Nicholas Favalli; Gabriele Bassi; Christian Pellegrino; Jacopo Millul; Roberto De Luca; Samuele Cazzamalli; Su Yang; Anika Trenner; Nour L. Mozaffari; Renier Myburgh; Mustafa Moroglu; Stuart J. Conway; Alessandro A. Sartori; Markus G. Manz; Richard A. Lerner; Peter K. Vogt; Jörg Scheuermann; Dario Neri
Nat. Chem., 2021, 13, 540-548
https://doi.org/10.1038/s41557-021-00660-y

Abstract

The encoding of chemical compounds with amplifiable DNA tags facilitates the discovery of small-molecule ligands for proteins. To investigate the impact of stereo- and regiochemistry on ligand discovery, we synthesized a DNA-encoded library of 670,752 derivatives based on 2-azido-3-iodophenylpropionic acids. The library was selected against multiple proteins and yielded specific ligands. The selection fingerprints obtained for a set of protein targets of pharmaceutical relevance clearly showed the preferential enrichment of ortho-, meta- or para-regioisomers, which was experimentally verified by affinity measurements in the absence of DNA. The discovered ligands included novel selective enzyme inhibitors and binders to tumour-associated antigens, which enabled conditional chimeric antigen receptor T-cell activation and tumour targeting.