Alexander K. Price; Brian M. Paegel
ACS Comb. Sci., 2020, 22(11), 649-655
https://doi.org/10.1021/acscombsci.0c00101

Abstract

DNA-encoded library (DEL) technology enables rapid, economical synthesis and exploration of novel chemical space. Reaction development for DEL synthesis has recently accelerated in pace with a specific emphasis on ensuring that the reaction does not compromise the integrity of the encoding DNA. However, the factors that contribute to a reaction’s “DNA compatibility” remain relatively unknown. We investigated several solid-phase reactions and encoding conditions and determined their impact on DNA compatibility. Conditions that minimized the accessibility of reactive groups on the DNA encoding tag (switching solvent, low temperature, double-stranded encoding tag) significantly improved compatibility. We showcased this approach in the multi-step synthesis of an acyldepsipeptide (ADEP1) fragment, which preserved 73% of DNA for a >100-fold improvement over canonical conditions. These results are particularly encouraging in the context of multi-step reaction sequences to access natural product-like scaffolds, and more broadly underscore the importance of reconciling the biophysical properties and reactivity of DNA with chemistry development to yield high-quality libraries of those scaffolds.