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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, 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.
Metadaten
Verfasserangaben:Amparo Garcia-Lopez, Francesca Tessaro, Hendrik R. A. JonkerORCiD, Anna WackerORCiDGND, Christian RichterORCiDGND, Arnaud Comte, Nikolaos Berntenis, Roland Schmucki, Klas Hatje, Olivier Petermann, Gianpaolo Chiriano, Remo Perozzo, Daniel Sciarra, Piotr Konieczny, Ignacio Faustino, Guy Fournet, Modesto Orozco, Ruben Artero, Friedrich Metzger, Martin Ebeling, Peter Goekjian, Benoît Joseph, Harald SchwalbeORCiDGND, Leonardo Scapozza
URN:urn:nbn:de:hebis:30:3-465746
DOI:https://doi.org/10.1038/s41467-018-04110-1
ISSN:2041-1723
Pubmed-Id:https://pubmed.ncbi.nlm.nih.gov/29795225
Titel des übergeordneten Werkes (Englisch):Nature Communications
Verlag:Nature Publishing Group UK
Verlagsort:[London]
Dokumentart:Wissenschaftlicher Artikel
Sprache:Englisch
Jahr der Fertigstellung:2018
Datum der Erstveröffentlichung:23.05.2018
Veröffentlichende Institution:Universitätsbibliothek Johann Christian Senckenberg
Datum der Freischaltung:05.06.2018
Freies Schlagwort / Tag:High-throughput screening; Molecular modelling; RNASolution-state NMR; Target validation
Jahrgang:9
Ausgabe / Heft:1, Art. 2032
Seitenzahl:12
Erste Seite:1
Letzte Seite:12
Bemerkung:
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/.
HeBIS-PPN:433825758
Institute:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe
Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs
Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ)
DDC-Klassifikation:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
Sammlungen:Universitätspublikationen
Sammlung Biologie / Sondersammelgebiets-Volltexte
Lizenz (Deutsch):License LogoCreative Commons - Namensnennung 4.0