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Protein chemical synthesis by native peptide ligation of unprotected peptide segments is an interesting complement and potential alternative to the use of living systems for producing proteins.[1] Actually, tremendous efforts are focused on the design of one-pot strategies allowing the assembly of three peptide segments.[2–5] The goal is to get rapid access to small proteins (less than 150 amino acid residues), while saving intermediate purification steps and obtaining the products in good yield. Such methods are gaining increasing significance for the study of protein function and appear as a potential option for producing various protein-based therapeutics currently under development.

To date, proteins were mainly assembled by sequential native chemical ligation (NCL)[6] or extended methodologies [7] in the C-to-N direction (for recent achievements, see Refs.[8, 9]). NCL involves the chemoselective ligation of a C …