Cycle Polyamide Motif for Recognition of the Minor Groove of DNA
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- 作者：David M. Herman ; James M. Turner ; Eldon E. Baird ; and Peter B. Dervan
- 刊名：Journal of the American Chemical Society
- 出版年：1999
- 出版时间：February 17, 1999
- 年：1999
- 卷：121
- 期：6
- 页码：1121 - 1129
- 全文大小：225K
- 年卷期：v.121,no.6(February 17, 1999)
- ISSN：1520-5126
文摘
Motifs for covalent linkage of side-by-side complexes of pyrrole-imidazole (Py-Im) polyamidesin the DNA minor groove provide for small molecules that specifically recognize predetermined sequenceswith subnanomolar affinity. Polyamide subunits linked by a turn-specific 
-aminobutyric acid () residueform hairpin polyamide structures. Selective amino-substitution of the prochiral 
-position of the -turn residuerelocates the cationic charge from the hairpin C terminus. Here we report the synthesis of pyrrole resin as wellas a solid-phase strategy for the preparation of cycle polyamides. The DNA binding properties of two eight-ring cycle polyamides were analyzed on a DNA restriction fragment containing six base pair match and mismatchbinding sites. Quantitative footprint titrations demonstrate that a cycle polyamide of sequence compositioncyclo-(-ImPyPyPy-(R)H2N-ImPyPyPy-) binds a 5'-AGTACT-3' site with an equilibrium association constantKa = 7.6 × 1010 M-1, a 3600-fold enhancement relative to the unlinked homodimer (ImPyPyPy-
-Dp)2·5'-AGTACT-3', and an 8-fold enhancement relative to hairpin analogue ImPyPyPy-(R)H2N-ImPyPyPy-C3-OH·5'-AGTACT-3'. Replacement of a single nitrogen atom with a C-H (Im
Py) regulates affinity andspecificity of the cycle polyamide by 2 orders of magnitude. The results presented here suggest that additionof a chiral -turn combined with placement of a second -turn within the hairpin structure provides a cyclepolyamide motif with favorable DNA binding properties.
-aminobutyric acid () residueform hairpin polyamide structures. Selective amino-substitution of the prochiral -position of the -turn residuerelocates the cationic charge from the hairpin C terminus. Here we report the synthesis of pyrrole resin as wellas a solid-phase strategy for the preparation of cycle polyamides. The DNA binding properties of two eight-ring cycle polyamides were analyzed on a DNA restriction fragment containing six base pair match and mismatchbinding sites. Quantitative footprint titrations demonstrate that a cycle polyamide of sequence compositioncyclo-(-ImPyPyPy-(R)H2N-ImPyPyPy-) binds a 5'-AGTACT-3' site with an equilibrium association constantKa = 7.6 × 1010 M-1, a 3600-fold enhancement relative to the unlinked homodimer (ImPyPyPy--Dp)2·5'-AGTACT-3', and an 8-fold enhancement relative to hairpin analogue ImPyPyPy-(R)H2N-ImPyPyPy-C3-OH·5'-AGTACT-3'. Replacement of a single nitrogen atom with a C-H (ImPy) regulates affinity andspecificity of the cycle polyamide by 2 orders of magnitude. The results presented here suggest that additionof a chiral -turn combined with placement of a second -turn within the hairpin structure provides a cyclepolyamide motif with favorable DNA binding properties.