Photoaffinity Ligand of Cystic Fibrosis Corrector VX-445 Identifies SCCPDH as an Off-Target.

ABSTRACT: Cystic fibrosis (CF) pharmacological correctors improve the cystic fibrosis transmembrane conductance regulator (CFTR) protein trafficking and function. Several side effects of these correctors and adverse drug interactions have been reported, emphasizing the need to understand off-targets. We synthesized VU439, a functionalized photoaffinity ligand (PAL) of VX-445. Chemoproteomics analysis by mass spectrometry (MS) was used to identify cross-linked proteins in CF bronchial epithelial cells expressing F508del CFTR. We identified saccharopine dehydrogenase-like oxidoreductase (SCCPDH), an uncharacterized putative oxidoreductase, as a VX-445-specific off-target. We also characterized changes in the metabolomic profiles of cells overexpressing SCCPDH to determine the consequence of binding of

SUBMITTER: Kim M 

PROVIDER: S-EPMC12281486 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature