Crosslinking of DNA-linked Ligands to Target Proteins for Enrichment from DNA-encoded Libraries

Overview

Journal Medchemcomm

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2017 Sep 27

PMID 28948007

Citations 19

Authors

Kyle E Denton

Casey J Krusemark

Affiliations

Soon will be listed here.

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 teathering 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.

Citing Articles

Small-molecule discovery through DNA-encoded libraries.

Peterson A, Liu D Nat Rev Drug Discov. 2023; 22(9):699-722.

PMID: 37328653 PMC: 10924799. DOI: 10.1038/s41573-023-00713-6.

Machine-Learning-Based Data Analysis Method for Cell-Based Selection of DNA-Encoded Libraries.

Hou R, Xie C, Gui Y, Li G, Li X ACS Omega. 2023; 8(21):19057-19071.

PMID: 37273617 PMC: 10233830. DOI: 10.1021/acsomega.3c02152.

Selection methods for proximity-dependent enrichment of ligands from DNA-encoded libraries using enzymatic fusion proteins.

Cai B, Mhetre A, Krusemark C Chem Sci. 2023; 14(2):245-250.

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PAC-FragmentDEL - photoactivated covalent capture of DNA-encoded fragments for hit discovery.

Ma H, Murray J, Luo H, Cheng X, Chen Q, Song C RSC Med Chem. 2022; 13(11):1341-1349.

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Recent advances in DNA-encoded dynamic libraries.

Shi B, Zhou Y, Li X RSC Chem Biol. 2022; 3(4):407-419.

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