Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

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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Amparo Garcia-Lopez, Francesca Tessaro, Hendrik Jonker, Anna Wacker, Christian Richter, et al.. Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes. Nature Communications, Nature Publishing Group, 2018, 9 (1), ⟨10.1038/s41467-018-04110-1⟩. ⟨hal-02115789⟩

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