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- W2803899091 abstract "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." @default.
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- W2803899091 date "2018-05-23" @default.
- W2803899091 modified "2023-10-17" @default.
- W2803899091 title "Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes" @default.
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- W2803899091 doi "https://doi.org/10.1038/s41467-018-04110-1" @default.
- W2803899091 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5966403" @default.
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