Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

  • Nat Commun. 2018 May 23;9(1):2032. doi: 10.1038/s41467-018-04110-1.
Amparo Garcia-Lopez  1 ,  Francesca Tessaro  2 ,  Hendrik R A Jonker  3 ,  Anna Wacker  3 ,  Christian Richter  3 ,  Arnaud Comte  4 ,  Nikolaos Berntenis  5 ,  Roland Schmucki  5 ,  Klas Hatje  5 ,  Olivier Petermann  2 ,  Gianpaolo Chiriano  2 ,  Remo Perozzo  2 ,  Daniel Sciarra  2 ,  Piotr Konieczny  6  7 ,  Ignacio Faustino  8 ,  Guy Fournet  4 ,  Modesto Orozco  8 ,  Ruben Artero  6  7 ,  Friedrich Metzger  5 ,  Martin Ebeling  5 ,  Peter Goekjian  4 ,  Benoît Joseph  4 ,  Harald Schwalbe  3 ,  Leonardo Scapozza  9
Affiliations
  • 1. Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. [email protected].
  • 2. Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland.
  • 3. 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.
  • 4. 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.
  • 5. Pharmaceutical Research and Early Development, F. Hoffmann-La Roche, Roche Innovation Center Basel, Grenzacherstrasse 124, 4070, Basel, Switzerland.
  • 6. Translational Genomics Group, Incliva Health Research Institute, Menendez Pelayo 4, 46010, Valencia, Spain.
  • 7. Department of Genetics and Interdisciplinary Research Structure for Biotechnology and Biomedicine (ERI BIOTECMED), University of Valencia, Dr Moliner 50, 46100, Burjassot, Spain.
  • 8. 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.
  • 9. Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Lausanne and University of Geneva, Rue Michel-Servet 1, 1211, Geneva, Switzerland. [email protected].
PMID: 29795225 DOI: 10.1038/s41467-018-04110-1
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.

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