{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:27:36Z","timestamp":1785421656012,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,12]]},"group-title":"Pharmacology and Toxicology","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"NIH","award":["R01-NS096976"],"award-info":[{"award-number":["R01-NS096976"]}]},{"name":"NIH","award":["R01-HD102071"],"award-info":[{"award-number":["R01-HD102071"]}]},{"name":"NIH","award":["R21-NS138525"],"award-info":[{"award-number":["R21-NS138525"]}]},{"name":"NIH","award":["U54-NS117170"],"award-info":[{"award-number":["U54-NS117170"]}]},{"name":"STXBP1 Foundation"},{"id":[{"id":"https:\/\/ror.org\/016kmmx43","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Syntaxin-binding protein 1 (\n                  <jats:italic>STXBP1<\/jats:italic>\n                  ) 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 (\n                  <jats:italic>STXBP1<\/jats:italic>\n                  )\n                  <jats:italic>C. elegans<\/jats:italic>\n                  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\n                  <jats:italic>stxbp1a<\/jats:italic>\n                  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\n                  <jats:italic>stxbp1a<\/jats:italic>\n                  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\n                  <jats:italic>stxbp1a<\/jats:italic>\n                  mutant zebrafish locomotion deficit. Electrophysiology studies in a\n                  <jats:italic>stxbp1b<\/jats:italic>\n                  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 treatment of STXBP1 disorders.\n                <\/jats:p>","DOI":"10.64898\/2026.05.07.723632","type":"posted-content","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T21:50:13Z","timestamp":1778622613000},"source":"Crossref","is-referenced-by-count":0,"title":["Virtual screening and zebrafish phenotype-based evaluation argues against repurposing 4-phenylbutyrate for STXBP1-related disorders"],"prefix":"10.64898","author":[{"given":"Aline","family":"Frick","sequence":"first","affiliation":[{"name":"Department of Neurological Surgery & Weill Institute for Neuroscience, University of California, San Francisco, CA, USA"},{"name":"Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4878-9955","authenticated-orcid":false,"given":"Paige","family":"Whyte-Fagundes","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery & Weill Institute for Neuroscience, University of California, San Francisco, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1975-9781","authenticated-orcid":false,"given":"Scott C.","family":"Baraban","sequence":"additional","affiliation":[{"name":"Department of Neurological Surgery & Weill Institute for Neuroscience, University of California, San Francisco, CA, USA"},{"name":"Helen Wills Institute of Neuroscience, University of California, Berkeley, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026051419050989000_2026.05.07.723632v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15120"},{"key":"2026051419050989000_2026.05.07.723632v1.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0054166"},{"key":"2026051419050989000_2026.05.07.723632v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3410"},{"key":"2026051419050989000_2026.05.07.723632v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2004.11.031"},{"key":"2026051419050989000_2026.05.07.723632v1.5","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000000291"},{"key":"2026051419050989000_2026.05.07.723632v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2021.105469"},{"key":"2026051419050989000_2026.05.07.723632v1.7","first-page":"82","article-title":"The Behavioral and Pharmacological Actions of NMDA Receptor Antagonism are Conserved in Zebrafish Larvae","volume":"23","year":"2010","journal-title":"Int J Comp Psychol"},{"key":"2026051419050989000_2026.05.07.723632v1.8","doi-asserted-by":"publisher","DOI":"10.1098\/rsbl.2022.0541"},{"key":"2026051419050989000_2026.05.07.723632v1.9","doi-asserted-by":"publisher","DOI":"10.1038\/nature12439"},{"key":"2026051419050989000_2026.05.07.723632v1.10","first-page":"18","article-title":"Some aspects of the pharmacology of clemizole hydrochloride","volume":"49","year":"1960","journal-title":"J Am Pharm Assoc Am Pharm Assoc"},{"key":"2026051419050989000_2026.05.07.723632v1.11","doi-asserted-by":"crossref","unstructured":"Furia, F. , Rigby, C. 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