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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Bio-Organic and Natural Products Chemistry Study Section (BNP)
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Schwab, John M
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Harvard University
Schools of Arts and Sciences
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Chan, Alix I; McGregor, Lynn M; Liu, David R (2015) Novel selection methods for DNA-encoded chemical libraries. Curr Opin Chem Biol 26:55-61
Maianti, Juan Pablo; McFedries, Amanda; Foda, Zachariah H et al. (2014) Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature 511:94-8
Guilinger, John P; Pattanayak, Vikram; Reyon, Deepak et al. (2014) Broad specificity profiling of TALENs results in engineered nucleases with improved DNA-cleavage specificity. Nat Methods 11:429-35
McDonald, Richard I; Guilinger, John P; Mukherji, Shankar et al. (2014) Electrophilic activity-based RNA probes reveal a self-alkylating RNA for RNA labeling. Nat Chem Biol 10:1049-54
Curtis, Edward A; Liu, David R (2014) A naturally occurring, noncanonical GTP aptamer made of simple tandem repeats. RNA Biol 11:682-92
Blakely, Brandon L; Dumelin, Christoph E; Trappmann, Britta et al. (2014) A DNA-based molecular probe for optically reporting cellular traction forces. Nat Methods 11:1229-32
McGregor, Lynn M; Jain, Tara; Liu, David R (2014) Identification of ligand-target pairs from combined libraries of small molecules and unpurified protein targets in cell lysates. J Am Chem Soc 136:3264-70
Curtis, Edward A; Liu, David R (2013) Discovery of widespread GTP-binding motifs in genomic DNA and RNA. Chem Biol 20:521-32
Niu, Jia; Hili, Ryan; Liu, David R (2013) Enzyme-free translation of DNA into sequence-defined synthetic polymers structurally unrelated to nucleic acids. Nat Chem 5:282-92
Hili, Ryan; Niu, Jia; Liu, David R (2013) DNA ligase-mediated translation of DNA into densely functionalized nucleic acid polymers. J Am Chem Soc 135:98-101

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