**3. Targeting functional defects in CFTR Protein: Small molecule CFTR modulators**

A number of small molecules have been designed to overcome the functional defects in CFTR protein caused by upstream gene mutations (Figure 1). These CFTR modulators can be classified into three families according to the specific functional defect that they target: premature stop codon suppressors, correctors, and potentiators [13].

**Premature stop codon suppressors, otherwise known as production correctors or readthrough agents,** encourage the cell to overlook any premature stop codons transcribed within the *CFTR* mRNA (Figure 1A). They instruct cellular ribosomes to read-through these prema‐ ture termination codons as the mRNA is being translated into protein. This encourages the production of full-length CFTR. Several *CFTR* mutations interfere with proper protein processing, resulting in misfolded CFTR that is degraded by the cell. **Correctors** focus on improving the processing and transport of CFTR protein to the cell surface (Figure 1B). By ensuring that CFTR is processed and folded correctly, the protein can be trafficked to the plasma membrane where it functions. Additional *CFTR* mutations allow this chloride ion channel to arrive at the plasma membrane, but cause defects in its gating or conductance ability. **Potentiators** work on these defects, to enhance opening of the channel or increasing the flow of chloride ions (Figure 1C) [13].

Lumacaftor (VX-809, Vertex Pharmaceuticals), for instance, is a CFTR corrector that increases trafficking of ∆F508-CFTR to the epithelial cell surface [14]. Lumacaftor has also been used in combination with ivacaftor (VX-770, Vertex Pharmaceuticals, trade name Kalydeco), a CFTR potentiator that improves the transport of chloride through CFTR channels rendered dys‐ functional by G551D or R560T missense mutations. By binding to the channels and inducing

**Figure 1. Small molecule CFTR modulators target functional defects within the CFTR protein.** Three types of CFTR modulators have been developed: premature stop codon suppressors **(A)**, correctors **(B)**, and potentiators **(C)**. These small molecules act by targeting the transcription, translation, protein processing, membrane trafficking, and ion trans‐ port functionality of the CFTR protein, respectively.

a non-conventional mode of gating, ivacaftor increases the probability that the chloride channel is open [14]. Another small molecule CFTR modulator, ataluren (PTC124, PTC Therapeutics, trade name Translarna in the EU), is a production corrector that makes ribo‐ somes less sensitive to G542X or W1282X nonsense mutations [15]. Overcoming these prema‐ ture stop codons allows the synthesis of full-length, functional CFTR. Together, these small molecule modulators focus on addressing the functional defects in a patient's own CFTR protein.
