Cyclo-Polyproline: Chameleonic All-Peptide Macrocycles With Induced-Fit Host-Guest Recognition

Area of Science:

• Supramolecular Chemistry
• Organic Synthesis
• Chemical Biology

Background:

• Traditional synthetic host macrocycles face limitations in control and functionalization.
• Developing novel macrocyclic scaffolds is crucial for advancing host-guest chemistry and supramolecular systems.

Purpose of the Study:

• To design, synthesize, and characterize a new class of all-peptide macrocycles, Cyclo-Polyprolines (CP).
• To explore the conformational flexibility and host-guest properties of CP scaffolds.
• To establish a versatile platform for functionalized proline-based hosts.

Main Methods:

• Fmoc-based solid-phase peptide synthesis (SPPS) for controlled macrocycle construction.
• Head-to-tail macrocyclization to create the CP scaffold.
• NMR spectroscopy and single-crystal X-ray diffraction for structural elucidation.
• Host-guest binding studies to demonstrate responsive capabilities.

Main Results:

• Successful synthesis and characterization of Cyclo-Polyprolines (CP) with high solubility.
• Discovery of a chameleonic conformational transition from cis to trans isomers driven by hydration.
• Demonstration of induced-fit binding and formation of an all-peptide pseudo-rotaxane.
• CP scaffolds exhibit tunable primary sequence and secondary structure control.

Conclusions:

• Cyclo-Polyprolines represent a robust and versatile platform for creating functionalized peptide-based hosts.
• The conformational responsiveness to hydration offers novel design principles for smart supramolecular systems.
• This methodology bridges supramolecular chemistry and enzyme mimetics with potential in medicinal chemistry, drug delivery, and organocatalysis.