Repairing mutated proteins – development of small molecules targeting defects in the cystic fibrosis transmembrane conductance regulator

Abstract

Although the development of CFTR-targeting agents has little access to structural information from crystal structures, several promising compounds have been discovered so far. Advanced virtual models of CFTR and high-throughput assays have helped the developmental programs. While Ivacaftor, the first of the CFTR potentiators, has now reached clinical use, CFTR corrector development has not been successful thus far. However, intense research of the mutation F508del, the mutation considered the most frequent in CF, could provide new causal treatment options in the future. Furthermore, the eventual synergy with multiple correctors may bring further success. CFTR modulators provide a new personalized therapeutic option where CF therapy is based on the mutations patients carry rather than by simply their symptoms.

Identification and Characterization of Novel CFTR Potentiators

“…Cystic fibrosis (CF) is the most common genetic (autosomal recessive) disease in Caucasians, with an estimated 80,000 CF diagnosed cases worldwide ( Lubamba et al, 2012 ; Hanrahan et al, 2013 ; Merk and Schubert-Zsilavecz, 2013 ; De Boeck et al, 2014 ). Current strategies for treatment of CF patients can be broadly divided into two main categories: agents that target downstream effects of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) dysfunction (i.e., symptomatic treatment) and agents that target the root cause of the disease, i.e., CFTR modulators which address the absent or dysfunctional CFTR in epithelial membranes.…”

Discovery of N-(2,4-Di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, Ivacaftor), a Potent and Orally Bioavailable CFTR Potentiator

“…Several classes of CFTR potentiators have been reported (Figure ) such as flavones (genistein), chromen-4-ones (UC CF -29), sulfonamides (SF-01), phenylglycines (PG-01), and our previously described pyrazoles (VRT-532). , It is speculated that these molecules interact directly with the nucleotide binding domain region of CFTR . However, many of these compounds display low potency, limited selectivity, and poor pharmacokinetic properties in preclinical species, making them unsuitable for development as human therapeutics .…”

Can Cystic Fibrosis Patients Finally Catch a Breath With Lumacaftor/Ivacaftor?

“…Moreover, the F508del mutation perturbs the native interactions between NBD1 and the coupling helix of MSD2 . The breakthrough finding was that misfolding of the defective F508del‐CFTR could be corrected by lowering the temperature (<30°C) or by employing chemical chaperones (e.g., glycerol) . For the first time, this indicated that defective CFTR function could be restored; this in turn led to extensive efforts by Vertex to identify small‐molecule CFTR modulators .…”

“…The breakthrough finding was that misfolding of the defective F508del‐CFTR could be corrected by lowering the temperature (<30°C) or by employing chemical chaperones (e.g., glycerol) . For the first time, this indicated that defective CFTR function could be restored; this in turn led to extensive efforts by Vertex to identify small‐molecule CFTR modulators . Mechanistically, CFTR modulators fall into three classes: 1) suppressors that prevent premature termination of protein synthesis (i.e., ataluren); 2) correctors that partially correct folding and processing defects (i.e., lumacaftor); and 3) potentiators that increase channel gating and conductance (i.e., ivacaftor).…”

“…However, lumacaftor/ivacaftor has yet to be approved for patients with G551D‐CFTR. Moreover, given that patients with G551D‐CFTR express CFTR on the epithelial cell surface, this may not prove successful due to the increase in CFTR turnover rates reported with lumacaftor/ivacaftor therapy ( Figure 2 ) . As patients are forced to take lumacaftor/ivacaftor or Kalydeco as a lifelong therapy, the impact on the healthcare budget is staggering .…”