Minor groove binding compounds that jump a gc base pair and bind to adjacent AT base pair sites.

Abstract:

:Most A/T specific heterocyclic diamidine derivatives need at least four A/T base pairs for tight binding to the DNA minor groove. Addition of a GC base pair to A/T sequences typically causes a large decrease in binding constant. The ability to target biologically important sequences of DNA could be significantly increased if compounds that could recognize A/T sites with an intervening GC base pair could be designed. The kinetoplast DNA sequence of parasitic microorganisms, for example, contains numerous three A/T binding sites that are separated by a single G. A series of compounds were prepared to target the AAAGTTT sequence as a model system for discovery of "G-jumpers". The new synthetic compounds have two aromatic-amidine groups for A/T recognition, and these are connected through an oxy-methylene linker to cross the GC. CD experiments indicated a minor groove binding mode, as expected, for these compounds. T(max), surface plasmon resonance, and isothermal titration calorimetry experiments revealed 1:1 binding to the AAAGTTT sequence with an affinity that depends on compound structure. Benzimidazole derivatives gave the strongest binding and had generally good solution properties. The binding affinities to the classical AATT sequence were similar to that for AAAGTTT for these extended compounds, but binding was weaker to the AAAGCTTT sequence with two intervening GC base pairs. Binding to both AAAGTTT and AATT was enthalpy driven for strong binding benzimidazole derivatives.

journal_name

Biochemistry

journal_title

Biochemistry

authors

Rahimian M,Kumar A,Say M,Bakunov SA,Boykin DW,Tidwell RR,Wilson WD

doi

10.1021/bi801944g

subject

Has Abstract

pub_date

2009-02-24 00:00:00

pages

1573-83

issue

7

eissn

0006-2960

issn

1520-4995

pii

10.1021/bi801944g

journal_volume

48

pub_type

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