Selenocysteine-mediated native chemical ligation

C-Terminal peptide thioesters are shown to react efficiently with peptide f ragments containing an N-terminal selenocysteine to give selenoproteins. In analogy to the native chemical ligation of thioesters and peptides contain ing N-terminal cysteines, the selenol presumably attacks the thioester nucl eophilically to give a selenoester intermediate that subsequently rearrange s to give a native chemical bond. The utility of this procedure was demonst rated by the synthesis of a selenium-containing derivative of bovine pancre atic trypsin inhibitor (BPTI) in which Cys(38) is replaced by selenocystein e. The artificial seienoprotein folds into a conformation similar to that o f wild-type BPTI and inhibits trypsin and chymotrypsin with unaltered affin ity.