Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes

Amparo Garcia-Lopez , Francesca Tessaro , Hendrik R A Jonker , Anna Wacker , Christian Richter , Arnaud Comte (1) , Nikolaos Berntenis , Roland Schmucki , Klas Hatje , Olivier Petermann , Gianpaolo Chiriano , Remo Perozzo , Daniel Sciarra , Piotr Konieczny , Ignacio Faustino , Guy Fournet (2) , Modesto Orozco , Ruben Artero , Friedrich Metzger , Martin Ebeling , Peter Goekjian (3) , Benoît Joseph (2) , Harald Schwalbe , Leonardo Scapozza

1 ICBMS - Institut de Chimie et Biochimie Moléculaires et Supramoléculaires
2 SMITh - Synthèse de Molécules d'Intérêt Thérapeutique
3 CO2GLYCO - Chimie Organique 2-Glycochimie

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.

Domains: Organic chemistry

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