Macromolecular Function Emerging from Intramolecular Peptide Stapling of Synthetic Polymers

Area of Science:

• Polymer Chemistry
• Biomaterials Science
• Nanotechnology

Background:

• Protein function relies on precise folding into specific architectures.
• Single-chain nanoparticles (SCNPs) are synthetic polymers crosslinked intramolecularly, inspired by natural protein folding.
• Current SCNP functionality is typically dictated by the polymer or crosslinker, not the crosslinking process.

Purpose of the Study:

• To explore the cyanopyridine-aminothiol click reaction for creating peptide-decorated SCNPs.
• To investigate emerging functionalities arising from the pyridine-thiazoline crosslinking process.
• To compare pyridine-thiazoline crosslinked SCNPs with disulfide crosslinked SCNPs.

Main Methods:

• Synthesis of dimethylacrylamide-based polymers with cysteine-terminated amino acid sequences (P1(C), P2(GDHC), P3(GDSC)).
• Intramolecular crosslinking of polymers to form SCNPs using the cyanopyridine-aminothiol click reaction.
• Comparison of SCNPs crosslinked via pyridine-thiazoline formation versus disulfide bonds.

Main Results:

• The formation of pyridine-thiazolines created metal-binding sites within SCNPs, demonstrated by iron complexation.
• Pyridine-thiazoline crosslinking modulated the hydrolytic activity of peptide sequences.
• GDHC-containing SCNPs showed increased hydrolytic activity, while GDSC-containing SCNPs showed decreased activity compared to disulfide-crosslinked counterparts.

Conclusions:

• The cyanopyridine-aminothiol click reaction provides a versatile method for creating functional SCNPs.
• Pyridine-thiazoline crosslinking introduces novel properties, including metal-binding and tunable enzymatic activity.
• This approach offers a pathway to engineer SCNPs with emergent functionalities beyond those of traditional crosslinking methods.