Open AccessStereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications
Author(s) -
Nicholas Favalli,
Gabriele Bassi,
Christian Pellegrino,
Jacopo Millul,
Roberto De Luca,
Samuele Cazzamalli,
Yang Su,
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
Publication year - 2021
Publication title -
nature chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 9.996
H-Index - 232
eISSN - 1755-4349
pISSN - 1755-4330
DOI - 10.1038/s41557-021-00660-y
Subject(s) - chemistry , dna , computational biology , ligand (biochemistry) , drug discovery , regioselectivity , combinatorial chemistry , chemical library , small molecule , biochemistry , receptor , catalysis , biology
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.