Chemo-enzymatic routes to lipopeptides and their colloidal properties.

A unique chemo-enzymatic route to lipopeptides was demonstrated herein that, relative to alternative methods such as solid-phase peptide synthesis (SPPS) and microbial synthesis, is simple, efficient, and scalable. Homo- and co-oligopeptides were synthesized from amino acid ethyl esters via protease catalysis in an aqueous media, followed by chemical coupling to fatty acids to generate a library of lipopeptides. Synthesized lipopeptides were built from hydrophobic moieties with chain lengths ranging from 8 to 18 and peptides consisting of oligo(L-Glu) or oligo(L-Glu-co-L-Leu) with an average of seven to eight repeating units. The chemical structures of the lipopeptides were characterized and confirmed by NMR and matrix-assisted laser desorption/ionization (MALDI). The colloidal and interfacial properties of these lipopeptides were characterized and compared in terms of the hydrophobic chain length, oligopeptide composition, and solution pH. The results showed correlation between the interfacial activity of the lipopeptides and the hydrophobicity of the fatty acid and oligopeptide headgroup, the effects of which have been semiquantitatively described in the manuscript. Results from these studies provide insights into design principles that can be further expanded in future work to access lipopeptides from protease-catalysis with improved control over sequence and exploring a wider range of peptide and lipid compositions to further tune lipopeptide biochemical and physical properties.