LAUSR

Self-assembling peptide materials are promising next generation materials with applications that include tissue engineering scaffolds, drug delivery, bionanomedicine, and enviro-responsive materials. Despite these advances, synthetic methods to form peptides and peptide-polymer conjugates still largely rely on solid phase peptide synthesis (SPPS) and N-carboxyanhydride ring opening polymerization (NCA-ROP), while green methods remain largely undeveloped. This work demonstrates a protease catalyzed peptide synthesis (PCPS) capable of directly grafting leucine ethyl ester (Leu-OEt) from the C-terminus of a methoxy poly(ethylene glycol)-phenylalanine ethyl ester macroinitiator in a one-pot, aqueous reaction. By using the natural tendency for hydrophobic amino acids to self-assemble during peptide polymerization, a large narrowing of the (Leu)x distributions for both mPEG45-b-Phe(Leu)x and oligo(Leu)x co-product, relative to oligo(Leu)x synthesized in the absence of macroinitiator (mPEG45-Phe-OEt), was achieved. A mechanism is described where in situ β-sheet co-assembly of mPEG45-b-Phe(Leu)x and oligo(Leu)x co-products during polymerization prevents peptide hydrolysis, providing a means to control the degree of polymerization (DP) and dispersity of diblock (Leu)x segments (MALDI-TOF x = 5.1, dispersity ≤1.02). The use of self-assembly to control the uniformity of peptides synthesized by PCPS paves the way for precise peptide block copolymer architectures with various polymer backbones and amino acid compositions synthesized by a green process.