| In 1967, the field of in vitro evolution was born when Spiegelman and coworkers demonstrated the first "extracellular Darwinian experiment". In vitro evolution strategies are now used routinely to isolated biopolymers with desired functional properties. In more recent years, our lab and others have been interested in applying evolution-based search strategies to synthetic compounds, as doing so could radically simplify small-molecule discovery, with applications in countless fields.; This thesis first reviews the new "chemical evolution" movement, discussing key advances and future directions of the field. Second, chemical methods for DNA-programmed library synthesis are presented, including the validation of comprehensive strategies for peptide and peptoid synthesis. Third, the chemical strategies are utilized to generate a DNA-programmed library of 100 million novel compounds. The library is subjected to multiple rounds of in vitro selection for protein binding, and it converges to a small number of sequence families, which are validated to represent true synthetic ligands. The work represents the first example of evolution-based discovery of synthetic compounds. |
