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Nucleic Acids Research Advance Access published online on April 1, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn116
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Chemistry

Pyrrole-imidazole hairpin polyamides with high affinity at 5'–CGCG–3' DNA sequence; influence of cytosine methylation on binding

Masafumi Minoshima, Toshikazu Bando, Shunta Sasaki, Jun Fujimoto and Hiroshi Sugiyama*

Department of Chemistry, Faculty of Science, Kyoto University, Kitashirakawa-oiwakecho, Sakyo-ku, Kyoto, 606-8502, Japan

*To whom correspondence should be addressed. Tel: +81 75 753 4002; Fax: +81 75 753 3670; Email: hs{at}kuchem.kuoto-u.ac.jp

Received December 12, 2007. Revised February 18, 2008. Accepted February 19, 2008.

To investigate the binding of 5'–CpG–3' sequences by small molecules, two pyrrole (Py)–imidazole (Im) hairpin polyamides, PyImPyIm–{gamma}–PyImPyIm–β–Dp (1) and PyIm–β–Im–{gamma}–PyIm–β–Im–β–Dp (2), which recognize the sequence 5'–CGCG–3', were synthesized. The binding affinities of the 5'–CGCG–3' sequence to the Py–Im hairpin polyamides were measured by surface plasmon resonance (SPR) analysis. SPR data revealed that dissociation equilibrium constants (Kd) of polyamides 1 and 2 were 1.1 (± 0.3) x 10–6 M and 1.7 (± 0.4) x 10–8 M, respectively. Polyamide 2 possesses great binding affinity for this sequence, 65-fold higher than polyamide 1. Moreover, when all cytosines in 5'–CpGpCpG–3' were replaced with 5-methylcytosines (mCs), the Kd value of polyamide 2 increased to 5.8 (± 0.7) x 10–9 (M), which indicated about 3-fold higher binding than the unmethylated 5'–CGCG–3' sequence. These results suggest that polyamide 2 would be suitable to target CpG-rich sequences in the genome.


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