Design of Sequence-Specific DNA Binding Molecules for DNA Methyltransferase Inhibition

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• 作者：JeenJoo S. Kang ; Jordan L. Meier ; Peter B. Dervan
• 刊名：Journal of the American Chemical Society
• 出版年：2014
• 出版时间：March 5, 2014
• 年：2014
• 卷：136
• 期：9
• 页码：3687-3694
• 全文大小：544K
• 年卷期：v.136,no.9(March 5, 2014)
• ISSN：1520-5126

文摘

The CpG dyad, an important genomic feature in DNA methylation and transcriptional regulation, is an attractive target for small molecules. To assess the utility of minor groove binding oligomers for CpG recognition, we screened a small library of hairpin pyrrole-imidazole polyamides targeting the sequence 5鈥?CGCG-3鈥?and assessed their sequence specificity using an unbiased next-generation sequencing assay. Our findings indicate that hairpin polyamide of sequence PyIm尾Im-纬-PyIm尾Im (<b>1b>), previously identified as a high affinity 5鈥?CGCG-3鈥?binder, favors 5鈥?GCGC-3鈥?in an unanticipated reverse binding orientation. Replacement of one 尾 alanine with Py to afford PyImPyIm-纬-PyIm尾Im (<b>3b>) restores the preference for 5鈥?CGCG-3鈥?binding in a forward orientation. The minor groove binding hairpin <b>3b> inhibits DNA methyltransferase activity in the major groove at its target site more effectively than <b>1b>, providing a molecular basis for design of sequence-specific antagonists of CpG methylation.