Recent extensions to native chemical ligation for the chemical synthesis of peptides and proteins

• Recent progress in ligation chemistry for the synthesis of peptides and proteins is outlined.
• Extensions of native chemical ligation at thiol and selenol amino acids.
• New C-terminal acyl donors for ligation-based assembly in the N-to-C and C-to-N directions.
• Use of new thiol additives for efficient one-pot ligation-desulfurization reactions.

Native chemical ligation continues to play a pivotal role in the synthesis of increasingly complex peptide and protein targets twenty years after its initial report. This opinion article will highlight a number of recent, powerful extensions of the technology that have expanded the scope of the reaction, accelerated ligation rates, enabled chemoselective post-ligation modifications, and streamlined the ligation of multiple peptide fragments. These advances have facilitated the synthesis of a number of impressive protein targets to date and hold great promise for the continued application of native chemical ligation for the detailed study of protein structure and function.

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