CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) is the target of mutations that cause cystic fibrosis (CF). The most common mutant CFTR allele in the Caucasian population is the deletion of phenylalanine at position 508 (ΔF508-CFTR). The ΔF508-CFTR mutation results in a CFTR protein capable of conducting chloride, but absent from the plasma membrane because of aberrant intracellular processing. While chemical chaperones have been developed to restore the folding of ΔF508-CFTR, CAL (also known as CFTR-associated ligand, PIST, GOPC, ROS, and FIG) directs the lysosomal degradation of CFTR in a dose-dependent fashion and reduces the amount of CFTR found at the cell surface.
Dartmouth researchers have now identified novel inhibitors that block the interaction or binding of CFTR and CAL by competitive displacement. By inhibiting this interaction with CAL, degradation-prone CFTR proteins are stabilized and the amount of CFTR protein at the cell surface is effectively increased. Indeed, representative peptide and peptidomimetic CAL inhibitors have been shown to increase the apical cell-surface expression and transepithelial chloride efflux of the most common CFTR mutation associated with CF. Accordingly, these inhibitors find application in increasing the cell surface expression of degradation-prone CFTR proteins and in the treatment for CF.
This technology is claimed in a pending patent application. We are seeking an industrial partner interested in its commercialization. (J467)
Last Updated: 7/24/12