A Lasso-Inspired Bicyclic Peptide: Synthesis, Structure and Properties.

Area of Science:

• Chemical synthesis
• Peptide chemistry
• Structural biology

Background:

• Lasso peptides are natural products with unique topologically interlocked structures.
• Sungsanpin is a natural lasso peptide known for its stability and complex architecture.
• Developing synthetic analogues of natural products can lead to novel biomaterials and therapeutics.

Purpose of the Study:

• To chemically synthesize a bicyclic peptide inspired by the natural lasso peptide sungsanpin.
• To characterize the synthesized bicyclic structure and confirm its lasso-like properties.
• To evaluate the potential of the bicyclic peptide as a scaffold for epitope grafting.

Main Methods:

• Combined solid-phase and in-solution chemical synthesis strategies.
• Mass spectrometry (MS) fragmentation for structural elucidation.
• Ion-mobility spectroscopy to assess topological features and behavior.
• Nuclear magnetic resonance (NMR) spectroscopy for detailed structural analysis and 3D structure prediction.

Main Results:

• Successful chemical synthesis of a bicyclic peptide topoisomer.
• Confirmation of a covalent linkage between the ring and loop, forming the bicyclic structure.
• Ion-mobility studies demonstrated lasso-like behavior consistent with the target structure.
• NMR analysis provided restraints for predicting the three-dimensional structure.
• The synthesized bicyclic peptide exhibited high proteolytic and thermal stability.

Conclusions:

• A novel bicyclic peptide, mimicking natural lasso peptides, was successfully synthesized.
• The synthesized structure possesses inherent stability and lasso-like characteristics.
• This bicyclic peptide scaffold holds promise for applications in epitope grafting and drug design.