Two of the most ubiquitous challenges in chemistry are how to control chemical reactivity and how to discover molecules with optimal properties from many possible structures. My laboratory has initiated a program to develop a new approach to addressing these two challenges that differs from the approaches most frequently taken by chemists. Our approach combines powerful aspects of natural biosynthesis and molecular evolution with the flexibility of synthetic organic chemistry. We discovered that DNA duplex formation exerts remarkable control over the effective molarity of DNA-linked reactants without structural requirements. The surprising generality of DNA-templated organic synthesis has enabled us to subject synthetic molecules to translation, selection, and amplification that parallel the molecular evolution of biological molecules in Nature. This proposal seeks to develop our initial studies in a direction that will further reveal the principles that underlie DNA-templated synthesis and, using these principles, further expand our synthetic capabilities. I believe that this approach to creating synthetic molecules already merits an early stage effort to couple DNA-templated organic synthesis with selection methods for discovering molecules with functional properties. As a result, I also propose to develop true selections (as opposed to screens) based on iterative rounds of protein binding, and to apply these selections to our first DNA-templated small molecule libraries. The development of these new areas may lead to the discovery of new functional synthetic molecules as research tools for probing biological functions or as leads for new therapeutics.
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