2026-04-20T03:09:05Zhttps://recercat.cat/oai/requestoai:recercat.cat:2445/1227802025-12-04T21:13:30Zcom_2072_1057col_2072_478781col_2072_478908col_2072_478917
urn:hdl:2445/122780
Targeting RNA structure in SMN2 reverses spinal muscular atrophy molecular phenotypes
García López, Amparo
Tessaro, Francesca
Jonker, Hendrik R. A.
Wacker, Anna
Richter, Christian
Comte, Arnaud
Berntenis, Nikolaos
Schmucki, Roland
Hatje, Klas
Petermann, Olivier
Chiriano, Gianpaolo
Perozzo, Remo
Sciarra, Daniel
Konieczny, Piotr
Faustino Pló, Ignacio
Fournet, Guy
Orozco López, Modesto
Artero, Ruben
Metzger, Friedrich
Ebeling, Martin
Goekjian, Peter
Joseph, Benoît
Schwalbe, Harald
Scapozza, Leonardo
Cribratge
Atròfia muscular
Medical screening
Muscular atrophy
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.
2018-06-05T07:25:41Z
2018-06-05T07:25:41Z
2018-05-23
2018-06-04T12:58:46Z
info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
Reproducció del document publicat a: http://dx.doi.org/10.1038/s41467-018-04110-1
Nature Communications, 2018, vol. 9, num. 2032
http://dx.doi.org/10.1038/s41467-018-04110-1
info:eu-repo/grantAgreement/EC/H2020/675728/EU//BioExcel
info:eu-repo/grantAgreement/EC/H2020/653706/EU//iNEXT
cc by (c) García López et al., 2018
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
Macmillan
Articles publicats en revistes (Bioquímica i Biomedicina Molecular)