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Published July 3, 1996 | public
Journal Article

Recognition of 5'-(A,T)GG(A,T)_2-3' Sequences in the Minor Groove of DNA by Hairpin Polyamides

Abstract

A series of four hairpin pyrrole−imidazole polyamides, ImImPy-γ-PyPyPy-β-Dp, PyPyPy-γ-ImImPy-β-Dp, AcImImPy-γ-PyPyPy-β-Dp, and AcPyPyPy-γ-ImImPy-β-Dp (Im = N-methylimidazole-2-carboxamide, Py = N-methylpyrrole-2-carboxamide, Dp = N,N-dimethylaminopropylamide, γ = γ-aminobutyric acid, β = β-alanine, and Ac = acetyl), designed for recognition of 5'-(A,T)GG(A,T)_2-3' sequences in the minor groove of DNA were synthesized using solid phase methodology and analyzed with respect to DNA binding affinity and sequence specificity. Quantitative DNase I footprint titration experiments reveal that the optimal polyamide ImImPy-γ-PyPyPy-β-Dp binds a designated 5'-TGGTT-3' match site with an equilibrium association constant of K_a = 1.0 × 10^8 M^(-1) and the single base pair mismatch sites, 5'-TGTTA-3' and 5'-GGGTA-3', with 50-fold and 100-fold-lower affinity, respectively (10 mM Tris·HCl, 10 mM KCl, 10 mM MgCl_2, and 5 mM CaCl_2, pH 7.0 and 22 °C). Polyamides of sequence composition AcImImPy-γ-PyPyPy-β-Dp and AcPyPyPy-γ-ImImPy-β-Dp, which differ only by the position of the γ-linker, bind with similar affinities and specificities. Recognition of sequences containing contiguous G·C base pairs expands the sequence repertoire available for targeting DNA with pyrrole−imidazole polyamides.

Additional Information

© 1996 American Chemical Society. Received March 6, 1996. Publication Date (Web): July 3, 1996. Abstract published in Advance ACS Abstracts, June 15, 1996. Acknowledgment. We are grateful to the National Institutes of Health (GM-27681) for research support, the National Institutes of Health for a research service award to M.E.P., and the Howard Hughes Medical Institute for a predoctoral fellowship to E.E.B.

Additional details

Created:
August 19, 2023
Modified:
October 18, 2023