A pH Sensitive High-Throughput Assay for miRNA Binding of a Peptide-Aminoglycoside (PA) Library

PLoS One. 2015 Dec 11;10(12):e0144251. doi: 10.1371/journal.pone.0144251. eCollection 2015.

Abstract

MicroRNAs (miRNA) are small RNAs that have a regulatory role in gene expression. Because of this regulatory role, miRNAs have become a new target for therapeutic compounds. Here, we outline an approach to target specific miRNAs using a high throughput capable assay and a 215 compound peptidic-aminosugar (PA) library. Aminosugars have been shown in a number of recent reports as important lead compounds that bind miRNA. In order to screen for compounds that bind miRNA, we have developed a high throughput displacement assay using a fluorescein-neomycin conjugated molecule (F-neo) as a probe for competitive miRNA binding compounds. We have applied the F-neo assay to four different miRNA constructs and the assay is applicable to most miRNAs, at various stages of processing. The results of the screen were validated by the determination of the IC50 for a select group of compounds from the library. For example, we identified eight compounds that bind to hsa-miR 504 with higher affinity than the parent neomycin. From the F-neo displacement assay we found that the number of binding sites differs for each miRNA, and the binding sites appear to differ both physically and chemically, with different affinity of the compounds resulting from the size of the molecule as well as the chemical structure. Additionally, the affinity of the compounds was dependent on the identity and position of the amino acid position of conjugation and the affinity of the compounds relative to other compounds in the library was miRNA dependent with the introduction of a second amino acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / metabolism
  • Aminoglycosides / metabolism*
  • Base Sequence
  • Binding Sites
  • Fluorescein / metabolism
  • High-Throughput Screening Assays / methods*
  • Humans
  • Hydrogen-Ion Concentration
  • Inhibitory Concentration 50
  • Kinetics
  • MCF-7 Cells
  • MicroRNAs / chemistry
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Molecular Sequence Data
  • Neomycin / chemistry
  • Neomycin / pharmacology
  • Nucleic Acid Conformation
  • Peptide Library*
  • Peptides / metabolism*
  • Protein Binding / drug effects
  • RNA Processing, Post-Transcriptional / drug effects

Substances

  • Amino Acids
  • Aminoglycosides
  • MicroRNAs
  • Peptide Library
  • Peptides
  • Neomycin
  • Fluorescein

Grants and funding

NUBAD, LLC provided support in the form of salaries for author J.D.W., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of J.D.W. are articulated in the 'author contributions' section.