Native chemical ligation (NCL), reported by Kent and co-workers in 1994, has revolutionized the field of chemical protein synthesis, enabling access to numerous site-specifically modified proteins. While NCL is regarded as the most widely used method for the construction of proteins, some intrinsic limitations of this seminal technology have catalysed the search for an alternative approach. Recently, the Payne group developed a selenium-mediated ligation methodology – the diselenide–selenoester ligation (DSL). First disclosed in 2015, DSL offers number of unique and exciting features, greatly expanding the scope of NCL. Typically, these ligations are performed by simply mixing the two suitably functionalized peptide fragments (peptide bearing a C-terminal selenoester and another peptide with an N-terminal diselenide) dissolved in a denaturing buffer without any exogenous thiols or other additives and proceed to completion within 1-10 minutes, even at sterically hindered junctions. Moreover, due to the lower pKa of selenocysteine compared to cysteine, the ligations can be performed over a wide pH range (pH 3–7) and owing to their additive-free nature, allow one-pot deselenization after ligation. Chemical synthesis of therapeutic peptides and proteins bearing site-specific posttranslational modifications (PTMs) using this rapid and highly efficient ligation methodology will be showcased during this seminar.
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