Olefin Metathesis For The Synthesis And Characterization Of An In-tether Chiral Center's Stapled Peptides

There exists a close relationship between biological activity and structure character of peptides.In most cases,the flexible structure of nativepeptides make it easy to be affected by protease hydrolysis and leading to the inefficient cell penetrating,it also affects the affinity of the target;so constraining peptides in active form is a useful way to improve their undruggable.Cell surface appear to promote uptake of cell-penetrating peptides?CPPs?,but their exact mechanism are unclear.Statistical analysis of the uptake patterns for the more than 200 modified peptides shows the most valuable properties-cell penetration properties are mainly related to the charge of the peptide and the modified location of the functional group.A number of methods have been described that either nucleate helix formation and/or constrain the conformational space available to a short polypeptide such that the helical conformation is more populated.Strategies for helix stabilization include salt bridges,metal chelates and covalent cyclization methods such as disulfide and lactam bridges.Because the i,i + 4,i + 7 and i + 11 positions reside on the same face of the ?-helix,covalently linking pairs of these side chains together can promote the helical conformation.Grubbs and Blackwell pioneered a non-native carbon–carbon bond constraint via a ring-closing metathesis reaction with O-allyl serine residues.This has since been elaborated on by Verdine and co-workers with the introduction of unnatural ?,?-disubstituted amino acids with olefin tethers into the peptide sequence.This new hydrocarbon-stapled backbone approach has provided a platform for a number of significant studies over the past decade.Combined with our recent study,we found that a chiral center of R configuration was introduced at the specific position of the peptide side chain.So by using RCM method to construct cyclic peptide into chiral center and RCM itself after cyclization occurs after the isomers.The question of whether the different isomers generated by the closed loop has the same nature to the helicity is placed in front of us.This prompted us to study the effect of the configuration of the configuration on the two stage structure of the polypeptide by using the RCM modified peptide.Based on the previous work,this study focuses on the influence of the chiral center on the structure.A short peptide model?X₁-AAA-X₂?was established to verify the effect of the side chain chiral center on the two stage conformation of Peptides Stapled.The HIV?FITC-Beta-Ala-ITF-X₁-DLL-X₂-YYGP-NH₂?peptides were selected as targets to verify the changes of the membrane properties after introducing the chiral center in the RCM method.?X₁,X₂ is a kind of S₅,mS₅,mS₅?2-Ph??.We conclude that the Z/R-staple peptide has the best ?-helix content and also has the best ability to penetrate the cell membrane.