General trends in the effects of VX-661 and VX-445 on the plasma membrane expression of clinical CFTR variants

Cystic fibrosis (CF) is caused by mutations that compromise the expression and/or function of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel. Most people with CF harbor a common misfolded variant (ΔF508) that can be partially rescued by therapeutic “correctors” that restore its expression. Nevertheless, many other CF variants are insensitive to correctors. Using deep mutational scanning, we quantitatively compare the effects of two correctors on the plasma membrane expression of 129 CF variants. Though structural calculations suggest corrector binding provides similar stabilization to most variants, it’s those with intermediate expression and mutations near corrector binding pockets that exhibit the greatest response. Deviations in sensitivity appear to depend on the degree of variant destabilization and the timing of misassembly. Combining correctors appears to rescue more variants by doubling the binding energy and stabilizing distinct cotranslational folding transitions. These results provide an overview of rare CF variant expression and establish new tools for precision pharmacology. [Display omitted] •The PME of CF variants is profiled by DMS•The variant-specific effects of two approved correctors are quantitatively mapped•Variant expression and binding site proximity influence corrector sensitivity•Allosteric correction arises from binding energetics and vectorial stabilization McKee et al. utilize deep mutational scanning (DMS) to survey deviations in the plasma membrane expression (PME) of 129 clinical variants of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel and how they respond to two FDA-approved cystic fibrosis (CF) drugs. This overview reveals factors associated with differences in the pharmacological properties of rare CF variants.