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A structure-specific small molecule inhibits a miRNA-200 family member precursor and reverses a type 2 diabetes phenotype
- Source :
- Cell Chem Biol
- Publication Year :
- 2022
- Publisher :
- Elsevier BV, 2022.
-
Abstract
- Summary MicroRNA families are ubiquitous in the human transcriptome, yet targeting of individual members is challenging because of sequence homology. Many secondary structures of the precursors to these miRNAs (pri- and pre-miRNAs), however, are quite different. Here, we demonstrate both in vitro and in cellulis that design of structure-specific small molecules can inhibit a particular miRNA family member to modulate a disease pathway. The miR-200 family consists of five miRNAs, miR-200a, -200b, -200c, -141, and -429, and is associated with type 2 diabetes (T2D). We designed a small molecule that potently and selectively targets pre-miR-200c’s structure and reverses a pro-apoptotic effect in a pancreatic β cell model. In contrast, an oligonucleotide targeting the RNA’s sequence inhibited all family members. Global proteomics and RNA sequencing analyses further demonstrate selectivity for miR-200c. Collectively, these studies establish that miR-200c plays an important role in T2D, and small molecules targeting RNA structure can be an important complement to oligonucleotides.
- Subjects :
- Clinical Biochemistry
Chemical biology
Biology
Ligands
Biochemistry
Article
Small Molecule Libraries
Transcriptome
Mice
Insulin-Secreting Cells
Drug Discovery
microRNA
Animals
Nucleic acid structure
Molecular Biology
Cells, Cultured
Pharmacology
Sequence Analysis, RNA
Oligonucleotide
RNA
Small molecule
Phenotype
Cell biology
MicroRNAs
Diabetes Mellitus, Type 2
Molecular Medicine
Subjects
Details
- ISSN :
- 24519456
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Cell Chemical Biology
- Accession number :
- edsair.doi.dedup.....a86828a51ecc8dbbf352689bf113bdd4