A Single-Stranded DNA-Encoded Chemical Library Based on a Stereoisomeric Scaffold Enables Ligand Discovery by Modular...

Area of Science:

• Medicinal Chemistry
• Molecular Biology
• Biotechnology

Background:

• DNA-encoded libraries (DELs) are powerful tools for drug discovery.
• Developing versatile and compliant DELs is crucial for identifying novel therapeutic agents.
• Glutamic acid derivatives offer a promising scaffold for library design.

Purpose of the Study:

• To design, construct, and characterize a versatile, Lipinski-compliant DNA-encoded library (DEL).
• To utilize the DEL for de novo identification of specific binders against pharmaceutically relevant proteins.
• To explore affinity maturation of identified binders through self-assembly with known ligands.

Main Methods:

• Construction of a DNA-encoded library (DEL) with 366,600 glutamic acid derivatives linked to DNA barcodes.
• Characterization of the single-stranded DNA (ssDNA) DEL format.
• Hybridization of the ssDNA DEL with DNA-coupled protein ligands for affinity maturation.

Main Results:

• Successful design, construction, and characterization of the GB-DEL library.
• Demonstrated ability of the library to identify de novo binders against pharmaceutically relevant proteins.
• Identification of affinity-matured compounds through self-assembly and selection.

Conclusions:

• The developed GB-DEL is a versatile platform for identifying novel protein binders.
• The library facilitates both de novo discovery and affinity maturation of drug candidates.
• This approach holds significant potential for accelerating pharmaceutical research and development.