Development of methodology forchemical synthesis of proteins based on kinetically controlled peptide bond formation

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N-Sulfanylethylanilide (SEAlide) peptides were developed with the aim of achieving facile synthesis of peptide thioesters. The SEAlide moiety was proved to function as a thioester in the presence of phosphate salts and to participate in native chemical ligation (NCL) with N-terminal cysteinyl peptides, and this has served as a powerful protein synthesis methodology. The reactivity of a SEAlide peptide (anilide vs thioester) can be easily tuned with or without the use of phosphate salts. This interesting property of SEAlide peptides allows sequential three-fragment or unprecedented four-fragment ligation for efficient one-pot peptide/protein synthesis. Chemical synthesis of 162-residue GM2AP was achieved using the kinetically controlled ligation based on the SEAlide chemistry.