Selection-based discovery of druglike macrocyclic peptides.

Area of Science:

• Biochemistry and Medicinal Chemistry
• Drug Discovery and Development

Background:

• Macrocyclic peptides are a novel therapeutic class targeting protein-protein interactions.
• Traditional drug discovery relies on high-throughput screening of small molecules.

Purpose of the Study:

• To review technologies for identifying bioactive macrocyclic peptides.
• To highlight recent advancements in macrocyclic peptide drug discovery.

Main Methods:

• Ribosomal translation for synthesizing peptide-based macrocycles.
• In vitro selection techniques for rapid screening of large compound libraries (>10^13 species).
• Chemical modification and genetic code engineering to enhance structural diversity.

Main Results:

• Enables extremely rapid screening (hours to days) of diverse macrocyclic peptide libraries.
• Significantly expands the structural diversity of peptide libraries.
• Facilitates identification of novel therapeutics modulating protein-protein interactions.

Conclusions:

• Macrocyclic peptides represent a powerful platform for drug discovery.
• Advancements in synthesis and screening accelerate the identification of therapeutic macrocycles.
• This approach offers a promising alternative to traditional small-molecule drug discovery.