| Nature uses evolution to discover functional nucleic acids and proteins. In order to apply this powerful approach to other chemical structures, a method is needed to translate an amplifiable information carrier such as DNA into arbitrary chemical structures. We have developed DNA-templated organic synthesis (DTS) as such a method. DTS can sequence-specifically generate products unrelated in structure to the DNA backbone, can proceed efficiently without functional group adjacency, can mediate sequence-programmed multistep small-molecule synthesis, and can enable reaction pathways that cannot be realized using conventional synthetic strategies. These properties of DTS allowed us to perform the first translation, selection and amplification of a library of oligonucleotides encoding a library of entirely synthetic macrocyclic peptide fumamarides. The methods developed here enable synthetic molecules to benefit from powerful manipulations previously available only to biological macromolecules. |
