial cells for the discovery of novel activators of G551D-CFTR. A class of bicyclooctane small molecule compounds that efficiently stimulate G551D-CFTR chloride channel activity was identified by high throughput screening via the FRT cell-based assay. This class of compounds selectively activates G551D-CFTR with a high affinity, whereas little effect of the compounds on wildtype CFTR can be seen. The discovery of a class of bicyclooctane G551D-CFTR activators will permit the analysis of structure-activity relationship of the compounds to identify ideal leads for in vivo therapeutic studies.

Key words: Cystic fibrosis, G551D-CFTR, Activators, Cell-based assay, Small molecule, High throughput screening