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Abstract
An amphiphilic DNA encoding platform was developed that allows the high-throughput evaluation of a large small-molecule library for a wide assortment of catalytic reactions in organic solvents. The cornerstone of this platform is a replicable, amphiphilic DNA that encodes a chemical library. Each member of the library is uniquely identifiable via a covalent attachment of encoded DNA (genotype) and small-molecule catalyst (phenotype). The amphiphilic nature of the DNA-encoded small-molecule library stems from the development of a PEG polymer that enables solubility in both aqueous and organic solvents. In vitro selection enables catalytically active members surviving the selection pressure intermolecular bond formation of the DNA code to an affinity tag to be separated from inactive members, PCR amplified and identified by high-throughput DNA sequencing. We explored the solubility, stability, and thermodynamics of PEGylated ssDNA in organic solvents, investigated the compatibility of PEGylated DNA as an encoding element during catalytic reactions in organic solvents, and developed methods to generate and screen a PEGylated DNA-encoded peptide library for catalytic activity in organic solvents.