Inhibition of pre-miRNA-136 processing by Dicer with small molecule BzDANP suggested the formation of ternary complex of pre-miR-136-BzDANP-Dicer

Bioorg Med Chem. 2019 May 15;27(10):2140-2148. doi: 10.1016/j.bmc.2019.03.031. Epub 2019 Mar 18.

Abstract

Small-molecule modulators, along with antisense oligonucleotide, would be powerful tools and potential drug candidates for modulating miRNA-related gene expressions. The mechanism of the inhibitory effect of the C-bulge binding small molecule BzDANP for the Dicer processing reaction of pre-miR-136 was discussed on the data obtained by SPR, NMR, and kinetic analysis for Dicer processing. SPR and NMR analysis showed the preference of BzDANP binding to the C-bulge. Michaelis-Menten analysis suggested the formation of a ternary complex pre-miR-136-BzDANP-Dicer during the Dicer-cleavage reaction of pre-miR-136 in the presence of BzDANP. The inhibitory effect of BzDANP is likely attributed to the slower reaction from the ternary complex than that from the binary pre-miR-136-Dicer complex.

Keywords: Bulge; Dicer; Inhibitor; Pre-miRNA; Small molecule; miRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DEAD-box RNA Helicases / antagonists & inhibitors
  • DEAD-box RNA Helicases / metabolism*
  • Electron Spin Resonance Spectroscopy
  • Humans
  • Magnetic Resonance Spectroscopy
  • MicroRNAs / chemistry*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Mutation
  • Naphthyridines / chemistry*
  • Naphthyridines / metabolism
  • Nucleic Acid Conformation
  • Protein Binding
  • RNA Precursors / chemistry
  • RNA Precursors / genetics
  • RNA Precursors / metabolism
  • Ribonuclease III / antagonists & inhibitors
  • Ribonuclease III / metabolism*
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / metabolism

Substances

  • MIRN136 microRNA, human
  • MicroRNAs
  • Naphthyridines
  • RNA Precursors
  • Small Molecule Libraries
  • DICER1 protein, human
  • Ribonuclease III
  • DEAD-box RNA Helicases