RT Journal Article
SR Electronic
T1 Latonduine analogues restore F508del-CFTR trafficking through modulation of PARP-3 and PARP-16 activity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.115.102418
DO 10.1124/mol.115.102418
A1 Graeme W Carlile
A1 Renaud Robert
A1 Elizabeth Matthes
A1 Qi Yang
A1 Roberto Solari
A1 Richard Hatley
A1 Colin M Edge
A1 John W Hanrahan
A1 David Y Thomas
A1 Raymond Andersen
A1 Veronique Birault
YR 2016
UL http://molpharm.aspetjournals.org/content/early/2016/05/18/mol.115.102418.abstract
AB ABSTRACT Cystic Fibrosis (CF) is a major lethal genetic disease caused by mutations in the CF transmembrane conductance regulator gene (CFTR). This encodes a chloride ion channel on the apical surface of epithelial cells. The most common mutation in CFTR (F508del-CFTR) generates a protein that is misfolded and retained in the endoplasmic reticulum. Identifying small molecules that correct this CFTR trafficking defect is a promising approach in CF therapy. To date however only modest efficacy has been reported for correctors in clinical trials. We identified the marine sponge metabolite latonduine, as a corrector. We have now developed a series of latonduine derivatives that are more potent F508del-CFTR correctors with one (McG315) having 10 fold increased corrector activity and an EC50 of 89nM. We show that the latonduine analogues inhibit poly-ADP ribose polymerase (PARP) isozymes 1, 3 and 16. Further our molecular modeling studies point to the latonduine analogues binding to the PARP nicotinamide-binding domain. We established the relationship between the ability of the latonduine analogues to inhibit PARP 16 and their ability to correct F508del-CFTR trafficking. We demonstrate that latonduine triggers correction by regulating the unfolded protein response (UPR) activator, inositol-requiring enzyme (IRE-1) activity via modulation of the level of its ribosylation by PARP-16. These results establish latonduines novel site of action as well as its proteostatic mechanism of action.