Mixed up minor groove binders: Convincing A·T specific compounds to recognize a G·C base pair

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4927-4932. doi: 10.1016/j.bmcl.2015.05.005. Epub 2015 May 19.

Abstract

DNA minor-groove-binding compounds have limited biological applications, in part due to problems with sequence specificity that cause off-target effects. A model to enhance specificity has been developed with the goal of preparing compounds that bind to two AT sites separated by G·C base pairs. Compounds of interest were probed using thermal melting, circular dichroism, mass spectrometry, biosensor-SPR, and molecular modeling methods. A new minor groove binder that can strongly and specifically recognize a single G·C base pair with flanking AT sequences has been prepared. This multi-site DNA recognition mode offers novel design principles to recognize entirely new DNA motifs.

Keywords: Biophysical analysis; Heterocyclic diamidines; Mixed DNA recognition; Rational design; Sequence specificity.

Publication types

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

MeSH terms

  • Base Pairing*
  • Base Sequence
  • Benzene Derivatives / chemistry*
  • DNA / chemistry*
  • Molecular Docking Simulation
  • Molecular Structure

Substances

  • Benzene Derivatives
  • DNA