Specificity, synergy, and mechanisms of splice-modifying drugs.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
29 Feb 2024
29 Feb 2024
Historique:
received:
22
02
2023
accepted:
10
02
2024
medline:
1
3
2024
pubmed:
1
3
2024
entrez:
29
2
2024
Statut:
epublish
Résumé
Drugs that target pre-mRNA splicing hold great therapeutic potential, but the quantitative understanding of how these drugs work is limited. Here we introduce mechanistically interpretable quantitative models for the sequence-specific and concentration-dependent behavior of splice-modifying drugs. Using massively parallel splicing assays, RNA-seq experiments, and precision dose-response curves, we obtain quantitative models for two small-molecule drugs, risdiplam and branaplam, developed for treating spinal muscular atrophy. The results quantitatively characterize the specificities of risdiplam and branaplam for 5' splice site sequences, suggest that branaplam recognizes 5' splice sites via two distinct interaction modes, and contradict the prevailing two-site hypothesis for risdiplam activity at SMN2 exon 7. The results also show that anomalous single-drug cooperativity, as well as multi-drug synergy, are widespread among small-molecule drugs and antisense-oligonucleotide drugs that promote exon inclusion. Our quantitative models thus clarify the mechanisms of existing treatments and provide a basis for the rational development of new therapies.
Identifiants
pubmed: 38424098
doi: 10.1038/s41467-024-46090-5
pii: 10.1038/s41467-024-46090-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1880Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM133777
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG011787
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA045508
Pays : United States
Organisme : ODCDC CDC HHS
ID : S10 OD020122
Pays : United States
Informations de copyright
© 2024. The Author(s).
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