Study On The Isomer Of Thymosin α1 For The Synthesis And Pharmacodynamics

Peptides that widespread in the nature are polymer of amino acid, most of which have various biological functions. Bioactive peptides possess many functions of nerve, hormone, immune regulation, anti-thrombus, anti- hypertension, anti-cholesterol, anti-bacteria, anti-cancer, anti-oxidation and cleaning free radical, etc. With the development of isolation and identification technique, more and more natural bioactive and medicine peptide compounds increasingly draw attention. Although many peptide sequences have been identified as potent bioactive agents, there are fundamental limitations associated with the development of peptides as therapeutics. The inherent conformational flexibility of a small peptide results in a myriad of conformations adopted by the peptide. In addition, there are a number of metabolic limitations restricting the use of peptides as therapeutics. Poor permeability across membranes, proteolytic degradation, rapid clearance, poor solubility in some cases, and a tendency to aggregate, all of which contribute to low pharmacodynamic of peptide for therapeutics.so there is a clear need for enhanced metabolic stability.The peptidomimetics is reconstruct the structure of peptide or displace the configuration of the peptide.due to the structure reconstruction,a great many peptidomimetic analog ptu up transform pharmacodynamics and pharmacokinetics quality, include bioactivity,selectivity,metabolize stability, enhance the absorbency and reduce the toxicity and so on.some peptidomimetic analog has used as curative.The use of peptidomimetics to overcome the limitations inherent in the physical characteristics of peptides has become an important strategy for improving the therapeutic potential of peptides. The term peptidomimetic is a broad term referring to any compound designed to perform the function of a peptide. Such functions include eliciting a specific biological effect through inhibition or agonist/antagonist activity. Generally, peptidomimetics are derived from a lead peptide sequence where structural modifications have been incorporated to improve binding affinity and/or metabolic resilience. Today, the method of designing peptidomimetics includes reform, circuit of amide-band and incorporation of non-protein amino acid, such as D-amino acid. The peptidomimetics incorporated D-amino acid can be classed into containing parts of D-amino acid and entire D-amino acid peptide in peptide. The peptides consisted entirely of D-amino acid have normal amino acid sequence and reverse amino acid sequence peptidomimetics. The activity of those peptidomimetics have many limitations, for instance, some have higher enzyme stability, but lower activity, even totally lost bioactivity. There are some mimetics difficult to synthesize, while the cost of synthesis materials of others mimetics is too high.A peptidomimetic approach with significant potential that has emerged in recent years is the use ofβ-amino acids.β-Amino acids are similar toα-amino acids in which they contain an amino terminus and a carboxyl terminus. However, these functional terminuses were separated by two carbon atoms. The peptides containingβ-amino acid have been named asβ-peptide, which can form definite secondary structure that resembles the naturalα-peptide, such as spiral, folder and corner, soβ-peptide possessed similar bioactivity toα-peptide, and have excellent stability against most protease,soβ-peptide will be a new compoud for mechanism study and the drug design.Tα1 is a very excellent immune regulator and therapeutics drug; however, it lacks ideal enzyme stability and bioavaiability. As external administration of active peptide, it was cleared quickly for its sensitivity to protease, so its response function is decreased significantly, which limits clinical application of Tα1. Researchers have to reform structure to overcome the limitations, so many peptidomimetics were designed.In this paper,we designed a isomer of Tα1 by usedβ-X substituted theAsp2,Asp6,Lys14and Lys20of Tα1 .The compound was synthesized by Fmoc solid phase synthesis strategy, and it's activity in vivo and vitro were researched.We studied immune activity in vitro of the designed peptidomimetic through external rosette, cell proliferation and inducing secretive IL-2. The results showed that: STα1 can enhance the T lymphocyte proliferation, the T lymphocyte proliferation rate of STα1 is is obviously higer than the rate of Tα1,and the best stimulate concetration of STα1 is just 4 percent of the best stimulate concetration of Tα1. For the activeity of induce T lymphocyte secret IL-2, STα1 is as good as Tα1. STa1 has excellent effect on E receptor's createation of T lymphocyte,the rosette rate of STα1 is is hiher than Tα1's,and the best stimulate concetration of STα1 is just 25 percent of the best stimulate concetration of Tα1.We just usedβ-X substituted the Asp2,Asp6,Lys14and Lys20of Tα1,the change of the first structure effect the second structure and the active site of the molecule ,and the bioactivity is beter than Tα1.For test the activity in vivo,we used H22 cell beared cancer mice as animol model,introduced cyclophsphamide to restrain cancer, at the same time peritoneal inject STα1,and emploied import thymosinα1(Zdaxain) and home-made thymosinα1 (mai pu xin) as the control, and seted blank and model group. After administrated ten days ,determine the folow index:the rate of restrain cancer, thymus exponent, lymphocyte transformation efficiency and the IL-2 level in serum. The results showed that: STα1 can assist cyclophsphamide to restrain cancer,can promote T lymphocyte proliferation and differentiation,can promote the secretion of IL-2, can enhance the immunity of the mice which bearing cancer.