Compositions and methods for inhibiting the interaction between CFTR and CAL
The present invention features compositions and methods for increasing the cell surface expression of degradation-prone CFTR proteins and preventing or treating cystic fibrosis. The invention provides peptides and peptidomimetics that selectively inhibit the interaction between CAL and mutant CFTR proteins, thereby stabilizing the CFTR and facilitating transport of the same to the cell surface.
1. A method for increasing cell surface expression of a degradation-prone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein comprising contacting a cell expressing a degradation-prone CFTR with an effective amount of a peptide comprising the amino acid sequence of (M/F/L/A/W)-(Q/P/F)-(S/T)-(S/T)-(K/I)-I (SEQ ID NO:1) or SEQ ID NO:24, or a derivative or peptidomimetic thereof, that selectively inhibits the interaction between the degradation-prone CFTR and CFTR-Associated Ligand thereby increasing cell surface expression of the degradation-prone CFTR protein as compared to cell surface expression in the absence of the agent.
2. The method of claim 1 , wherein the degradation-prone CFTR is ΔF508 CFTR or R1066C CFTR.
3. The method of claim 1 , wherein the peptide, derivative or peptidomimetic is 6 to 20 residues in length.
4. The method of claim 1 , wherein the peptide is derivatized with a label, one or more post-translational modifications, and/or a cell-penetrating sequence.
5. The method of claim 1 , wherein the peptidomimetic comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, or SEQ ID NO:33.
6. A method for treating cystic fibrosis comprising administering to a subject in need of treatment an effective amount of a peptide comprising the amino acid sequence of (M/F/L/A/W)-(Q/P/F)-(S/T)-(S/T)-(K/I)-I (SEQ ID NO:1) or SEQ ID NO:24, or a derivative or peptidomimetic thereof, that selectively inhibits the interaction between a degradation-prone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and CFTR-Associated Ligand thereby treating the subject's cystic fibrosis.
7. The method of claim 6 , wherein the degradation-prone CFTR is ΔF508 CFTR or R1066C CFTR.
8. The method of claim 6 , wherein the peptide, derivative or peptidomimetic is 6 to 20 residues in length.
9. The method of claim 6 , wherein the peptide is derivatized with a label, one or more post-translational modifications, and/or a cell-penetrating sequence.
10. The method of claim 6 , wherein the peptidomimetic comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, or SEQ ID NO:33.
11. A purified peptide comprising the amino acid sequence of SEQ ID NO:24.
12. A peptidomimetic comprising the amino acid sequence of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, or SEQ ID NO:33.
13. A pharmaceutical composition comprising the peptide of claim 11 in admixture with a pharmaceutically acceptable carrier.
14. A pharmaceutical composition comprising the peptidomimetic of claim 12 in admixture with a pharmaceutically acceptable carrier.