Method for synthesizing monopegylation fixed point modification thymopoietin

Abstract

The invention provides a method for synthesizing monopegylation fixed piont modification thymopoietin, which belongs to the field of biomedicine. According to the method, firstly, a solid phase is adopted for synthesizing TP5 containing protecting groups, the defect that the fluorenylmethyl chloroformate (FMOC) unit removal operation of the method in the prior art is difficult to carry out is avoided, then, the modified polyethylene glycol is connected onto the lysine side chain amino at the fixed point in a liquid phase, the goal of fixed point modification is reached, simultaneously, the space steric hindrance of the solid phase wang resin is avoided through the liquid phase environment, finally, all protecting groups are removed in one step through palladium carbon catalytic hydrogenation to obtain the pegylation thymopoietin with the long-action effect, the synthesis process is simple and convenient, the cost is low, the yield is high (the total yield is higher than 20 percent), and the industrial production is convenient. The pegylation thymopoietin synthesized by the method can not be easily hydrolyzed by esoteric protease, the renal clearance can be obviously reduced because the molecular weight is heavy, and the internal circulation time is greatly prolonged, so the goals of obviously prolonging the half-life period and improving the bioavailability of organisms are reached.

Description

Technical field [0001] The present invention is the field of biomedical technology and involves a synthesis method for a single polyethylene glycol fixed -point modification. Background technique [0002] The thymopptide (TP5) is an artificial synthetic small molecular peptide. Its amino acid sequence is served as ARG-LYS-Asp-Val-Tyr. It has the same biological activity of the body's immune balance as the endogenous thymine Ⅱ.For a variety of immune dysfunction or low, TP5 can make the immune function normal through the two -way regulatory effect of promoting or suppressing.At present, it is clinically used to treat tumors and autoimmune diseases.However, after the TP5 is injected in the human body, it is quickly degraded by protease and amino peptidase. The half -life of the drug prototype is only 30 seconds.At present, only frozen dried powder injections and solution -type injections are available in clinical applications. Therefore, for patients with long -term medication, TP5...

AI Technical Summary

Problems solved by technology

But, the reaction of this method will be carried out on the wang resin of the Lys (PEG) macromolecule that has condensed earlier, repeatedly condensation removes operations such as Fmoc

Since the steric hindrance between the wang resin as the carrier polymer and the PEG (5000da) polymer is too large, the removal of Fmoc is related to the steric hindrance, and the reaction conditions are limited by the steric hindrance conditions. Therefore, the protection of Fmoc removal is not only limited by wang The steric hindrance of the resin carrier and the limitation of the steric hindrance of the PEG (5000da) polymer make it difficult to remove the FMOC unit

Simultaneously, it is also difficult to carry out the amino acid condensation reaction of the next step between the solid-phase wang resin and the PEG polymer, and the synthesis unit will be repeatedly operated, resulting in a large amount of waste of raw materials, and the yield of PEGylated thymopentin is also low. only 2%

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