Split-and-pool synthesis and characterization of peptide tertiary amide library

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Biochemistry

Background:

• Peptidomimetics, including peptoids, are valuable for identifying protein ligands.
• Current peptoid libraries often yield low-affinity ligands due to a lack of conformational constraint.
• Peptoids are proteolysis-resistant and cell-permeable, making them attractive scaffolds.

Purpose of the Study:

• To introduce a novel class of peptidomimetics: peptide tertiary amides (PTAs).
• To explore the potential of PTAs as a source of high-affinity protein ligands.
• To develop a synthetic strategy for creating diverse PTA libraries.

Main Methods:

• Utilized a new synthetic route to access peptide tertiary amides (PTAs).
• Employed a combination of split-and-pool and sub-monomer synthesis strategies.
• Synthesized a sample one-bead one-compound (OBOC) library of PTAs.

Main Results:

• PTA molecules exhibit significant conformational constraint due to side chains on both alpha-carbon and main chain nitrogen.
• These constrained PTAs are highly structured in solution.
• The developed method enables the synthesis of OBOC PTA libraries.

Conclusions:

• PTAs represent a promising superfamily of peptidomimetics with potential for high-affinity ligand discovery.
• The conformational rigidity of PTAs may overcome limitations of existing peptidomimetics.
• The described synthetic approach facilitates the generation of diverse PTA libraries for screening.