Native chemical ligation allows the splicing of unprotected peptides and proteins by amide bonds via reaction of peptide C-terminal thioesters with peptide N-terminal cysteins. The original require-ment for N-terminal cystein has recently been circumvented by introduction of various auxiliary groups, such as 1-phenyl-2-mercaptoethyl and 4,5-dimethoxy-2-mercaptobenzyl (Dmmb). These auxiliary groups have during SPPS been protected by acid-labile groups. Accordingly, the auxiliary mercapto group is deprotected simultaneously with the overall peptide deprotection. Acidic deprotections of the auxiliary mercapto groups however limit the methods to ligation of two peptide fragments, because sequences containing combinations of thioesters and unprotected mercapto auxiliary groups will be internally reactive.
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