Programming inactive RNA-binding small molecules into bioactive degraders.
Journal
Nature
ISSN: 1476-4687
Titre abrégé: Nature
Pays: England
ID NLM: 0410462
Informations de publication
Date de publication:
Jun 2023
Jun 2023
Historique:
received:
11
08
2021
accepted:
17
04
2023
medline:
2
6
2023
pubmed:
25
5
2023
entrez:
24
5
2023
Statut:
ppublish
Résumé
Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure-activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L
Identifiants
pubmed: 37225982
doi: 10.1038/s41586-023-06091-8
pii: 10.1038/s41586-023-06091-8
pmc: PMC10232370
doi:
Substances chimiques
2-5A-dependent ribonuclease
EC 3.1.26.-
MicroRNAs
0
MIRN155 microRNA, human
0
RNA, Messenger
0
Endoribonucleases
EC 3.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
169-179Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s).
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