Author: ["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"]
CITE.CC academic search helps you expand the influence of your papers.
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. A DNA-encoded chemical library based on regio- and stereoisomers of phenylalanine has been synthesized and used for affinity-based selections against multiple target proteins. This approach led to the isolation and validation of potent ligands capable of CAR T-cell activation and tumour targeting.Cite this article
Favalli, N., Bassi, G., Pellegrino, C. et al. Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications. Nat. Chem. (2021). https://doi.org/10.1038/s41557-021-00660-y 