Enhancing the Potency of F508del Correction: A Multi-Layer Combinational Approach to Drug Discovery for Cystic Fibrosis

Abstract

With better understanding of the cellular and molecular pathophysiology underlying cystic fibrosis (CF), novel drugs are being developed that specifically target the molecular defects of the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-activated chloride channel on the plasma membrane that causes CF. Starting with cell-based high-throughput screening, small molecules have been identified that are able to fix specific molecular defects of various disease-causing CFTR mutants. With the successful development of ivacaftor, a "potentiator" that enhances CFTR chloride channel activity, new types of small-molecule compounds that "correct" the misfolding and misprocessing of the most common CF-causing mutation, F508del, are actively being sought for. Recent studies focused on the potential mechanisms of action of some of the investigational CFTR "correctors" shed new light on how the F508del mutant can be targeted in an attempt to ameliorate the clinical symptoms associated with CF. A multi-layer combinational approach has been proposed to achieve the high-potency correction necessary for significant clinical outcome. The mechanistic insights obtained from such studies will shape the future therapeutics development for the vast majority of CF patients.

Keywords: CFTR; Cystic fibrosis; Drug discovery; F508del; High-throughput screen; Molecular chaperones; Protein misfolding.

Figure 1. F508del: misfolding, rescue and drug discovery strategy

(A) wild-type CFTR conformation. (B) F508del CFTR conformation. (C) Small-molecule modulators of F508del CFTR and their impact on its conformation. I, Class I corrector; II, Class II corrector; CR, chaperone regulator; NS, NBD1 stabilizer; P, potentiator; and SS, surface stabilizer. (D) Multi-layer combinational strategy for the development of high-potency F508del correctors.