Development Of Side-chain Extended Diaminodiacids For Structure-activity Relationships Of Peptide Mimics

Disulfide-rich peptides are an important class of active molecules in the organism.Because of their participation in regulating many life movement processes and having higher targeting selectivity,they have become the medicinal targets for disease treatment.For example,insulin and linaclotide have been approved by the FDA to treat diabetes and improve abdominal pain symptoms.The disulfide bond plays an important role in maintaining the rigidity of the polypeptide structure and regulating biological activity.However,the natural disulfide bonds will be destroyed by some reducing conditions in the organism,such as disulfide isomerase,etc.,which will change the structure of the polypeptide,which will affect the biological activity.Therefore,it is of great significance to develop different methods to replace natural disulfide bonds.The predecessors developed a method of connecting two amino acid fragments as a structural unit to replace natural disulfide bonds in polypeptides,which is called the diaminodiacid strategy.This method has proved to have broad application prospects in the replacement of disulfide bonds of many different polypeptides.However,in the process of disulfide bond replacement,the torsional stress caused by diaminodiacids of different structures is different,resulting in differences in structure and natural peptides,which in turn has many adverse effects on the activity of the peptides.This paper has carried out two aspects of research work on this issue.On the one hand,the homocysteine precursor was used to synthesize the chain-extension diaminodiacid easily and efficiently,and the synthesis of oxytocin mimics confirmed its practicality in disulfide bond replacement.On the other hand,a toolboxes with flexible chain length and chain structure were constructed and successfully applied to the replacement of two pairs of disulfide bonds in the antimicrobial peptide TPI.It provides an effective tool for the study between the conformational change caused by diaminodiacid substitution and the activity of peptides.In summary,this paper has carried out a series of research work on diaminodiacids of different chain lengths and chain structures,which has provided a useful tool for the modification of natural peptides,and has been used for the synthesis of medicinal cyclic peptide and its structure-activity relationship laid the foundation.