The diversity of splicing modifiers acting on A -1 bulged 5 -splice sites reveals rules for rational drug design - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Nucleic Acids Research Année : 2024

The diversity of splicing modifiers acting on A -1 bulged 5 -splice sites reveals rules for rational drug design

Résumé

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.
Fichier principal
Vignette du fichier
gkae201.pdf (2.3 Mo) Télécharger le fichier
Origine Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-04576074 , version 1 (15-05-2024)

Identifiants

Citer

Florian Malard, Antje C Wolter, Julien Marquevielle, Estelle Morvan, Agathe Ecoutin, et al.. The diversity of splicing modifiers acting on A -1 bulged 5 -splice sites reveals rules for rational drug design. Nucleic Acids Research, 2024, 52 (8), pp.4124-4136. ⟨10.1093/nar/⟩. ⟨hal-04576074⟩

Collections

CNRS INC-CNRS
29 Consultations
8 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More