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

Smith AR, Ikkanda BA, Holman GG, Iverson BL - Biochemistry (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United States.

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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Structures of the adipicacid-containing tetraintercalator 1 and the Gly3Lys linker-containing tetraintercalators 2 and 3 showing N to C amide bond directionality.Tetraintercalator 2 has an N-terminal free amine, whilethe N-terminal amine of 3 is capped as the acetamide.NDI intercalating units are denoted with letters for reference.
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fig2: Structures of the adipicacid-containing tetraintercalator 1 and the Gly3Lys linker-containing tetraintercalators 2 and 3 showing N to C amide bond directionality.Tetraintercalator 2 has an N-terminal free amine, whilethe N-terminal amine of 3 is capped as the acetamide.NDI intercalating units are denoted with letters for reference.

Mentions: By changing the major groove-binding modulein 1 fromadipic acid to the Gly3Lys linker, we found the putativetetraintercalators 2 and 3 have an overallbackbone directionality and no longer exhibit C2 symmetry. To emphasize this point, the arrows in Figure 2 indicate N to C directionality in the amide bondsof the backbones for 1–3. Although 1 could be synthesized by cross-linking two bisintercalators on theresin with adipic acid, 2 and 3 had to besynthesized in a linear, stepwise fashion.


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

Smith AR, Ikkanda BA, Holman GG, Iverson BL - Biochemistry (2012)

Structures of the adipicacid-containing tetraintercalator 1 and the Gly3Lys linker-containing tetraintercalators 2 and 3 showing N to C amide bond directionality.Tetraintercalator 2 has an N-terminal free amine, whilethe N-terminal amine of 3 is capped as the acetamide.NDI intercalating units are denoted with letters for reference.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3369501&req=5

fig2: Structures of the adipicacid-containing tetraintercalator 1 and the Gly3Lys linker-containing tetraintercalators 2 and 3 showing N to C amide bond directionality.Tetraintercalator 2 has an N-terminal free amine, whilethe N-terminal amine of 3 is capped as the acetamide.NDI intercalating units are denoted with letters for reference.
Mentions: By changing the major groove-binding modulein 1 fromadipic acid to the Gly3Lys linker, we found the putativetetraintercalators 2 and 3 have an overallbackbone directionality and no longer exhibit C2 symmetry. To emphasize this point, the arrows in Figure 2 indicate N to C directionality in the amide bondsof the backbones for 1–3. Although 1 could be synthesized by cross-linking two bisintercalators on theresin with adipic acid, 2 and 3 had to besynthesized in a linear, stepwise fashion.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin, Texas 78712, United States.

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.

Show MeSH
Related in: MedlinePlus