Amparo Garcia-Lopez, Francesca Tessaro, Hendrik R. A. Jonker, Anna Wacker, Christian Richter, 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 Schwalbe, Leonardo Scapozza
- 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.
MetadatenAuthor: | 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 |
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URN: | urn:nbn:de:hebis:30:3-465746 |
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DOI: | https://doi.org/10.1038/s41467-018-04110-1 |
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ISSN: | 2041-1723 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/29795225 |
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Parent Title (English): | Nature Communications |
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Publisher: | Nature Publishing Group UK |
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Place of publication: | [London] |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2018 |
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Date of first Publication: | 2018/05/23 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2018/06/05 |
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Tag: | High-throughput screening; Molecular modelling; RNASolution-state NMR; Target validation |
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Volume: | 9 |
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Issue: | 1, Art. 2032 |
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Page Number: | 12 |
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First Page: | 1 |
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Last Page: | 12 |
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Note: | 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/. |
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HeBIS-PPN: | 433825758 |
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Institutes: | Biochemie, Chemie und Pharmazie / Biochemie und Chemie |
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| Exzellenzcluster / Exzellenzcluster Makromolekulare Komplexe |
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| Wissenschaftliche Zentren und koordinierte Programme / Sonderforschungsbereiche / Forschungskollegs |
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| Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ) |
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Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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Sammlungen: | Universitätspublikationen |
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| Sammlung Biologie / Sondersammelgebiets-Volltexte |
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Licence (German): | Creative Commons - Namensnennung 4.0 |
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