Peptide And Glycopeptide Ligation Via Direct Aminolysis Of Selenoester

Peptide has widespread applications in the fields of biomedical drugs and materials.Therefore,it is essential to develop efficient methods to synthesize complex peptides.In 1994,the native chemical ligation(NCL)method was developed by Kent's group.This method usually requires a C-terminal peptide thioester,and a cysteine residue as the N-terminal.As the low abundance of cysteine residue in proteins(ca.1.5%),the NCL strategy is limited by the ligation site.Therefore,peptides modified with sulfur residues at the N terminus were developed by researchers in the field,which overcame the limitation of the ligation site.However,the process requires additional desulfuration reaction and becomes more complicated.Direct aminolysis of a peptide thioester fragment with another peptide fragment is an alternative method to synthesize complex peptide,which does not need the cysteine residue at the ligation site.On the other hand,this method always suffers from some limitations:the reaction rate is slow,and there are some racemization product.So improving the efficiency of direct aminolysis remains a challenge in the field of chemical synthesis peptide and protein.Due to the selenolate group is relatively more nucleophilic and easily to leave,so selenol-derivatives and selenoesters were successfully explored in protein ligation in recent years.Our group proposed that C-terminus was modified to selenoester,and then react with N-terminus of the other peptide,the method could achieve more efficient ligation.The main work of this paper:(1)The reactivity of different leaving groups was compared,such as selenoester,thioester and oxoester;(2)The reaction conditions was optimized;(3)Whether the epimerization occurred or not at the ligation site;(4)The scope of selenoester aminolysis reaction was expanded;(5)Selenoester aminolysis strategy was applied in the synthesis of a 40-mer MUC1 repeat glycopeptide.Our results suggest that this method featured high reaction rates(3-10 h)and high yields(73%-95%),meanwhile,no racemization product was observed in the reaction process,in addition,the strategy was not limited by the ligation site.Furthermore,this method can be applied to synthesize the glycopeptide and protins which have complex structures.