PUBLICATION
Virtual Screening and Zebrafish Phenotype-Based Evaluation Argues Against Repurposing 4-Phenylbutyrate for STXBP1-Related Disorders
- Authors
- Frick, A., Whyte-Fagundes, P., Baraban, S.C.
- ID
- ZDB-PUB-260611-1
- Date
- 2026
- Source
- Pharmacology research & perspectives 14: e70285 (Journal)
- Registered Authors
- Baraban, Scott
- Keywords
- behavior, pharmacology, seizure, zebrafish
- MeSH Terms
- none
- PubMed
- 42268630 Full text @ Pharmacol Res Perspect
Citation
Frick, A., Whyte-Fagundes, P., Baraban, S.C. (2026) Virtual Screening and Zebrafish Phenotype-Based Evaluation Argues Against Repurposing 4-Phenylbutyrate for STXBP1-Related Disorders. Pharmacology research & perspectives. 14:e70285.
Abstract
Syntaxin-binding protein 1 (STXBP1) mutations lead to severe epilepsy, intellectual disability, developmental delay, and movement disorder. Effective treatments for these conditions do not exist. Recent studies in Munc18-1 (STXBP1) C. elegans models demonstrate that 4-phenylbutyrate (4-PBA) or related pharmacological chaperones stabilize Munc18-1 protein levels and rescue locomotion deficits. These studies suggest a novel treatment strategy for these patients. Here, we used a stxbp1a zebrafish model with a profound movement disorder to screen 4-PBA and alternative structural analogs identified using artificial intelligence (AI)-based screening. Automated locomotion assays conducted on larval stxbp1a mutant zebrafish at 5 days post-fertilization (dpf) confirm and extend the movement disorder endophenotype. Drug treatment (4-PBA or 16 identified candidates) failed to rescue the stxbp1a mutant zebrafish locomotion deficit. Electrophysiology studies in a stxbp1b zebrafish model characterized by spontaneous seizure activity (i.e., epilepsy) failed to detect a reduction in ictal-like events with 4-PBA treatment. Taken together, our results suggest caution in repurposing 4-PBA or related compounds for the treatment of STXBP1 disorders.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping