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Reprogramming of Protein-Targeted Small-Molecule Medicines to RNA by Ribonuclease Recruitment
- Source :
- J Am Chem Soc
- Publication Year :
- 2021
- Publisher :
- American Chemical Society (ACS), 2021.
-
Abstract
- Reprogramming known medicines for a novel target with activity and selectivity over the canonical target is challenging. By studying the binding interactions between RNA folds and known small-molecule medicines and mining the resultant dataset across human RNAs, we identified that Dovitinib, a receptor tyrosine kinase (RTK) inhibitor, binds the precursor to microRNA-21 (pre-miR-21). Dovitinib was rationally reprogrammed for pre-miR-21 by using it as an RNA recognition element in a chimeric compound that also recruits RNase L to induce the RNA's catalytic degradation. By enhancing the inherent RNA-targeting activity and decreasing potency against canonical RTK protein targets in cells, the chimera shifted selectivity for pre-miR-21 by 2500-fold, alleviating disease progression in mouse models of triple-negative breast cancer and Alport Syndrome, both caused by miR-21 overexpression. Thus, targeted degradation can dramatically improve selectivity even across different biomolecules, i.e., protein versus RNA.
- Subjects :
- RNase P
Nephritis, Hereditary
Triple Negative Breast Neoplasms
Quinolones
Biochemistry
Article
Catalysis
Receptor tyrosine kinase
Small Molecule Libraries
Chimera (genetics)
Ribonucleases
Colloid and Surface Chemistry
medicine
Humans
Ribonuclease
Alport syndrome
Protein Kinase Inhibitors
Molecular Structure
biology
Chemistry
Receptor Protein-Tyrosine Kinases
RNA
General Chemistry
medicine.disease
Small molecule
Cell biology
MicroRNAs
biology.protein
Benzimidazoles
Reprogramming
Subjects
Details
- ISSN :
- 15205126 and 00027863
- Volume :
- 143
- Database :
- OpenAIRE
- Journal :
- Journal of the American Chemical Society
- Accession number :
- edsair.doi.dedup.....fd8c5fb1f8b565de4b32fef39f908357