PTI-801 (posenacaftor) shares a common mechanism with VX-445 (elexacaftor) to rescue p.Phe508del-CFTR

• DOI: 10.1016/j.ejphar.2024.176390
• Publication Date: 2024-02-08T03:38:58Z
• Authors: Filipa C. Ferreira; Margarida D. Amaral; Mafalda Bacalhau; Miquéias Lopes-Pa...
• Keywords: Potentiator

The deletion of a phenylalanine at position 508 (p.Phe508del) in the CFTR anion channel is most prevalent variant people with Cystic Fibrosis (CF). This impairs folding and stability CF transmembrane conductance regulator (CFTR) protein, resulting its defective trafficking premature degradation. Over last years, therapeutic accomplishments have been attained developing small molecules that partially correct p.Phe508del-CFTR defects; however, mechanism action (MoA) these compounds has only started to be uncovered. In this study, we employed biochemical, fluorescence microscopy, functional assays examine efficacy properties PTI-801, newly developed corrector. To exploit MoA, assessed PTI-801 effects combination low temperature, genetic revertants (the cis p.Val510Asp, p.Gly550Glu, p.Arg1070Trp, 4RK) other correctors. Our results demonstrated rescues processing, PM trafficking, function (upon agonist stimulation) greater correction ABBV-2222, FDL-169, VX-661, or VX-809, but not VX-445. Although exhibited no potentiator activity on temperature- corrector-rescued p.Phe508del-CFTR, compound displayed similar behavior VX-445 revertants. Such evidence associated lack additivity when were combined indicates they share common binding site defects. Despite high dual corrector combinations restored conformational stability, as shown by lower half-life mutant protein compared WT-CFTR. summary, likely shares MoA rescuing thus being feasible alternative for development novel capacity rescue stability.