García López, AmparoTessaro, FrancescaJonker, Hendrik R. A.Wacker, AnnaRichter, ChristianComte, ArnaudBerntenis, NikolaosSchmucki, RolandHatje, KlasPetermann, OlivierChiriano, GianpaoloPerozzo, RemoSciarra, DanielKonieczny, PiotrFaustino Pló, IgnacioFournet, GuyOrozco López, ModestoArtero, RubenMetzger, FriedrichEbeling, MartinGoekjian, PeterJoseph, BenoîtSchwalbe, HaraldScapozza, Leonardo2018-06-052018-06-052018-05-232041-1723https://hdl.handle.net/2445/122780Modification 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.12 p.application/pdfengcc by (c) García López et al., 2018http://creativecommons.org/licenses/by/3.0/es/CribratgeAtròfia muscularMedical screeningMuscular atrophyinfo:eu-repo/semantics/article2018-06-04info:eu-repo/semantics/openAccess29795225