Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides that Restore Trafficking and Activity of ΔF508-CFTR - PubMed (original) (raw)

Potential Agents for Treating Cystic Fibrosis: Cyclic Tetrapeptides that Restore Trafficking and Activity of ΔF508-CFTR

Darren M Hutt et al. ACS Med Chem Lett. 2011.

Abstract

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 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 4-9. Although 15 had less potent IC(50) 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.

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Figures

Chart 1

Chart 1. Cyclic Tetrapeptides and Pseudotetrapeptides

Figure 1

Figure 1

Cyclic tetrapeptides restore cell surface CFTR activity to ΔF508-CFTR. (a) Yellow fluorescent protein (YFP)-quenching curves for CFBE41o-YFP cells alone (black open circles) or treated for 24 h with DMSO (taupe stars), 1 μM 15 (red crosses), or 1 μM vorinostat (2; blue open squares) after stimulation with forskolin and genistein. (b) YFP-quenching curves for CFBE41o-(YFP) cells treated for 24 h with 15 and stimulated with forskolin and genistein in the presence (pink crosses) or absence (red crosses) of CFInh172. Control: DMSO in the absence (blue squares) or presence (light blue squares) of CFInh172. Abbreviations: RFU, relative fluorescence units; A.U., arbitrary units.

Figure 2

Figure 2

Cyclic tetrapeptides restore trafficking to ΔF508-CFTR. Western blot analysis of CFTR glycoforms following treatment with the indicated compounds.

Figure 3

Figure 3

Iodide ion flux data for 11 (blue open squares) and 12 (red open triangles), which differ only in the Zn2+-binding ketone (11) or hydroxamic acid (12) moiety, at 1 μM; results for 0.1% DMSO control (taupe stars) and absence of treatment (black open circles). Abbreviations: See Figure 1.

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