Correction of F508del-CFTR trafficking by the sponge alkaloid latonduine is modulated by interaction with PARP

Graeme W. Carlile*, Robert A. Keyzers, Katrina A. Teske, Renaud Robert, David E. Williams, Roger G. Linington, Christopher A. Gray, Ryan M. Centko, Luping Yan, Suzana M. Anjos, Heidi M. Sampson, Donglei Zhang, Jie Liao, John W. Hanrahan, Raymond J. Andersen, David Y. Thomas

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause CF. The most common mutation, F508 deletion, causes CFTR misfolding and endoplasmic reticulum retention, preventing it from trafficking to the cell surface. One approach to CF treatment is to identify compounds that correct the trafficking defect. We screened a marine extract collection and, after extract, deconvolution identified the latonduines as F508del-CFTR trafficking correctors that give functional correction in vivo. Using a biotinylated azido derivative of latonduine, we identified the poly(ADP-ribose) polymerase (PARP) family as latonduine target proteins. We show that latonduine binds to PARPs 1, 2, 3, 4, 5a, and 5b and inhibits PARP activity, especially PARP-3. Thus, latonduine corrects F508del-CFTR trafficking by modulating PARP activity. Latonduines represent pharmacologic agents for F508del-CFTR correction, and PARP-3 is a pathway for the development of CF treatments.

Original languageEnglish (US)
Pages (from-to)1288-1299
Number of pages12
JournalChemistry and Biology
Issue number10
StatePublished - Oct 26 2012

ASJC Scopus subject areas

  • Drug Discovery
  • Molecular Medicine
  • Molecular Biology
  • Biochemistry
  • Clinical Biochemistry
  • Pharmacology


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