Development Of New Protection Groups For The Chemical Synthesis Of Diaminodiacid

Due to its structural and compositional characteristics,cyclic peptides have good biological activity,high target cell selectivity and excellent metabolic stability,and thus are considered to be a very promising type of diagnostic and therapeutic molecule.At the same time,cyclic peptide drugs have also been widely studied for their advantages of high specificity and high safety.At present,representative cyclic peptide drugs such as insulin and hepcidin have been applied to the treatment of diabetes and iron overload diseases.Polypeptide macrocycles generally lock their conformation by forming one or more pairs of disulfide bonds,thereby helping to stabilize their thermodynamic and chemical stability.However,disulfide bonds are easily broken in the body in the presence of hydrolytic enzymes such as disulfide isomerase and in a reducing environment,thereby losing their biological activity.Therefore,there is an urgent need to develop various polypeptide disulfide substitutes to solve such problems.The predecessors have developed a variety of strategies for peptide disulfide simulations,in which Diaminodiaicd has been shown to be an effective strategy in place of disulfide bonds.However,the developed Diaminodiacid has its inherent defects and imperfections.In the synthesis of polypeptides,heavy metal reagents are used to remove the protective groups of the Diaminodiacid.Unfortunately,heavy metal residues can adversely affect the efficacy of pharmaceutical peptides.This paper developed two new types of diaminodioic acid that successfully solved the above problems We developed a class of Diaminoacids based on Dmab / iv Dde protection of three different carbon chain types(C-S,S-C,C-C)and verified their usefulness by simulating oxytocin synthesis.In addition,we also developed another truly orthogonal Diaminodiacid based on Tbe / Mtt protection,and used it for oxytocin and hepcidin synthesis,validating its utility.Compared with natural disulfide cyclic peptide,the Diaminodiacid-substituted cyclic peptide is more stable and has only one to two atomic differences from the natural disulfide bond,avoiding structurally large perturbations.In summary,two novel Diaminodiacids were developed and used in the disulfide simulation of peptides.Successfully avoids the problem of disulfide bond fragmentation in cyclic peptide drugs.Compared with the previous methods,this strategy has the advantages of friendly deprotection conditions,avoidable mismatch,etc,and can be applied to the synthesis and research of various cyclopeptide drugs.