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http://hdl.handle.net/2445/122780
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DC Field | Value | Language |
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dc.contributor.author | García López, Amparo | - |
dc.contributor.author | Tessaro, Francesca | - |
dc.contributor.author | Jonker, Hendrik R. A. | - |
dc.contributor.author | Wacker, Anna | - |
dc.contributor.author | Richter, Christian | - |
dc.contributor.author | Comte, Arnaud | - |
dc.contributor.author | Berntenis, Nikolaos | - |
dc.contributor.author | Schmucki, Roland | - |
dc.contributor.author | Hatje, Klas | - |
dc.contributor.author | Petermann, Olivier | - |
dc.contributor.author | Chiriano, Gianpaolo | - |
dc.contributor.author | Perozzo, Remo | - |
dc.contributor.author | Sciarra, Daniel | - |
dc.contributor.author | Konieczny, Piotr | - |
dc.contributor.author | Faustino Pló, Ignacio | - |
dc.contributor.author | Fournet, Guy | - |
dc.contributor.author | Orozco López, Modesto | - |
dc.contributor.author | Artero, Ruben | - |
dc.contributor.author | Metzger, Friedrich | - |
dc.contributor.author | Ebeling, Martin | - |
dc.contributor.author | Goekjian, Peter | - |
dc.contributor.author | Joseph, Benoît | - |
dc.contributor.author | Schwalbe, Harald | - |
dc.contributor.author | Scapozza, Leonardo | - |
dc.date.accessioned | 2018-06-05T07:25:41Z | - |
dc.date.available | 2018-06-05T07:25:41Z | - |
dc.date.issued | 2018-05-23 | - |
dc.identifier.issn | 2041-1723 | - |
dc.identifier.uri | http://hdl.handle.net/2445/122780 | - |
dc.description.abstract | Modification of SMN2 exon 7 (E7) splicing is a validated therapeutic strategy against spinal muscular atrophy (SMA). However, a target-based approach to identify small-molecule E7 splicing modifiers has not been attempted, which could reveal novel therapies with improved mechanistic insight. Here, we chose as a target the stem-loop RNA structure TSL2, which overlaps with the 5′ splicing site of E7. A small-molecule TSL2-binding compound, homocarbonyltopsentin (PK4C9), was identified that increases E7 splicing to therapeutic levels and rescues downstream molecular alterations in SMA cells. High-resolution NMR combined with molecular modelling revealed that PK4C9 binds to pentaloop conformations of TSL2 and promotes a shift to triloop conformations that display enhanced E7 splicing. Collectively, our study validates TSL2 as a target for small-molecule drug discovery in SMA, identifies a novel mechanism of action for an E7 splicing modifier, and sets a precedent for other splicing-mediated diseases where RNA structure could be similarly targeted. | - |
dc.format.extent | 12 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Macmillan | - |
dc.relation.isformatof | Reproducció del document publicat a: http://dx.doi.org/10.1038/s41467-018-04110-1 | - |
dc.relation.ispartof | Nature Communications, 2018, vol. 9, num. 2032 | - |
dc.relation.uri | http://dx.doi.org/10.1038/s41467-018-04110-1 | - |
dc.rights | cc by (c) García López et al., 2018 | - |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/es/ | - |
dc.source | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) | - |
dc.subject.classification | Cribratge | - |
dc.subject.classification | Atròfia muscular | - |
dc.subject.other | Medical screening | - |
dc.subject.other | Muscular atrophy | - |
dc.title | Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/publishedVersion | - |
dc.date.updated | 2018-06-04T12:58:46Z | - |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/H2020/675728/EU//BioExcel | - |
dc.relation.projectID | info:eu-repo/grantAgreement/EC/H2020/653706/EU//iNEXT | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
dc.identifier.pmid | 29795225 | - |
Appears in Collections: | Articles publicats en revistes (Bioquímica i Biomedicina Molecular) Articles publicats en revistes (Institut de Recerca Biomèdica (IRB Barcelona)) |
Files in This Item:
File | Description | Size | Format | |
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s41467-018-04110-1.pdf | 2.6 MB | Adobe PDF | View/Open |
This item is licensed under a Creative Commons License