ABCMdb

PMID: 21299497

Zhang W, Penmatsa H, Ren A, Punchihewa C, Lemoff A, Yan B, Fujii N, Naren AP
Functional regulation of cystic fibrosis transmembrane conductance regulator-containing macromolecular complexes: a small-molecule inhibitor approach.
Biochem J. 2011 Apr 15;435(2):451-62., 2011-04-15 [PubMed]

Sentences

No. Mutations Sentence Comment

185 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His The data also imply that: (i) targeting PDZ domain-based protein-protein interactions within the CFTR-NHERF2-LPA2-containing macromolecular complexes can locally regulate CFTR Cl-channel function, which might provide potential therapeutic targets for treating CFTR-related diseases; and (ii) compound CO-068 could be a seed compound for developing improved leads to augment CFTR function in CF patients who have CFTR mutants with impaired channel function, such as G551D or R117H. Login to comment 208 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp In summary, compound CO-068 increases both basal and FSK-induced CFTR-dependent submucosal glands fluid secretion in pig, a finding that could be potentially useful to restore the impaired mucociliary clearance process in diseased airways due to a dysfunctional CFTR Cl-channel such as the G551D-CFTR mutant. Login to comment 235 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His To further study the regulatory roles of PDZ domain-based protein-protein interactions within the macromolecular complexes on regulating CFTR Cl-channel function, and to explore the potential therapeutic value of using such an approach to treat diseases associated with dysfunctional CFTR protein (e.g. G551D-CFTR and R117H-CFTR), we screened a specially designed chemical library and identified a compound (compound CO-068) that preferentially disrupts the LPA2-NHERF2 interaction. Login to comment 255 ABCC7 p.Gly551Asp ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Arg117His Moreover, the present study suggests that by targeting different PDZ domain-based protein-protein interactions within the macromolecular complexes, we can modulate CFTR channel function on a use-dependent mode for treating different diseases, that is, targeting the LPA2-NHERF2 interaction to potentiate CFTR Cl-channel function for drug development to treat CF (especially those due to the presence of G551D- or R117H-CFTR); and targeting the CFTR-NHERF2 interaction to down-regulate CFTR Cl-channel function for drug development to treat CFTR-mediated secretory diarrhoea. Login to comment