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Quantitative Validation and Application of the Photo-Cross-Linking Selection for Double-Stranded DNA-Encoded
Xinyuan Wu1,2, Yujie Chen1,2, Weiwei Lu1
1State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China.
Bioconjugate Chemistry
|October 5, 2022
Summary
This study introduces a novel photo-cross-linking selection method for DNA-encoded compound libraries (DELs) to identify moderate-affinity ligands. This new approach successfully screened both high- and moderate-affinity ligands, advancing drug discovery.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Drug Discovery
Background:
- DNA-encoded compound library (DEL) technology accelerates target hit discovery.
- Current DEL selection methods primarily identify high-affinity ligands, potentially missing moderate-affinity candidates crucial for drug development.
Purpose of the Study:
- To design and validate a photo-cross-linking selection method for DNA-encoded compound libraries (DELs) to screen moderate-affinity ligands.
- To develop dual-stranded DNA-encoded libraries (dsDELs) incorporating photo-activatable cross-linking groups.
Main Methods:
- Construction of two photo-cross-linking libraries with varying linker lengths connecting a diazirine group to DNA-encoded compounds.
- UV irradiation to activate the diazirine group for covalent bonding with target proteins within proximity.
- Validation of the screening system using quantitative PCR (qPCR) and next-generation sequencing (NGS) technologies.
Main Results:
- Successful demonstration of the photo-cross-linking DEL screening system's feasibility in a model selection experiment.
- Identification and selection of both high-affinity and moderate-affinity ligands from the constructed libraries.
- Verification of ligand selection through qPCR and NGS analysis.
Conclusions:
- The developed photo-cross-linking selection method effectively expands the scope of DEL screening to include moderate-affinity ligands.
- This technique offers a promising strategy for discovering novel drug candidates with tunable affinities.
- The study validates a new tool for accelerating hit discovery in pharmaceutical research.
