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C-terminal modification peptide analysis method

A synthetic method and technology of modifying groups, which are applied in the field of synthesis of C-terminal modified peptides, can solve the problems of increasing difficulty in post-processing, increasing the difficulty of chemical synthesis of such peptides, and reducing the yield of target peptides.

Active Publication Date: 2017-07-07
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For the modification of the C-terminus of the polypeptide, the modification of the amino group is generally completed by directly performing an amide bond reaction with the carboxyl group at the C-terminus of the peptide chain in the liquid phase; A diamino-type Linker is introduced between the C-terminal carboxyl group of the peptide chain and the modified carboxyl group. This method will undoubtedly increase the difficulty of chemical synthesis of this type of peptide, because it generally undergoes two amide bond reactions in the liquid phase, so that It will greatly increase the difficulty of the post-processing of the synthesis, and will greatly reduce the yield of the target peptide

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0023] Example 1 NH 2 -(CH 2 ) 8 - Preparation of NH-2-Chlorotrityl Chloride Resin

[0024] Weigh 250 grams of 2-Chlorotrityl Chloride Resin with a degree of substitution of 0.8 mmol / g in a solid-phase reaction column, add DMF, and swell with nitrogen gas bubbles for 60 minutes; weigh 57.7 grams (400 mmol) of octyldiamine, dissolve it with DMF, and Add 90.0ml DIPEA (500mmol) in an ice-water bath at ℃, add to the reaction column, react for 1 hour, add 200ml methanol and 200ml DIPEA, mix and seal for 0.5h, wash with DCM three times, drain the resin after shrinking with methanol, and obtain NH 2 -(CH 2 ) 8 -NH-2-ChlorotritylChloride Resin.

Embodiment 2

[0025] Example 2 Fmoc-Phe-NH-(CH 2 ) 8 - Preparation of NH-2-Chlorotrityl Chloride Resin

[0026] Take by weighing the NH that embodiment 1 obtains 2 -(CH 2 ) 8 -NH-2-Chlorotrityl Chloride Resin 100 grams in the solid phase reaction column, add DMF, nitrogen bubble swelling for 60 minutes; weigh Fmoc-Phe-OH 23.22 grams (60mmol), HOBt9.72 grams (72mmol), HBTU 33.8 gram (60mmol), dissolved in DMF, 15.6ml DIPEA (72mmol) was added in an ice-water bath at 0°C, activated for 5 minutes, added to the reaction column, after 2 hours of reaction, added 70ml acetic anhydride and 60ml pyridine, mixed and sealed for 24 hours, washed with DCM three times , the resin is dried after methanol shrinkage, and Fmoc-Phe-NH-(CH 2 ) 8 -NH-2-ChlorotritylChloride Resin, 124g of resin with a detection substitution degree of 0.51mmol / g.

Embodiment 3

[0027] The preparation of embodiment 3 ibiratide peptide resin

[0028] The structure of ibiratide is: H-Met(O 2 )-Glu-His-Phe-D-Lys-Phe-NH-(CH 2 ) 8 -NH 2 .

[0029] Fmoc-Phe-NH-(CH 2 ) 8 - NH-2-ChlorotritylChloride Resin 98 g (50 mmol) was placed in a solid-phase reaction column, DMF was added, and nitrogen bubbled to swell for 60 minutes; the Fmoc protecting group was removed with DBLK, and washed 6 times with DMF. Weigh 468 g (100 mmol) of Fmoc-D-Lys(Boc)-OH, 16.3 g (120 mmol) of HOBt, dissolve in DMF, add 15.1 g of DIC (120 mmol) in an ice-water bath at 0°C, activate for 5 minutes, and add to the reaction column. After 2 hours of reaction, the resin was washed three times with DMF, the Fmoc protecting group was removed with DBLK, six times with DMF, and three times with DCM. Repeat the above coupling operation, and sequentially couple Fmoc-Phe-OH, Fmoc-His(Trt)-OH, Fmoc-Glu(OtBu)-OH, Boc-Met(O 2 )-OH. After the reaction was completed, it was shrunk with methano...

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Abstract

The invention provides a C-terminal modification peptide analysis method. The method is characterized by including steps: 1) coupling an amino at one end of a diamino compound to solid-phase synthesized resin; 2) adopting an Fmoc solid-phase peptide synthesis strategy to sequentially couple amino acids to an amino at the other end of the diamino compound so as to obtain fully-protected polypeptide resin; 3) splitting fully-protected polypeptides from resin to obtain the fully-protected polypeptides; 4) removing protecting groups from the fully-protected polypeptides to obtain targeted C-terminal modification peptides; or 5) coupling the fully-protected polypeptides with carboxylic modification groups to obtain the targeted C-terminal modification peptides. The C-terminal modification peptide analysis method has advantages of simplicity in operation, energy saving, environmental friendliness, yield increase and the like.

Description

technical field [0001] A synthetic method for preparing C-terminal modified peptides. Background technique [0002] Peptide modification, as an important means to change the main chain structure and side chain groups of the peptide chain, plays an increasingly important role in changing the physical and chemical properties of peptide compounds and solving their effective utilization in vivo. There have been a large number of literature reports. , the modified polypeptide drug can significantly reduce immunogenicity, reduce side effects, increase water solubility, prolong the action time in vivo, change its biodistribution, etc., and significantly improve the efficacy of the drug. [0003] At present, the chemical modification of the C-terminus of polypeptides is becoming a research hotspot, and the introduction of some small molecule drugs at the C-terminus has become a new research direction. For the modification of the C-terminus of the polypeptide, the modification of th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K1/107C07K1/06C07K1/04C07K7/06
CPCC07K1/04C07K1/062C07K1/107C07K7/06C07K1/06Y02P20/55
Inventor 伍柯瑾戴政清宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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