Catalysis of Native Chemical Ligation and Expressed Protein Ligation by Alkylselenols

-acylurea peptides, giving α-SeESNa species. We have determined the rate constants for the ligation with preformed α-SeESNa peptides and show that it is a superior catalyst compared to the known 4-mercaptophenylacetic and 4-mercaptobenzoic acids. The utility of SeESNA was proved through the synthesis of the cardiotoxin A5, a snake venom peptide that contains eight cysteines, without orthogonal cysteine protection. Importantly, it has enabled expressed protein ligation under folding conditions with extraordinary speed, as shown with the Sonic Hedgehog and SUMO2 proteins. Thus, SeESNa is envisaged to have broad applicability in synthetic and semisynthetic protein chemistry.