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

• Published in: Journal of the American Chemical Society Vol. 116; no. 18; pp. 7983 - 7988
• Main Authors: Mrksich, Milan, Parks, Michelle E, Dervan, Peter B
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 01.09.1994; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; NETROPSIN; FOOTPRINT TITRATION; COMPLEX; DISTAMYCIN; BIS(PYRIDINE-2-CARBOXAMIDONETROPSIN)(CH2)3-6; 2-DIMENSIONAL NMR; DIMERS; BINDING
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja00097a004

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), beta-alanine (beta Ala), 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 x 10(7) M(-1) (10 mM Tris HCl, 10 mM KCl, 10 mM MgCl2, and 5 mM CaCl2 at pH 7.0 and 22 degrees 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.