Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

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RESEARCH PRODUCT

Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

Guy Fournet Remo Perozzo Gianpaolo Chiriano Martin Ebeling Modesto Orozco Hendrik R. A. Jonker Francesca Tessaro Piotr Konieczny Olivier Petermann Ignacio Faustino Roland Schmucki Benoã®t. Joseph Leonardo Scapozza Christian Richter Peter G. Goekjian Friedrich Metzger Daniel Sciarra Amparo Garcia-lopez Nikolaos Berntenis Harald Schwalbe Ruben Artero Klas Hatje Anna Wacker Arnaud Comte

subject

0301 basic medicine Indoles COMPOUND LIBRARIES Drug Evaluation Preclinical General Physics and Astronomy Biotecnologia Animals Genetically Modified Exon Molecular Targeted Therapy Regulatory Elements Transcriptional lcsh:Science HUMAN-DISEASE GENES BIOACTIVE SMALL MOLECULES Multidisciplinary Chemistry Drug discovery [CHIM.ORGA]Chemical Sciences/Organic chemistry Q Imidazoles MUTATION PATTERN Exons SMA*3. Good health Cell biology Survival of Motor Neuron 2 Protein Phenotype Cribratge RNA splicing NUCLEOTIDE STRUCTURE Drosophila MESSENGER-RNA COMPUTATIONAL TOOLS Medical screening MYOTONIC-DYSTROPHY Science Muscular atrophy Article General Biochemistry Genetics and Molecular Biology Genètica molecular Muscular Atrophy Spinal 03 medical and health sciences ddc:570 SPLICING MODIFIERS medicine Animals Humans HIV-1 TAR RNA Messenger Atròfia muscular Messenger RNA Alternative splicing RNA General Chemistry Spinal muscular atrophy medicine.disease Alternative Splicing 030104 developmental biology RNA lcsh:Q RNA Splice Sites HeLa Cells

description

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.

year	journal	country	edition	language
2018-05-23	Nature Communications

10.1038/s41467-018-04110-1 https://doaj.org/article/cc1752fb9d394b0fb636e7fca670afcc