Potential Agents for Treating Cystic Fibrosis: Cyclic TetrapeptidesThat Restore Trafficking and Activity of del-F508-CFTR

Darren M. Hutt, Christian Adam Olsen, Chris J. Vickers, David Herman, Monica A. Chalfant, Ana Montero, Luke J. Leman, Renner Burkle, Bruce E. Maryanoff, William E. Balch, M. Reza Ghadiri

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Cystic fibrosis (CF) is a loss-of-function disease caused by mutations in the CF transmembrane conductance regulator (CFTR) protein, a chloride ion channel that localizes to the apical plasma membrane of epithelial cells. The most common form of the disease results from the deletion of phenylalanine-508 (ΔF508), leading to the accumulation of CFTR in the endoplasmic reticulum with a concomitant loss of chloride flux. We discovered that cyclic tetrapeptides, such as 11, 14, and 15, are able to correct the trafficking defect and restore the cell surface activity of ΔF508-CFTR. Although this class of cyclic tetrapeptides is known to contain inhibitors of certain histone deacetylase (HDAC) isoforms, their HDAC inhibitory potencies did not directly correlate with their ability to rescue ΔF508-CFTR. In full HDAC profiling, 15 strongly inhibited HDACs 1, 2, 3, 10, and 11 but not HDACs 49. Although 15 had less potent IC50 values than reference agent vorinostat (2) in HDAC profiling, it was markedly more potent than 2 in rescuing ΔF508-CFTR. We suggest that specific HDACs can have a differential influence on correcting ΔF508-CFTR, which may reflect both deacetylase and protein scaffolding actions.
Keyword: HDAC inhibition,Cyclic peptides,CFTR,Cystic fibrosis
Original languageEnglish
JournalA C S Medicinal Chemistry Letters
Issue number2
Pages (from-to)703-707
Publication statusPublished - 2011
Externally publishedYes

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© American Chemical Society

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