Highly pure DNA-encoded chemical libraries by dual-linker solid-phase synthesis

Science. 2024 Jun 14;384(6701):1259-1265. doi: 10.1126/science.adn3412. Epub 2024 Jun 13.

Abstract

The first drugs discovered using DNA-encoded chemical library (DEL) screens have entered late-stage clinical development. However, DEL technology as a whole still suffers from poor chemical purity resulting in suboptimal performance. In this work, we report a technique to overcome this issue through self-purifying release of the DEL after magnetic bead-based synthesis. Both the first and last building blocks of each assembled library member were linked to the beads by tethers that could be cleaved by mutually orthogonal chemistry. Sequential cleavage of the first and last tether, with washing in between, ensured that the final library comprises only the fully complete compounds. The outstanding purity attained by this approach enables a direct correlation of chemical display and encoding, allows for an increased chemical reaction scope, and facilitates the use of more diversity elements while achieving greatly improved signal-to-noise ratios in selections.

MeSH terms

  • DNA* / chemistry
  • Drug Discovery* / methods
  • Small Molecule Libraries* / chemical synthesis
  • Small Molecule Libraries* / chemistry
  • Solid-Phase Synthesis Techniques* / methods

Substances

  • DNA
  • Small Molecule Libraries