Rapid Generation of Hypervariable Chemical Libraries

Combinatorial peptidomimetic libraries facilitate the economical identification and refinement of lead compounds directed at diverse therapeutic targets. Further development of selection-based approaches to drug discovery utilizing such libraries is impeded, however, both by the slow pace of library generation and by the physical limitations to library diversity inherent to current methods. To overcome these barriers, we describe here the adaptation of peptide flow synthesis technology to the generation of combinatorial libraries. Using a simple and accessible semi-automated flow platform, we demonstrate methods for library synthesis including both canonical and noncanonical amino acid building blocks in a format that quickens the pace of library synthesis from days to < 1 hour per library while permitting individual library size orders of magnitude beyond current approaches up to a physical maximum of 10¹⁹ members. Flow synthesis is thus a powerful approach for the rapid generation of hypervariable libraries for selection-based drug discovery.