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Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
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, w...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966403/ https://www.ncbi.nlm.nih.gov/pubmed/29795225 http://dx.doi.org/10.1038/s41467-018-04110-1 |
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author | Garcia-Lopez, Amparo Tessaro, Francesca Jonker, Hendrik R. A. Wacker, Anna Richter, Christian Comte, Arnaud Berntenis, Nikolaos Schmucki, Roland Hatje, Klas Petermann, Olivier Chiriano, Gianpaolo Perozzo, Remo Sciarra, Daniel Konieczny, Piotr Faustino, Ignacio Fournet, Guy Orozco, Modesto Artero, Ruben Metzger, Friedrich Ebeling, Martin Goekjian, Peter Joseph, Benoît Schwalbe, Harald Scapozza, Leonardo |
author_facet | Garcia-Lopez, Amparo Tessaro, Francesca Jonker, Hendrik R. A. Wacker, Anna Richter, Christian Comte, Arnaud Berntenis, Nikolaos Schmucki, Roland Hatje, Klas Petermann, Olivier Chiriano, Gianpaolo Perozzo, Remo Sciarra, Daniel Konieczny, Piotr Faustino, Ignacio Fournet, Guy Orozco, Modesto Artero, Ruben Metzger, Friedrich Ebeling, Martin Goekjian, Peter Joseph, Benoît Schwalbe, Harald Scapozza, Leonardo |
author_sort | Garcia-Lopez, Amparo |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5966403 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59664032018-05-25 Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes Garcia-Lopez, Amparo Tessaro, Francesca Jonker, Hendrik R. A. Wacker, Anna Richter, Christian Comte, Arnaud Berntenis, Nikolaos Schmucki, Roland Hatje, Klas Petermann, Olivier Chiriano, Gianpaolo Perozzo, Remo Sciarra, Daniel Konieczny, Piotr Faustino, Ignacio Fournet, Guy Orozco, Modesto Artero, Ruben Metzger, Friedrich Ebeling, Martin Goekjian, Peter Joseph, Benoît Schwalbe, Harald Scapozza, Leonardo Nat Commun Article 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. Nature Publishing Group UK 2018-05-23 /pmc/articles/PMC5966403/ /pubmed/29795225 http://dx.doi.org/10.1038/s41467-018-04110-1 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Garcia-Lopez, Amparo Tessaro, Francesca Jonker, Hendrik R. A. Wacker, Anna Richter, Christian Comte, Arnaud Berntenis, Nikolaos Schmucki, Roland Hatje, Klas Petermann, Olivier Chiriano, Gianpaolo Perozzo, Remo Sciarra, Daniel Konieczny, Piotr Faustino, Ignacio Fournet, Guy Orozco, Modesto Artero, Ruben Metzger, Friedrich Ebeling, Martin Goekjian, Peter Joseph, Benoît Schwalbe, Harald Scapozza, Leonardo Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes |
title | Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes |
title_full | Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes |
title_fullStr | Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes |
title_full_unstemmed | Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes |
title_short | Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes |
title_sort | targeting rna structure in smn2 reverses spinal muscular atrophy molecular phenotypes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966403/ https://www.ncbi.nlm.nih.gov/pubmed/29795225 http://dx.doi.org/10.1038/s41467-018-04110-1 |
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