Hairpin Peptide Motif. A New Class of Oligopeptides for Sequence-Specific Recognition in the Minor Groove of Double-Helical DNA

Peptides which bind in the minor groove of DNA as antiparallel side-by-side dimers can be linked head-to-tail to afford a new class of hairpin oligopeptides with enhanced sequence specificity for DNA. Four hexapeptides were synthesized wherein the terminal amine and carboxyl groups of tris(N-methylpyrrolecarboxamide) (P3) and N-methylimidazole-2-carboxamide-netropsin (2-ImN), respectively, have been connected with glycine (Gly), β-alanine (βAla), 4-aminobutyric acid (GABA), and 5-aminovaleric acid (Ava) amino acids. The hexapeptide 2-ImN-GABA-P3 binds 5'-TGTTA-3' sites with a binding affinity of 7.6 × 10⁷ M^-1 (10 mM Tris-HCl, 10 mM KC1,10 mM MgCl₂, and 5 mM CaCl₂ at pH 7.0 and 22 ⁰ C). The general and efficient synthetic methodology for preparation of head-to-tail linked peptides should allow the design of a new class of hairpin peptides for specific recognition of many different sequences in the minor groove of DNA.