The DOI matches its Crossref record; 5 of the 5 references it cites were found in a registry or an index.
The diversity of splicing modifiers acting on A-1 bulged 5′-splice sites reveals rules for rational drug design
Open accessAbstract
Pharmacological modulation of RNA splicing by small molecules is an emerging facet of drug discovery. In this context, the SMN2 splicing modifier SMN-C5 was used as a prototype to understand the mode of action of small molecule splicing modifiers and propose the concept of 5′-splice site bulge repair. In this study, we combined in vitro binding assays and structure determination by NMR spectroscopy to identify the binding modes of four other small molecule splicing modifiers that switch the splicing of either the SMN2 or the HTT gene. Here, we determined the solution structures of risdiplam, branaplam, SMN-CX and SMN-CY bound to the intermolecular RNA helix epitope containing an unpaired adenine within the G-2A-1G+1U+2 motif of the 5′-splice site. Despite notable differences in their scaffolds, risdiplam, SMN-CX, SMN-CY and branaplam contact the RNA epitope similarly to SMN-C5, suggesting that the 5′-splice site bulge repair mechanism can be generalised. These findings not only deepen our understanding of the chemical diversity of splicing modifiers that target A-1 bulged 5′-splice sites, but also identify common pharmacophores required for modulating 5′-splice site selection with small molecules.
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Crooke, S. T., Baker, B. F., Crooke, R. M., & Liang, X.-H. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00162-z · Cited by 775
SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy
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“In recent decades, synthetic tools that enable the modulation of 5 (cid:2) -splice site selection and the correction of alternative splicing have emerged and have begun to offer therapeutics for inherited diseases ( 12–16 ).”
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Metadata
- Authors
- Malard, F., Wolter, A. C., Marquevielle, J., Morvan, E., Ecoutin, A., Rüdisser, S. H., Allain, F. H. T., & Campagne, S.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2024-03-30
- Volume
- 52
- Issue
- 8
- Pages
- 4124-4136
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- OpenAlex
- W4393339805
- Cited by
- 1,273
- References
- 5
- FWCI
- 21.84
- Type
- journal article
- Language
- en
- Open access
- gold
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- Malard, F., Wolter, A. C., Marquevielle, J., Morvan, E., Ecoutin, A., Rüdisser, S. H., Allain, F. H. T., & Campagne, S. (2024). The diversity of splicing modifiers acting on A-1 bulged 5′-splice sites reveals rules for rational drug design. Nucleic Acids Research. https://doi.org/10.1093/nar/gkae201
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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