title: Subtle recognition of 14-base pair DNA sequences via threading polyintercalation.
abstract: Small molecules that bind DNA in a sequence-specific manner could act as antibiotic, antiviral, or anticancer agents because of their potential ability to manipulate gene expression. Our laboratory has developed threading polyintercalators based on 1,4,5,8-naphthalene diimide (NDI) units connected in a head-to-tail fashion by flexible peptide linkers. Previously, a threading tetraintercalator composed of alternating minor-major-minor groove-binding modules was shown to bind specifically to a 14 bp DNA sequence with a dissociation half-life of 16 days [Holman, G. G., et al. (2011) Nat. Chem. 3, 875-881]. Herein are described new NDI-based tetraintercalators with a different major groove-binding module and a reversed N to C directionality of one of the minor groove-binding modules. DNase I footprinting and kinetic analyses revealed that these new tetraintercalators are able to discriminate, by as much as 30-fold, 14 bp DNA binding sites that differ by 1 or 2 bp. Relative affinities were found to correlate strongly with dissociation rates, while overall C(2) symmetry in the DNA-binding molecule appeared to contribute to enhanced association rates.
authors.affiliation: Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United States.
authors.forename: Amy Rhoden
authors.initials: AR
authors.lastname: Smith
authors.forename: Brian A
authors.initials: BA
authors.lastname: Ikkanda
authors.forename: Garen G
authors.initials: GG
authors.lastname: Holman
authors.forename: Brent L
authors.initials: BL
authors.lastname: Iverson
mesh_terms: D020029:Base Pairing; D001483:Base Sequence; D001665:Binding Sites; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018983:DNA Footprinting; D003850:Deoxyribonuclease I / Q000378:metabolism; D007094:Imides / Q000737:chemistry* / Q000494:pharmacology*; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D009690:Nucleic Acid Conformation
chemical_list: D007094:Imides; D007364:Intercalating Agents; D009281:Naphthalenes; C542131:naphthalenediimide; D004247:DNA; D003850:Deoxyribonuclease I