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

## TL;DR

This study identifies a new off-target protein for a cystic fibrosis drug, which may explain some side effects and highlights the need for drug optimization.

## Contribution

The study identifies SCCPDH as a novel off-target of the CF corrector VX-445 using a photoaffinity ligand and chemoproteomics.

## Key findings

- SCCPDH is a specific off-target of VX-445 identified through chemoproteomics.
- VX-445 binding to SCCPDH disrupts amino acid metabolism and shows potential inhibitory activity.
- The off-target effect may explain psychological symptoms observed in patients.

## 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 VX-445 to SCCPDH. These data show dysregulation
of amino acid metabolism and a potential inhibitory activity of VX-445
on SCCPDH. The identified off-target may explain the exacerbation
of psychological symptoms observed in the clinic, thus emphasizing
the need for further optimization of correctors.