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Synthesis method of GCGR/GLP-1R double-target agonist polypeptide

A technology of GLP-1R and synthesis method, which is applied in the field of synthesis of polypeptide compounds, can solve the problems of resin shrinkage, easy folding, prolonging reaction time, etc., and achieve the effects of reducing difficulty, improving purity and yield, and simplifying process steps

Pending Publication Date: 2022-07-26
SHENZHEN TURIER BIOTECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to the long sequence of GLP-1 analogues and more hydrophobic amino acids, it is easy to form folds when synthesized by the method of gradual condensation of amino acids, resulting in serious shrinkage of the resin and prolonging the reaction time, resulting in more crude peptides and product properties. Very close impurities, such as racemic impurities of D-His

Method used

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  • Synthesis method of GCGR/GLP-1R double-target agonist polypeptide
  • Synthesis method of GCGR/GLP-1R double-target agonist polypeptide
  • Synthesis method of GCGR/GLP-1R double-target agonist polypeptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0080] The preparation of the Fmoc-Gly-CTC resin that the substitution degree of embodiment 1 is 0.8mmol / g

[0081] A. 10 g (13 mmol) of 2-CTC resin with a substitution degree of 1.3 mmol / g was added to the reaction kettle, 100 mL of DCM was added, after mixing for 2 min, the DCM was filtered off, then 100 mL of DCM was added, after 40 min of mixing, the DCM was filtered off, and finally added 100 mL of DCM, after mixing for 2 min, the DCM was filtered off, and the resin was used for later use.

[0082] B. Weigh 9.81g of Fmoc-Gly-OH and 5.35g of HOBT in a beaker, add 100mL of DMF and 5.46mL of DIEA, stir and activate the solution at 0-10°C for 5min, pour it into the CTC resin obtained in step A , and mixed for 4h at 20-25°C. After the reaction was completed, 100 mL of DMF was added, and the DMF was filtered off. 4 mL of methanol and 5.46 mL of DIEA were added and mixing continued for 1 h. After the reaction was completed, suction filtration, and the resin was washed with DM...

Embodiment 2

[0084] The preparation of the Fmoc-Gly-CTC resin that the substitution degree of embodiment 2 is 1.0mmol / g

[0085]A. 10g (16mmol) of 2-CTC resin with a substitution degree of 1.6mmol / g was added to the reactor, 100mL of DCM was added, after mixing for 2min, the DCM was filtered off, then 100mL of DCM was added, after 40min of mixing, the DCM was filtered off, and finally added 100 mL of DCM, after mixing for 2 min, the DCM was filtered off, and the resin was used for later use.

[0086] B. Weigh 9.81g of Fmoc-Gly-OH and 5.35g of HOBT in a beaker, add 100mL of DMF and 5.46mL of DIEA, stir and activate the solution at 0-10°C for 5min, pour it into the CTC resin obtained in step A , and mixed for 4h at 20-25°C. After the reaction was completed, 100 mL of DMF was added, and the DMF was filtered off. 4 mL of methanol and 5.46 mL of DIEA were added and mixing continued for 1 h. After the reaction was completed, suction filtration, and the resin was washed with DMF 5 times, 100 m...

Embodiment 3

[0088] Example 3 Preparation of S1-S4 peptide resin Boc-His(π-MBom)-D-Ser(tBu)-Gln(Trt)-Gly-CTC resin

[0089] A. All the Fmoc-Gly-CTC resin obtained in Example 1 was poured into the reaction kettle, swollen and mixed with 100 mL of DCM for 15 min and then drained. Add 100 mL of 20% piperidine / DMF solution (ie DBLK solution) by volume, mix at 20-30° C. for 5 min, and then drain. 100 mL of DMF was added, mixed for 5 min, and then drained. Add 100 mL of DBLK solution with a volume concentration of 100 mL, mix at 20-30 °C for 10 min, and then drain. 100 mL of DMF was added, mixed for 5 min, and then drained. Repeat washing with DMF 8 times, 100 mL each time, mixing for 5 min each time, and after the seventh washing, use pH test paper to detect the filtrate, and the result shows that the pH is 6.5-7.0 is qualified.

[0090] B. Weigh 12.20g of Fmoc-Gln(Trt)-OH, 3.03g of DIC and 2.7g of HOBT in a clean 1L beaker in turn, add 100mL of DMF / DCM solution with a volume ratio of 1:1, p...

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Abstract

The invention discloses a synthesis method of a GCGR / GLP-1R double-target agonist polypeptide, which comprises the following steps: carrying out solid-phase synthesis on GCGR / GLP-1R double-target agonist polypeptide S1-S4 fragment resin, and cracking and purifying to obtain a first fragment; synthesizing lysine with a side chain group of the GCGR / GLP-1R double-target excitation polypeptide as a second fragment; the preparation method comprises the following steps: sequentially coupling amino acids or peptide fragments according to the peptide sequence of the GCGR / GLP-1R double-target agonist polypeptide to obtain peptide resin of the GCGR / GLP-1R double-target agonist polypeptide, and then splitting and purifying to obtain the refined peptide of the GCGR / GLP-1R double-target agonist polypeptide. The production of racemization impurities such as D-His, D-Thr and D-Phe and + Gly impurities can be reduced, the purification difficulty of a crude product is remarkably reduced, the purity and yield of the GCGR / GLP-1R double-target agonist polypeptide are greatly improved, and the production cost is reduced.

Description

technical field [0001] The present invention relates to a method for synthesizing a polypeptide compound, in particular to a method for synthesizing a GCGR / GLP-1R dual-target agonist polypeptide. Background technique [0002] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by human intestinal L cells, which can promote the secretion of insulin, inhibit the secretion of glucagon, and has the effect of reducing blood sugar concentration. For the treatment of type II diabetes. However, native GLP-1 is unstable in vivo and is susceptible to rapid degradation by dipeptidyl peptidase-IV (DPP-IV). [0003] GCGR / GLP-1R dual-target agonist polypeptide has dual agonistic effects of glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR). Polypeptide compounds, which have the characteristics of high enzymatic stability, high biological activity, and no adverse reactions, can significantly improve the degree of BDL-induced cholestatic liver fibrosis in rat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/72C07K1/04C07K1/08
CPCC07K14/72
Inventor 唐青林邓强
Owner SHENZHEN TURIER BIOTECH CO LTD
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