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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
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.
Subject(s):	-Cribratge -Atròfia muscular -Medical screening -Muscular atrophy
Rights:	cc by (c) García López et al., 2018 http://creativecommons.org/licenses/by/3.0/es/
Document type:	Article Article - Published version
Published by:	Macmillan
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