Michelle Keller; Dimitar Petrov; Andreas Gloger; Bastien Dietschi; Kilian Jobin; Timon Gradinger; Adriano Martinelli; Louise Plais; Yuichi Onda; Dario Neri; Jörg Scheuermann
Science, 2024, 384(6701), 1259-1265
https://doi.org/10.1126/science.adn3412

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. DNA-encoded chemical libraries enable screening of an enormous number of prospective drug compounds in parallel. The idea is that the functional components of each prospective drug are encoded with a DNA sequence that can be amplified later to identify the structure of a hit. However, incomplete syntheses can introduce errors in matching the tag to the functionality. Keller et al. devised a dual linker technique to ensure fidelity. Orthogonally cleavable linkers tether the first and last introduced components to a bead. Cutting both linkers successively, with washing in between, release only complete structures. —Jake S. Yeston