Association of a peptoid ligand with the apical loop of pri-miR-21 inhibits cleavage by Drosha.
We have found a small molecule that specifically inhibits cleavage of a precursor to the oncogenic miRNA, miR-21, by the microprocessor complex of Drosha and DGCR8. We identified novel ligands for the apical loop of this precursor from a screen of 14,024 N-substituted oligoglycines (peptoids) in a microarray format. Eight distinct compounds with specific affinity were obtained, three having affinities for the targeted loop in the low micromolar range and greater than 15-fold discrimination against a closely related hairpin. One of these compounds completely inhibits microprocessor cleavage of a miR-21 primary transcript at concentrations at which cleavage of another miRNA primary transcript, pri-miR-16, is little affected. The apical loop of pri-miR-21, placed in the context of pri-miR-16, is sufficient for inhibition of microprocessor cleavage by the peptoid. This compound also inhibits cleavage of pri-miR-21 containing the pri-miR-16 apical loop, suggesting an additional site of association within pri-miR-21. The reported peptoid is the first example of a small molecule that inhibits microprocessor cleavage by binding to the apical loop of a pri-miRNA.
Jason P
JP
Diaz
Rachel
R
Chirayil
Sara
S
Chirayil
Martin
M
Tom
Katie J
KJ
Head
Kevin J
KJ
Luebke
D006801:Humans; D008274:Magnesium / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D015394:Molecular Structure; D019151:Peptide Library; D034444:Peptoids / Q000235:genetics* / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*
C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D019151:Peptide Library; D034444:Peptoids; D054852:Small Molecule Libraries; C517918:DROSHA protein, human; D043244:Ribonuclease III; D008274:Magnesium
Drosha; RNA hairpin loop; miR-21; miRNA processing; peptoid