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Encoded Display of Chemical Libraries on Nanoparticles as a Versatile Selection Tool To Discover Protein Ligands
Kang Ju Lee1, Hee Myeong Wang1, Minkyung Kim1
1Department of Chemistry and Division of Advanced Materials Science, Pohang University of Science and Technology (POSTECH), Pohang 37673, South Korea.
Journal of the American Chemical Society
|February 26, 2025
Summary
A novel nano-enabled DNA-encoded library (DEL) strategy overcomes limitations of conventional DEL by displaying molecules on nanoparticles. This allows for expanded chemical diversity and robust synthesis using organic solvents, enabling efficient drug discovery.
Area of Science:
- Chemical Biology
- Drug Discovery
- Nanotechnology
Background:
- DNA-encoded library (DEL) technology is crucial for identifying ligands but faces challenges with DNA solubility and stability in organic solvents.
- These limitations restrict the chemical space and diversity of libraries synthesized using conventional DEL methods, often requiring aqueous conditions.
Purpose of the Study:
- To introduce nanoDEL, a new strategy that displays library molecules and DNA tags on nanoparticles for enhanced DEL synthesis.
- To overcome the solubility and stability issues of DNA in conventional DEL, enabling broader reaction scope and increased structural diversity.
Main Methods:
- Library molecules and DNA tags are conjugated to the surface of nanoparticles, creating the nanoDEL system.
- DEL synthesis is performed in organic solvents, accommodating air-sensitive and moisture-sensitive reactions.
- Multiple DNA tags per nanoparticle enhance DNA damage tolerance, ensuring feasible sequence analysis via amplification.
Main Results:
- nanoDEL demonstrated successful affinity selection against streptavidin.
- Potent small-molecule kinase inhibitors and stapled peptide inhibitors were discovered with nanomolar dissociation constants.
- Efficient synthesis of large combinatorial libraries, including those with moisture-sensitive steps, was achieved on nanoparticles.
Conclusions:
- nanoDEL technology expands the capabilities of DEL by utilizing nanoparticles for improved synthesis and stability.
- This approach facilitates the use of diverse organic reactions, leading to the discovery of potent inhibitors for biological targets.
- nanoDEL offers a robust and versatile platform for accelerating drug discovery through enhanced library synthesis.
