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Originally published in Science Express on 19 August 2004
Science 10 September 2004:
Vol. 305. no. 5690, pp. 1601 - 1605
DOI: 10.1126/science.1102629
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Reports

DNA-Templated Organic Synthesis and Selection of a Library of Macrocycles

Zev J. Gartner, Brian N. Tse, Rozalina Grubina, Jeffrey B. Doyon, Thomas M. Snyder, David R. Liu*

The translation of nucleic acid libraries into corresponding synthetic compounds would enable selection and amplification principles to be applied to man-made molecules. We used multistep DNA-templated organic synthesis to translate libraries of DNA sequences, each containing three "codons," into libraries of sequence-programmed synthetic small-molecule macrocycles. The resulting DNA-macrocycle conjugates were subjected to in vitro selections for protein affinity. The identity of a single macrocycle possessing known target protein affinity was inferred through the sequence of the amplified DNA template surviving the selection. This work represents the translation, selection, and amplification of libraries of nucleic acids encoding synthetic small molecules rather than biological macromolecules.

Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.

* To whom correspondence should be addressed. E-mail: drliu{at}fas.harvard.edu

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