Peptide Macrocycles Developed from Precisely Regulated Multiple Cyclization of Unprotected Peptides

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Peptide macrocycles are valuable scaffolds for drug development, acting as ligands and inhibitors.
• Novel macrocyclization strategies are crucial for advancing peptide drug design.
• Existing methods may lack efficiency or require protection/deprotection steps.

Purpose of the Study:

• To develop an efficient strategy for synthesizing novel macrocyclic peptide scaffolds.
• To utilize a one-pot cyclization method for unprotected peptides.
• To explore the potential of these scaffolds in drug discovery.

Main Methods:

• Employed a one-pot cyclization reaction of unprotected peptides with 2,3,5,6-tetrafluoroterephthalonitrile (4F-2CN).
• Designed peptide bicycles featuring fused N-terminal and C-terminal rings with the 4F-2CN benzene core.
• Characterized the resulting structurally hyperconstrained macrocyclic peptides.

Main Results:

• Successfully synthesized novel peptide bicycles via an efficient one-pot cyclization.
• Achieved precise regulation and high efficiency in the macrocyclization process.
• Demonstrated the formation of rigidifying fused ring systems.

Conclusions:

• The reported method provides an efficient route to novel, structurally hyperconstrained peptide macrocycles.
• These macrocyclic peptide scaffolds are promising for developing targeted protein inhibitors and ligands.
• This strategy holds potential for advancing peptide-based drug discovery.