Protein function results from the precise folding of polypeptides into bespoke architectures. Taking inspiration from nature, the field of single-chain nanoparticles (SCNPs), intramolecularly crosslinked synthetic polymers, emerged. In contrast to nature, the function of SCNPs is generally defined by the parent polymer or the applied crosslinker, rather than by the crosslinking process itself. This work explores the cyanopyridine-aminothiol click reaction to crosslink peptide-decorated polymers intra-macromolecularly to endow the resulting SCNPs with emerging functionality, resulting from the conversion of N-terminal cysteine units into pyridine-thiazolines. Dimethylacrylamide based polymers with different cysteine-terminated amino acid sequences tethered to their sidechains are investigated (P1 (C), P2 (GDHC), P3 (GDSC)) and intramolecularly crosslinked into SCNPs. Since the deprotection of the parent polymers yields disulfide-based SCNPs, a direct comparison between disulfide and pyridine-thiazolines crosslinked SCNPs is possible. This comparison revealed two emerging properties of the pyridine-thiazoline crosslinked SCNPs: 1) The formation of pyridine-thiazolines gave rise to metal binding sites within the SCNP, which complexed iron. 2) Depending on the peptide sequence in the precursor polymer, the hydrolytic activity of the peptide sequences is either increased (GDHC) or decreased (GDSC) upon pyridine-thiazoline formation compared to identical SCNPs based on disulfide crosslinks.
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