A Macrocyclic Peptide Ligand Binds the Oncogenic MicroRNA-21 Precursor and Suppresses Dicer Processing

MicroRNAs (miRNAs) help orchestrate cellular growth and survival through post-transcriptional mechanisms. The dysregulation of miRNA biogenesis can lead to cellular growth defects and chemotherapeutic resistance and plays a direct role in the development of many chronic diseases. Among these RNAs, m...

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Veröffentlicht in:ACS chemical biology 2017-06, Vol.12 (6), p.1611-1620
Hauptverfasser: Shortridge, Matthew D, Walker, Matthew J, Pavelitz, Tom, Chen, Yu, Yang, Wen, Varani, Gabriele
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container_end_page 1620
container_issue 6
container_start_page 1611
container_title ACS chemical biology
container_volume 12
creator Shortridge, Matthew D
Walker, Matthew J
Pavelitz, Tom
Chen, Yu
Yang, Wen
Varani, Gabriele
description MicroRNAs (miRNAs) help orchestrate cellular growth and survival through post-transcriptional mechanisms. The dysregulation of miRNA biogenesis can lead to cellular growth defects and chemotherapeutic resistance and plays a direct role in the development of many chronic diseases. Among these RNAs, miR-21 is consistently overexpressed in most human cancers, leading to the down-regulation of key tumor-suppressing and pro-apoptotic factors, suggesting that inhibition of miR-21 biogenesis could reverse these negative effects. However, targeted inhibition of miR-21 using small molecules has had limited success. To overcome difficulties in targeting RNA secondary structure with small molecules, we developed a class of cyclic β-hairpin peptidomimetics which bind to RNA stem-loop structures, such as miRNA precursors, with potent affinity and specificity. We screened an existing cyclic peptide library and discovered a lead structure which binds to pre-miR21 with K D = 200 nM and prefers it over other pre-miRNAs. The NMR structure of the complex shows that the peptide recognizes the Dicer cleavage site and alters processing of the precursor to the mature miRNA in vitro and in cultured cells. The structure provides a rationale for the peptide binding activity and clear guidance for further improvements in affinity and targeting.
doi_str_mv 10.1021/acschembio.7b00180
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source ACS Publications; MEDLINE
subjects Animals
Anticarcinogenic Agents - chemistry
Cell Line
DEAD-box RNA Helicases - antagonists & inhibitors
DEAD-box RNA Helicases - metabolism
Humans
Ligands
MicroRNAs - antagonists & inhibitors
MicroRNAs - metabolism
Peptide Library
Peptides, Cyclic - metabolism
Peptides, Cyclic - pharmacology
Peptidomimetics - metabolism
Peptidomimetics - pharmacology
Protein Binding
Ribonuclease III - antagonists & inhibitors
Ribonuclease III - metabolism
RNA Processing, Post-Transcriptional
Substrate Specificity
title A Macrocyclic Peptide Ligand Binds the Oncogenic MicroRNA-21 Precursor and Suppresses Dicer Processing
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