Multicycle Peptides Based On Regio-Selective Selenium-Ether Reaction

Peptides represent a class of pharmaceutical compounds,molecularly poised between small molecules(<500 Da)and proteins(>5000 Da),the two most extensive classes of well-established therapeutic agents in the pharmaceutical industry.Peptides filled the gap in drug development,research in peptide therapeutic drugs has steadily increased.Compared to small molecules,peptides have great advantage of binding to the target protein with a flat surfaces.Besides,Peptides present high potency,high selectivity and low toxicity to the organism.Compared to biomacromolecules,peptides are easier to synthesized and modified,and the smaller molecular weight improved the cell permeabilitys.However,peptide’s development has been limited by their short half-life,low plasma stability and bad oral bioavailability.They usually cleavaged by cellular proteolytic enzymes,and clearanced by hepatic and renal activities.In order to improve the stability of peptide,scientists have developed many ways to modify it.The the simplest one is cyclization.Cyclic peptides have a more compact and rigid structure,which lead to a better stability.Moreover,cyclization can make the hydrophilic groups buried inside the peptide to improve its cell permeabilitys.In addition,Cyclic peptides can mimic many structural features of protein interfaces more closely,the selectivity and affinity can be improved by predesign.Disulfide bond is one of the commonest methods to cyclize peptide,and it is also the main way of posttranslational covalent modifications that occur during peptide folding.It can be found in many natural peptides.However,when peptide contains more than one disulfide bonds,it will lead to mismatching of cysteines.How to direct the rational folding of multicyclic peptides from the fully reduced peptides is still a big problem.Convenient and efficient strategies that can generate structurally-diverse and isomerically-pure multicycle peptide scaffolds are still in demand.Thus,we developed a stragety can synthesize multicycle peptides relies on highly regio-selective cyclization of selenocysteine with halogenated residues in peptides.There are three chapters included:Chapter 1:The history and potential of peptides are introduced,especially the importance of multicycle peptides.Then,we categorized different ways to cyclize peptides,and methods of direct the rational folding of disulfide bonds.Finally,we proposed the research ideas and significance of this paper.Chapter 2:We report a general,robust and efficient regio-selective way to cyclize divers peptides by using selenocysteine(Sec),cysteine(Cys)and N-terminal chloroacetyl group.The conditions were optimized and kinetics was investigated.Selenoether and disulfide bond was formed selectively under mild condition,and isomerically-pure bicyclic peptides were formed.We also changed the disulfide bond into thioether bond by using small molecule crosslinks.In the end,we extended the peptide chains and immobilized it to tricyclic peptides by a small molecule crosslink.Chapter 3:The third chapter improved the peptide scaffolds on the base of the second chapter.The penicillamine(Pen)and CXPen motif were introduced,and a "one pot" strategy to generate tricycle peptides relies on highly regio-selective cyclization of selenoester and disulfide bond without protecting groups was developed.We established different tricycle patterns by using this method.At last,we summarized this study and look forward to its practical application.