Construction Of Unnatural Amino Acid Molecular Toolboxes For Synthesis Of Active Cyclic Peptides And Structure-activity Relationship Research

Cyclic peptide drugs have higher biological activity,target selectivity and metabolic stability,so they have become a potential target for clinical drug development.In addition to the head and tail cyclic peptide drugs,according to the connection type of the amino acid side chains on the polypeptide,cyclic peptide drugs can be divided into amide cyclic peptides,disulfide bond cyclic peptides,thioether bond cyclic peptides and so on.Chemical synthesis provides an effective scheme for accurately obtaining various types of active cyclic peptides and studying their structure-activity relationships.Focusing on the preparation and application of different types of cyclic peptides,this work has carried out the following three researches:Lactam cyclic peptide drugs,such as Bumenotide,can be used to treat diseases such as sexual dysfunction.However,the previous synthetic strategies of such amide cyclic peptides often require the introduction of heavy metal reagents,which may result in contamination of the product cyclic peptide with heavy metals.Therefore,we have applied a series of Tbeoc/Tbe-protected amino acid toolboxes that synthesize a series of lactam cyclic peptides under mild and heavy metal-free conditions,and verify that the synthesized bacteriostatic peptides still have native activities.Disulfide bonds are prone to cleavage or mismatch under reducing conditions or disulfide bond isomerases,resulting in loss of their activity.Diaminodiacids are used as non-reducible structural units to replace disulfide bonds in disulfide-bonded cyclic peptides,thereby constructing disulfide-bonded peptide mimics with enhanced stability.In this paper,two types of diaminodiacids have been developed to supplement the current molecular toolboxes of diaminodiacids.1.We have developed a six-atom thioether diaminodiacid with flexible chain length and chain structure,and used it to synthesize bacteriostatic peptides and verify that its activity is similar to native activity.2.However,we found that the thioether bond may be oxidized to sulfoxide under oxidizing conditions.Therefore,we have also developed a new type of ether bond diaminodiacid and verified that the disulfide bond cyclic peptide mimetics substituted by ether bond remain stable under oxidative conditions.In summary,this thesis constructs a series of unnatural amino acid molecular toolboxes that can be used for the preparation of lactam cyclic peptides and disulfide-bonded cyclic peptide mimics,and lays the foundation for the study of the structure-activity-activity relationship of such cyclic peptides.