A DNA-Encoded Chemical Library Based on Peptide Macrocycles

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Molecular Biology

Background:

• Macrocyclic peptides offer unique therapeutic potential due to their structural diversity and stability.
• DNA-encoded libraries (DELs) enable the screening of vast chemical spaces for drug discovery.
• Efficient methods for library synthesis and screening are crucial for identifying novel bioactive compounds.

Purpose of the Study:

• To synthesize and characterize a novel DNA-encoded library of macrocyclic peptide derivatives.
• To utilize copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) for macrocycle formation within the library.
• To screen the library against target proteins for the identification of specific binders.

Main Methods:

• Construction of a DNA-encoded library (YO-DEL) comprising over 1.25 million macrocyclic peptide derivatives.
• Incorporation of proteinogenic and non-proteinogenic amino acids as building blocks.
• Application of copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC) for DNA-compatible macrocyclization.
• Screening using affinity capture and photocrosslinking techniques against target proteins.

Main Results:

• Successful synthesis and DNA-encoding of the YO-DEL library with 1,254,838 compounds.
• Identification of specific binders against human serum albumin (HSA) and carbonic anhydrases.
• Discovery of binders targeting NKp46, a natural killer cell receptor.

Conclusions:

• The developed DNA-encoded macrocyclic peptide library is a powerful tool for identifying novel protein binders.
• The YO-DEL platform demonstrates the utility of CuAAC in constructing diverse macrocyclic peptide libraries for drug discovery.
• The identified binders represent potential leads for therapeutic or diagnostic applications targeting albumin, carbonic anhydrases, or NKp46.