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Impact of organic chemistry conditions on DNA durability in the context of DNA-encoded library technology

ABSTRACT: Summary High-power screening (HPS) technologies, such as DNA-encoded library (DEL) technology, could exponentially increase the dimensions of the chemical space accessible for drug discovery. The intrinsic fragile nature of DNA is associated with cumbersome limitations and DNA durability (e.g., depurination, loss of phosphate groups, adduct formation) is compromised in numerous organic chemistry conditions that require empirical testing. An atlas of reaction conditions (temperature, pH, solvent/buffer, ligands, oxidizing reagents, catalysts, scavengers in function of time) that have been systematically tested in multiple combinations, indicates precisely limits useful for DEL construction. More importantly, this approach could be used broadly to effectively evaluate DNA-compatibility of any novel on-DNA chemical reaction, and it is compatible with different molecular methodologies. This atlas and the general approach presented, by allowing novel reaction conditions to be performed in presence of DNA, should greatly help in expanding the DEL chemical space as well as any field involving DNA durability. Graphical abstract Highlights • Comprehensive atlas of numerous reaction conditions compatible with DNA• Molecular approach to test DNA durability in a time-dependent manner• Impact of different treatments (e.g., temperatures, pHs, catalysts, ligands) on DNA• Importance of DNA content (GC %) and DNA nature for stability Organic chemistry; Biochemistry

SUBMITTER: Sunkari Y

PROVIDER: S-EPMC10470182 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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