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Issue 10, 2016
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Crosslinking of DNA-linked ligands to target proteins for enrichment from DNA-encoded libraries

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Abstract

Achieving sufficient enrichment of ligands from DNA-encoded libraries for detection can be difficult, particularly for low affinity ligands within highly complex libraries. To address this challenge, we present an approach for crosslinking DNA-linked ligands to target proteins using electrophilic or photoreactive groups. The approach involves the tethering of a ssDNA oligonucleotide to a DNA-encoded molecule to enable attachment of a reactive group post-synthetically via DNA hybridization. Crosslinking traps ligand–protein complexes while in solution and allows for stringent washing conditions to be applied in the subsequent purification. Five reactive groups (tosyl, NHS ester, sulfonyl fluoride, phenyl azide, and diazirine) were tested for crosslinking efficiency and specificity with three DNA-linked ligands to their target proteins. In a model selection, crosslinking resulted in improved enrichment of both high and a low affinity ligands in comparison to a selection with a solid-phase immobilized protein.

Graphical abstract: Crosslinking of DNA-linked ligands to target proteins for enrichment from DNA-encoded libraries

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Publication details

The article was received on 27 May 2016, accepted on 29 Jul 2016 and first published on 02 Aug 2016


Article type: Research Article
DOI: 10.1039/C6MD00288A
Citation: Med. Chem. Commun., 2016,7, 2020-2027
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    Crosslinking of DNA-linked ligands to target proteins for enrichment from DNA-encoded libraries

    K. E. Denton and C. J. Krusemark, Med. Chem. Commun., 2016, 7, 2020
    DOI: 10.1039/C6MD00288A

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