Subtle recognition of 14-base pair DNA sequences via threading polyintercalation.

Biochemistry
Amy Rhoden SmithBrent L Iverson

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.

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Citations

Aug 8, 2013·Journal of the American Chemical Society·Amy Rhoden Smith, Brent L Iverson
Sep 27, 2014·Chemical Communications : Chem Comm·Catherine L LyallSimon E Lewis
Apr 16, 2016·Chemical Communications : Chem Comm·B A Ikkanda, B L Iverson
Apr 15, 2014·Bioorganic & Medicinal Chemistry·Izabella CzerwinskaShigeori Takenaka
Aug 27, 2016·Chemical Reviews·Mohammad Al KobaisiSheshanath V Bhosale
Aug 25, 2020·Chemistry of Heterocyclic Compounds·Andrey M ZhirovIvan V Borovlev
Sep 29, 2020·Beilstein Journal of Organic Chemistry·Poulami JanaIvo Piantanida

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Methods Mentioned

BETA
footprinting
NMR
electrophoresis

Software Mentioned

Quantity One

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