CFTR potentiators: from bench to bedside

Abstract

One major breakthrough in cystic fibrosis research in the past decade is the development of drugs that target the root cause of the disease—dysfunctional CFTR protein. One of the compounds, Ivacaftor or Kalydeco, which has been approved for clinical use since 2012, acts by promoting the gating function of CFTR. Our recent studies have led to a gating model that features an energetic coupling between NBD dimerization and gate opening/closing in CFTR’s TMDs. Based on this model, we showed that ATP analogs can enhance CFTR gating by facilitating NBD dimerization, whereas Ivacaftor works by stabilizing the open channel conformation of the TMDs. This latter idea also explains the near omnipotence of Ivacaftor. Furthermore, this model marks multiple approaches to synergistically boost the open probability of CFTR by influencing distinct molecular events that control gating conformational changes.

Cystic fibrosis transmembrane conductance regulator (CFTR): Making an ion channel out of an active transporter structure

“…Additional structural information may also shed new light on the mechanism of operation of the channel gate (which still appears closed in the nearopen state of Figure 2-4), as well as the role of the R domain (which is absent from all CFTR structures presented in this article). Identification of key structural differences between the open and closed channel states may also help in the development of CFTR "potentiators"substances that bind to CFTR and increase its activity that are currently used for the treatment of CF patients [9,46] in particular if such substances act by binding preferentially to the open channel and stabilizing its structure [45].…”

Potentiation of the cystic fibrosis transmembrane conductance regulator Cl−channel by ivacaftor is temperature independent

“…To restore function to F508del-CFTR, combination therapy with small molecule CFTR correctors and potentiators is required (39,50). Based on its mechanism of dysfunction (45), multiple CFTR correctors will likely be required to repair misfolding of nucleotide-binding domain 1 (NBD1) and restore correct domain assembly (52), leading to the delivery of F508del-CFTR to the plasma membrane.…”

Mucoviscidosis: fisiopatología, genética, aspectos clínicos y terapéuticos

“…La prueba de concepto se realizó para la mutación G551D, situada en un punto crucial de la interfase entre NBD1 y NBD2, y suprime la abertura de poros, dependiente de ATP [26] . VX-770 (ivacaftor) es un potenciador que restaura la abertura de los poros del CFTR-G551D a un nivel idéntico al de la proteína de tipo silvestre [27] .…”