Photoaffinity Ligand of Cystic Fibrosis Corrector VX-445 Identifies SCCPDH as an Off-Target
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".