New Synthetic Method And Application Of Thioether-bonded Bicyclic Peptide

Compared with linear peptides,thioether-bonded bicyclic peptide has a rigid structure,high metabolic stability and good tissue penetration,and thus is considered to be a promising framework for the peptide drug discovery.The thioether-bonded bicyclic peptide library can be constructed by high-throughput screening techniques(such as combinatorial libraries and phage display).The thiol bisalkylation reaction is a widely used reaction for constructing thioether-bonded bicyclic peptide.In this strategy,bisalkylating reagents are used to crosslink the two cysteine side chain residues of the linear precursor peptide.The connectivity of the two thioether bonds will affect the biological activity of the thioether-bonded bicyclic peptide.Therefore,how to precisely control the formation of the two thioether bonds is very important for the preparation of the thioether-bonded bicyclic peptide.In order to ensure the formation of two pairs of thioether bonds at the desired positions,the synthesis of bicyclic peptides usually requires two pairs of orthogonal cysteine side chain protecting groups.A variety of orthogonal cysteine protecting groups have been developed.Although these groups provide suitable approaches for thioether-bonded bicyclic peptides,there are still many inconveniences in practical use(for example,the removal of protective groups requires heavy metals,or there are too many steps in the synthesis of protecting groups).Here,our study provides a more convenient and low-cost strategy for the synthesis of thioether-bonded bicyclic peptide.This method uses two common and inexpensive Cys-protecting groups: Trt and SStBu.Due to the exchange reaction between the thiol and the disulfide bond,the mercapto group and the SStBu group cannot coexist under weak alkaline conditions.Because of this,people usually think that it is impossible to selectively crosslink the free sulfhydryl groups in the presence of the SStBu protecting groups.Our study found that,in DIPEA-containing DMF solution,peptides containing both sulfhydryl groups and SStBu groups can undergo selective thiol dialkylation while maintaining the integrity of SStBu groups.This strategy provides a simpler method for the synthesis of thioether-bonded bicyclic peptides.In summary,this study has developed a more convenient and low-cost strategy for the synthesis of thioether-bonded bicyclic peptide.This method utilizes Trt-and SStBuprotected groups to synthesize thioether bicyclic peptides.In this strategy,the process of forming two pairs of sulfide bonds in the solution can be easily traced by chromatography.We believe that this work will provide a practically useful strategy to promote the synthesis and activity optimization of thioether-bonded bicyclic peptides.