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Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/122780
Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
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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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GARCÍA LÓPEZ, Amparo, et al. Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes. Nature Communications. 2018. Vol. 9, num. 2032. ISSN 2041-1723. [consulted: 14 of June of 2026]. Available at: https://hdl.handle.net/2445/122780