5n5c

Publication Abstract from PubMed

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.

Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes.,Garcia-Lopez A, Tessaro F, Jonker HRA, Wacker A, Richter C, Comte A, Berntenis N, Schmucki R, Hatje K, Petermann O, Chiriano G, Perozzo R, Sciarra D, Konieczny P, Faustino I, Fournet G, Orozco M, Artero R, Metzger F, Ebeling M, Goekjian P, Joseph B, Schwalbe H, Scapozza L Nat Commun. 2018 May 23;9(1):2032. doi: 10.1038/s41467-018-04110-1. PMID:29795225^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.