5 DNAテンプレート合成法とin vitroセレクション法を応用した新規機能分子探索法の研究(口頭発表の部)

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DNA-templated organic synthesis (DTS) has recently emerged as a general approach to translate DNA templates into DNA-linked synthetic small molecules. DNA templates not only direct chemistries to construct small molecules but also serve as amplifiable bar codes used to identify the chemical structure of the small molecules. Therefore, through DTS, synthetic small molecules can now be subjected to in vitro selection methods for discovery of novel functional molecules. We are interested in exploring the potential of a selection-based approach to the discovery of functional small molecules. In order to discover protein binding small molecules, we have developed a selection method suitable for small-molecule products of DTS. The method involves an affinity pull-down assay of the DNA-linked ligands using a target protein immobilized on beads, followed by PCR amplification and sequencing of DNA templates encoding the bound ligands to identify chemical structures of small molecules that bound to proteins. We have found that our selection method can provide up to a 10^4-fold enrichment of the active ligand in a single step at a very minute scale (<1 pmol of total library compounds and a protein target). Encouraged by these results, we are currently in the process of evaluating the protein binding properties of a library of 1000-membered DNA-linked small molecules derived from an N-acyloxazolidine core structure. In principle, this integrated discovery system based on DNA-encoded small molecule libraries and in vitro selection should be useful for the discovery of novel synthetic small molecules with any desired protein binding functions. Unique properties of DTS inspired us to pursue a new approach to reaction discovery. Specific juxtaposition of two DNA-linked substrates by DNA duplex formation among others in a single highly dilute solution would enable rapid and simultaneous examination of their bond-forming reactivity. The use of DNA microarray technology as a novel high-throughput DNA sequence identification method for in vitro selection led us to discover an efficient carbon-carbon bond forming reaction between a terminal alkyne and alkene in the presence of a palladium salt. Although this approach is only applicable to DNA compatible aqueous reaction conditions, it should be a powerful methodology for discovering unknown reactions between different types of substrates under a vast range of reaction conditions that are yet to be explored.
天然有機化合物討論会の論文
2006-09-15

5 DNAテンプレート合成法とin vitroセレクション法を応用した新規機能分子探索法の研究(口頭発表の部)

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