Expanding the Recognition of the Minor Groove of DNA by Incorporation of β-Alanine in Hairpin Polyamides

Clay C.C. Wang, Ulf Ellervik, Peter B. Dervan

Research output: Contribution to journalArticlepeer-review

Abstract

In order to expand the recognition code by hairpin polyamides to include DNA sequences of the type 5′-CWWC-3′ two polyamides, PyPyPyPy-(R)H2Nγ-ImPyPyIm-β-Dp (1) and PyPyPyPy-(R)H2Nγ-ImPy-β-Im-β-Dp (2) were synthesized which have in common an Py/Im pair in the terminal position for targeting C·G but differ with respect to internal placement of a β-alanine residue. The equilibrium association constants (Ka) were determined at four DNA sites which differ at a single common position, 5′-TNTACA-3′ (N=T, A, G, C). Quantitative DNase I footprint titration experiments reveal that the eight-ring hairpin PyPyPyPy-(R)H2Nγ-ImPyPyIm-β-Dp (1) binds the four binding sites with similar affinities, Ka=1.3-1.9×1010M-1 indicating that there is no preference for the position N. In contrast, a redesigned polyamide PyPyPyPy-(R)H2Nγ-ImPy-β-Im-β-Dp (2) that places an internal flexible aliphatic β-alanine to the 5′-side of a key imidazole group bound the match site 5′-TCTACA-3′ with high affinity and good sequence discrimination (Ka(match)=4.9×1010M-1 and the single base pair mismatch sites with 5- to 25-fold lower affinity). These results expand the repertoire of sequences targetable by hairpins and emphasize the importance of β-alanine as a key element for minor groove recognition. © 2001 Elsevier Science Ltd.
Original languageEnglish
Pages (from-to)653-657
JournalBioorganic and Medicinal Chemistry
Volume9
Issue number3
DOIs
Publication statusPublished - 2001
Externally publishedYes

Subject classification (UKÄ)

  • Biochemistry and Molecular Biology
  • Organic Chemistry

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