Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

Article Article scientifique Article Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes eng 2018-05-23 author Garcia Lopez Amparo Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. amparo.garcialopez@unige.ch. 789109 author Tessaro Francesca 0000-0001-8672-885X Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. 809979 author Jonker Hendrik R A Institut für Organische Chemie und Chemische Biologie, Center for Biomolecular Magnetic Resonance (BMRZ), Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Strasse 7, 60438, Frankfurt, Germany. author Wacker Anna 0000-0001-5892-5661 Institut für Organische Chemie und Chemische Biologie, Center for Biomolecular Magnetic Resonance (BMRZ), Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Strasse 7, 60438, Frankfurt, Germany. author Richter Christian 0000-0002-5420-2826 Institut für Organische Chemie und Chemische Biologie, Center for Biomolecular Magnetic Resonance (BMRZ), Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Strasse 7, 60438, Frankfurt, Germany. author Comte Arnaud Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), UMR CNRS 5246, University Claude Bernard Lyon 1, 43 Bd du 11 Novembre 1918, F-69622, Villeurbanne cedex, France. author Berntenis Nikolaos Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. author Schmucki Roland Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. author Hatje Klas Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. author Petermann Olivier 0000-0001-8080-6896 Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. 624997 Section des sciences pharmaceutiques (FARMA) author Chiriano Gianpaolo Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. 784524 author Perozzo Remo Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. 625237 author Sciarra Daniel Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. 845713 author Konieczny Piotr 0000-0003-2644-5502 Translational Genomics Group, Incliva Health Research Institute, Menendez Pelayo 4, 46010, Valencia, Spain.,Department of Genetics and Interdisciplinary Research Structure for Biotechnology and Biomedicine (ERI BIOTECMED), University of Valencia, Dr Moliner 50, 46100, Burjassot, Spain. author Faustino Ignacio Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology (BIST), Joint BSC-IRB Research Program in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain. author Fournet Guy Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), UMR CNRS 5246, University Claude Bernard Lyon 1, 43 Bd du 11 Novembre 1918, F-69622, Villeurbanne cedex, France. author Orozco Modesto Institute for Research in Biomedicine (IRB), Barcelona Institute of Science and Technology (BIST), Joint BSC-IRB Research Program in Computational Biology, Baldiri Reixac 10, 08028, Barcelona, Spain. author Artero Ruben 0000-0003-1596-047X Translational Genomics Group, Incliva Health Research Institute, Menendez Pelayo 4, 46010, Valencia, Spain.,Department of Genetics and Interdisciplinary Research Structure for Biotechnology and Biomedicine (ERI BIOTECMED), University of Valencia, Dr Moliner 50, 46100, Burjassot, Spain. author Metzger Friedrich Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. author Ebeling Martin Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland. author Goekjian Peter 0000-0001-9457-2218 Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), UMR CNRS 5246, University Claude Bernard Lyon 1, 43 Bd du 11 Novembre 1918, F-69622, Villeurbanne cedex, France. author Joseph Benoît Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), UMR CNRS 5246, University Claude Bernard Lyon 1, 43 Bd du 11 Novembre 1918, F-69622, Villeurbanne cedex, France. author Schwalbe Harald 0000-0001-5693-7909 Institut für Organische Chemie und Chemische Biologie, Center for Biomolecular Magnetic Resonance (BMRZ), Johann Wolfgang Goethe-University Frankfurt, Max-von-Laue-Strasse 7, 60438, Frankfurt, Germany. author Scapozza Leonardo 0000-0003-1079-648X Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. leonardo.scapozza@unige.ch. 600318 Section des sciences pharmaceutiques (FARMA) 10.1038/s41467-018-04110-1 29795225 2041-1723 PMC5966403 https://www.nature.com/articles/s41467-018-04110-1 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. Dewey 615 Swiss National Science Foundation Identification and characterization of novel antibacterial compounds using protozoan hosts 130016 CH 31 Section des sciences pharmaceutiques 17 false 880 Biochimie pharmaceutique Nature communications 9 1 a12a452e-3005-49d7-beb0-5cbbd51b7c80 Article (Published version) Public Article_scientifique_from_crossref.pdf 2660706 application/pdf CC BY-4.0 f51e703f5c46b250f1ef836b17d169170c6022642c197d628a32d23823b59e3f openAccess Faculté des sciences / Section des sciences pharmaceutiques

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Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes	Nature communications			2018	1	0

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