Please use this identifier to cite or link to this item:
http://hdl.handle.net/2445/122780
Title: | Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes |
Author: | García López, 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 Pló, Ignacio Fournet, Guy Orozco López, Modesto Artero, Ruben Metzger, Friedrich Ebeling, Martin Goekjian, Peter Joseph, Benoît Schwalbe, Harald Scapozza, Leonardo |
Keywords: | Cribratge Atròfia muscular Medical screening Muscular atrophy |
Issue Date: | 23-May-2018 |
Publisher: | Macmillan |
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. |
Note: | Reproducció del document publicat a: http://dx.doi.org/10.1038/s41467-018-04110-1 |
It is part of: | Nature Communications, 2018, vol. 9, num. 2032 |
URI: | http://hdl.handle.net/2445/122780 |
Related resource: | http://dx.doi.org/10.1038/s41467-018-04110-1 |
ISSN: | 2041-1723 |
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 | |
---|---|---|---|---|
s41467-018-04110-1.pdf | 2.6 MB | Adobe PDF | View/Open |
This item is licensed under a
Creative Commons License