A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant

Nat Chem. 2011 Sep 25;3(11):875-81. doi: 10.1038/nchem.1151.

Abstract

A long-lived and sequence-specific ligand-DNA complex would make possible the modulation of biological processes for extended periods. For this purpose, we are investigating a polyintercalation approach to DNA recognition in which flexible chains of aromatic units thread back and forth repeatedly through the double helix. Here we describe the DNA-binding behaviour of a threading tetra-intercalator. Specific binding was observed on a relatively long DNA strand that strongly favoured a predicted 14 base-pair sequence. Kinetic studies revealed a multistep association process, with sequence specificity that primarily derives from large differences in dissociation rates. The rate-limiting dissociation rate constant of the tetra-intercalator complex dissociating from its preferred binding site was extremely slow, corresponding to a half-life of 16 days. This is one of the longest non-covalent complex half-lives yet reported and, to the best of our knowledge, the longest for a DNA-binding molecule.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • DNA / chemistry*
  • Intercalating Agents / chemistry*
  • Kinetics
  • Naphthalimides / chemical synthesis
  • Naphthalimides / chemistry*
  • Nucleic Acid Conformation
  • Peptides / chemical synthesis
  • Peptides / chemistry*

Substances

  • Intercalating Agents
  • Naphthalimides
  • Peptides
  • amino acetamide-NDI-lysyl-beta-alanyl-beta-alanyl-beta-alanyl-NDI-lysyl-adipamide-lysyl-NDI-beta-alanyl-beta-alanyl-beta-alanyl-lysyl-NDI-amino acetamide
  • DNA

Associated data

  • PubChem-Substance/125092099
  • PubChem-Substance/125092100
  • PubChem-Substance/125092101