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A structure-specific small molecule inhibits a miRNA-200 family member precursor and reverses a type 2 diabetes phenotype

Authors :
Laurent Knerr
Hafeez S. Haniff
Samantha M. Meyer
Alexander Adibekian
Haruo Aikawa
Malin Lemurell
Xiaohui Liu
Daniel Abegg
Matthew D. Disney
Yuquan Tong
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.

Details

ISSN :
24519456
Volume :
29
Database :
OpenAIRE
Journal :
Cell Chemical Biology
Accession number :
edsair.doi.dedup.....a86828a51ecc8dbbf352689bf113bdd4