Collaboration on DNA sequence-specific recognition by small molecules

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By the completion of the human genome project, many diseases including cancer, hereditary and viral diseases can be understood by the DNA sequence level. Control of the specific gene expression will provide ultimate gene therapy. Minor groove binding polyamides containing N-methylpyrrole and N-methylimidazole amino acids exhibit promising performance based on the recognition of nucleic acid sequences. Various types of sequence-specific DNA binding agents are developed and used for the regulation of gene expression. In this collaboration, we synthesized novel type of polyamide-alkylator conjugates and unnatural DNA and investigated molecular basis of sequence specific recognition by small molecules including pyrrole-imidazole polyamides. These synthetic compounds alkylated predetermined DNA sequences selectively, and also some of them possessed selective potency for certain cancer cell lines. One of the future directions of rational design of molecular medicine in the post genome era is proposed.