Restoration of Cellular Homeostasis by Vx-445 Under ER Stress Conditions: Insights from Biochemical and Proteomic Assays _ DARTS 3

Multiple intracellular and extracellular factors can impair protein folding, leading to protein misfolding diseases (PMDs). Cystic fibrosis (CF) is a notable example, whose pharmacological management relies on combinations of modulators—such as the corrector Vx-445, that targets the defect in the cystic fibrosis transmembrane conductance regulator (CFTR).

In vitro binding assays so far are unable to demonstrate a direct interaction between the corrector and CFTR in the cellular environment, leaving its precise mechanism of action unresolved. Thus, this study aims to investigate the role of Vx-445 in neuronal cells, following the induction of ER stress with Thapsigargin, a specific inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA), by a multi-disciplinary approach involving biochemical assays, label-free and functional proteomics.