Nucleophilic Initiation of Episulfide Anionic Ring-Opening Polymerization by Amino Acids and Oligopeptides

Peptide-polymer conjugates are promising molecules because they combine the biological functionality of peptides with the versatile properties of polymers, enabling applications in drug delivery, biomaterials, and nanomedicine with enhanced stability, biocompatibility, and tailored functionalities. Until now, the grafting-to approach has been the predominant strategy for synthesizing these biohybrids. By comparison, grafting-from techniques are relatively less diverse. Mainly, radical grafting-from techniques have also been developed, but they present a number of limitations, including a limited variety of polymerizable monomers and the introduction of nonbiodegradable polymer chains. The AROP-based grafting-from strategy offers a promising, yet still underexplored, route for synthesizing peptide-polymer conjugates bearing heteroatom-containing polymer side chains. We report an original AROP grafting-from strategy using primary amines as attachment sites, <i>N</i>-acetyl homocysteine thiolactone as a linker, and propylene sulfide as a monomer. The grafting-from technique was optimized using various protected and unprotected amino acids as model scaffolds. In addition, the regioselective functionalization of primary amine lateral substituents of lysine residues over chain-end amines was demonstrated. The method was then extended to dipeptides and tripeptides. Surprisingly, the grafting-from polymerization was demonstrated to also occur in a controlled manner using oligopeptide initiators bearing unprotected terminal carboxylic acid end-groups. Furthermore, this technique was applied to the introduction of polythioether grafts on the KLVFF peptide sequence (Lys-Leu-Val-Phe-Phe), which is a key recognition motif found in the amyloid-β (Aβ) protein, a protein strongly associated with Alzheimer's disease.