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No disease\u2010modifying therapy exists to treat these disorders, and while chemical chaperones have been shown to alleviate neuronal dysfunction caused by missense mutations in Munc18\u20101, their required high concentrations and potential toxicity necessitate a Munc18\u20101\u2010targeted therapy. Munc18\u20101 is essential for neurotransmitter release, and mutations in Munc18\u20101 have been shown to cause neuronal dysfunction via aggregation and co\u2010aggregation of the wild\u2010type protein, reducing functional Munc18\u20101 levels well below hemizygous levels. Here, we identify two pharmacological chaperones via structure\u2010based drug design, that bind to wild\u2010type and mutant Munc18\u20101, and revert Munc18\u20101 aggregation and neuronal dysfunction\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , providing the first targeted treatment strategy for these severe pediatric encephalopathies.\n                  <\/jats:p>","DOI":"10.15252\/emmm.202012354","type":"journal-article","created":{"date-parts":[[2020,12,18]],"date-time":"2020-12-18T08:25:36Z","timestamp":1608279936000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Targeted stabilization of Munc18\u20101 function via pharmacological chaperones"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0302-1582","authenticated-orcid":false,"given":"Debra","family":"Abramov","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7602-5402","authenticated-orcid":false,"given":"Noah Guy Lewis","family":"Guiberson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Daab","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoonmi","family":"Na","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory A","family":"Petsko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7394-2419","authenticated-orcid":false,"given":"Manu","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8968-248X","authenticated-orcid":false,"given":"Jacqueline","family":"Burr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,17]]},"reference":[{"key":"BFEMMM202012354_CR1","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.15120","author":"D Abramov","year":"2020","unstructured":"Abramov D, Guiberson NGL, Burre J (2020) STXBP1 encephalopathies: clinical spectrum, disease mechanisms, and therapeutic strategies. 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