TY  - JOUR
A1  - Garcia-Lopez, Amparo
A1  - Tessaro, Francesca
A1  - Jonker, Hendrik R. A.
A1  - Wacker, Anna
A1  - Richter, Christian
A1  - Comte, Arnaud
A1  - Berntenis, Nikolaos
A1  - Schmucki, Roland
A1  - Hatje, Klas
A1  - Petermann, Olivier
A1  - Chiriano, Gianpaolo
A1  - Perozzo, Remo
A1  - Sciarra, Daniel
A1  - Konieczny, Piotr
A1  - Faustino, Ignacio
A1  - Fournet, Guy
A1  - Orozco, Modesto
A1  - Artero, Ruben
A1  - Metzger, Friedrich
A1  - Ebeling, Martin
A1  - Goekjian, Peter
A1  - Joseph, Benoît
A1  - Schwalbe, Harald
A1  - Scapozza, Leonardo
T1  - Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
T2  - Nature Communications
N2  - 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.
KW  - High-throughput screening
KW  - Molecular modelling
KW  - RNASolution-state NMR
KW  - Target validation
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/46574
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-465746
SN  - 2041-1723
N1  - 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/.
VL  - 9
IS  - 1, Art. 2032
SP  - 1
EP  - 12
PB  - Nature Publishing Group UK
CY  - [London]
ER  -