期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04110-1
关键词
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资金
- University of Geneva
- Swiss National Science Foundation (SNSF) (Sinergia) [CRSI33-130016]
- Protein Kinase Research (Pro-Kinase) [LSHB-CT-2004-503467]
- European Molecular Biology Organization (EMBO) [ALTF 253-2012]
- Schmidheiny Foundation
- SMA Europe [17623, 19243]
- BioNMR
- iNEXT
- German Research Foundation (DFG) [CRC902]
- state of Hesse
- ERC Council (SimDNA)
- Spanish Ministry of Science and Competiveness [BFU2014-61670-EXP, BFU2014-52864-R]
- Generalitat Valenciana (Santiago Grisolia PhD programme)
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.
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