Proteostasis Therapeutics, Inc. announced the publication of nonclinical data on the mechanism of action of nesolicaftor (PTI-428). The Dukovski et al., paper demonstrates that amplifiers bind directly to poly(rC)-binding protein 1 (PCBP1). PCBP1 belongs to a large family of RNA-binding proteins that regulate the production of cystic fibrosis transmembrane conductance regulator (CFTR) just before the protein prepares to fold and assemble itself for delivery to its final destination in the cell membrane where it works by regulating ion flow. The authors show that the binding of amplifiers for PCBP1 is specific to CFTR because the binding affinity is enhanced through a portion of mRNA that is only present in CFTR. This leads to improved stability of CFTR mRNA and results in greater CFTR protein production. By improving the efficiency by which the CFTR protein is produced, amplifiers are orthogonally delivering more protein for folding and trafficking and thereby increasing CFTR function when coupled with a corrector and a potentiator. Thus, amplifiers represent a promising new and mechanistically novel class of CFTR therapeutic that may be useful as a monotherapy or in combination with other CFTR modulators.