DNA-Encoded Combinatorial Library of Macrocyclic Peptoids.

Area of Science:

• Medicinal Chemistry
• Synthetic Chemistry
• Drug Discovery

Background:

• Developing novel molecular libraries is crucial for identifying new therapeutic agents.
• Cyclic peptoids offer conformational rigidity, making them promising scaffolds for drug design.
• Targeting challenging biological interactions, such as protein-protein interactions, requires innovative molecular approaches.

Purpose of the Study:

• To design and synthesize a large DNA-encoded one-bead one-compound library of cyclic peptoids.
• To establish an efficient screening method for identifying cyclic peptoid ligands against target proteins.
• To develop a simplified structure determination process for hit compounds and minimize false positives.

Main Methods:

• Synthesis of a DNA-encoded library comprising over 11 million unique cyclic peptoids.
• Affinity-based screening of the library to identify compounds binding to a target protein.
• Development of a simple PCR amplification method for DNA tags on single beads for structure elucidation.
• Implementation of a sublibrary screening strategy to mitigate coding DNA tag interference.

Main Results:

• Successful identification of cyclic peptoid ligands for a target protein using the developed library and screening method.
• Demonstration of a simplified, non-high-throughput sequencing approach for determining the structures of identified hit compounds.
• Validation of a sublibrary screening strategy that effectively reduces false positives.

Conclusions:

• The developed DNA-encoded cyclic peptoid library and screening method are simple, robust, and efficient for discovering biologically active molecules.
• This approach is particularly valuable for identifying modulators of challenging targets like protein-protein interactions.
• Macrocyclic peptoids, with their inherent conformational rigidity, represent a promising class of compounds for future drug discovery efforts.