A kind of polypeptide and its use and preparation method

A technology of pramlintide and amino acids, which is applied to the preparation method of peptides, chemical instruments and methods, and medical preparations containing active ingredients, etc., which can solve the problems of high frequency of administration, unacceptable, short half-life, etc.

Active Publication Date: 2020-04-24
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The half-life is short, and it needs to be injected 2 to 3 times a day (administration before the main meal). The frequency of administration is high, and the patient must bear the pain of injection 2 to 3 times a day, which is not easy to accept

Method used

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  • A kind of polypeptide and its use and preparation method
  • A kind of polypeptide and its use and preparation method
  • A kind of polypeptide and its use and preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0285] The preparation of the Fmoc-Tyr(tBu)-MBHAResin whose degree of substitution is about 0.25mmol / g in embodiment 1

[0286] Take 2.5kg of RinkAmideMBHAResin resin (1.0mol in total) with a degree of substitution of 0.4mmol / g, add it to a solid-phase reaction column, wash it twice with DMF, swell the resin with DMF for 30 minutes, and remove it twice with 20% DBLK solution Fmoc, 10 minutes each time, and then the resin was washed 6 times with DMF. Fmoc-Tyr(tBu)-OH (0.8eq, 0.8mol, g), HOBt (0.96eq, 0.96mol, 130g) and DIPCDI (0.96eq, 0.96mol, 121g) were dissolved in DCM with a volume ratio of 1:1 The solution was mixed with DMF, added to a solid-phase reaction column, and reacted at room temperature for 2 hours. After the reaction, wash twice with DMF and twice with DCM. Then add a mixture of pyridine (5eq, 5mol, 396g) and acetic anhydride (5eq, 5mol, 505g) to seal the resin for 6h (add appropriate DMF to make it stir and disperse evenly). After washing 4 times with DMF and...

Embodiment 2

[0287] Embodiment 2 stearic acid-(γGlu)-[Lys 1 Preparation of side chain]-pramlintide

[0288] 2.1 Coupling of amino acids

[0289] Get 398g, 0.1mol Fmoc-Tyr(tBu)-MBHAResin resin prepared in Example 1 is added in the solid-phase reaction column, washed 2 times with DMF, after 30 minutes with DMF swelling resin, adopt 20% DBLK solution to remove twice Fmoc, 10 minutes each time, and then the resin was washed 6 times with DMF. Fmoc-Thr(tBu)-OH (5eq, 0.5mol, 199g), HOBt (6eq, 0.6mol, 81g) and DIPCDI (6eq, 0.6mol, 76g) were dissolved in DCM and DMF with a volume ratio of 1:1 and mixed The solution was added to a solid-phase reaction column, and reacted at room temperature for 2 hours, and the resin was detected to be colorless and transparent with 5% ninhydrin / ethanol solution. After the reaction was completed, it was washed 3 times with DMF.

[0290] According to the above coupling method, according to the pramlintide peptide sequence, sequentially couple Fmoc-Asn 35 (Trt)-O...

Embodiment 3

[0302] Example 3 Lauric acid-(γGlu)-[Lys 1 Preparation of side chain]-pramlintide

[0303] 3.1 Coupling of amino acids

[0304] Get 398g, 0.1mol Fmoc-Tyr(tBu)-MBHAResin resin prepared in Example 1 is added in the solid-phase reaction column, washed 2 times with DMF, after 30 minutes with DMF swelling resin, adopt 20% DBLK solution to remove twice Fmoc, 10 minutes each time, and then the resin was washed 6 times with DMF. Fmoc-Thr(tBu)-OH (5eq, 0.5mol, 199g), HOBt (6eq, 0.6mol, 81g) and DIPCDI (6eq, 0.6mol, 76g) were dissolved in DCM and DMF with a volume ratio of 1:1 and mixed The solution was added to a solid-phase reaction column, and reacted at room temperature for 2 hours, and the resin was detected to be colorless and transparent with 5% ninhydrin / ethanol solution. After the reaction was completed, it was washed 3 times with DMF.

[0305] According to the above coupling method, according to the pramlintide peptide sequence, sequentially couple Fmoc-Asn 35 (Trt)-OH, F...

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PUM

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Abstract

The invention relates to the field of polypeptide synthesis and especially relates to a polypeptide and its use and preparation method. The polypeptide has any one of the amino acid sequences (I), (II) and (III), in the amino acid sequence (I), amino acids at the first site, the ninth site, the 20th site, the 30th site, the 34th site and / or the 36th site of pramlintide are modified, the amino acid sequence (II) is an amino acid sequence obtained by substituting, deleting or adding one or more amino acids to the amino acid sequence (I), and the amino acid sequence (III) is at least 70% homologous with the amino acid sequence (I) or (II). The pramlintide derivatives have prolonged pharmacokinetic properties and superior pharmacodynamic properties. Therefore, the pancreatic amyloid polypeptide derivatives do not need to be injected as frequently as the existing pramlintide acetate. The method has the advantages of novel technology, mild synthesis conditions and simple and stable process.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a polypeptide and its use and preparation method. Background technique [0002] Amylin is a polypeptide hormone secreted by β cells, which participates in postprandial blood sugar control and can slow down the absorption of food in the small intestine. Pramlintide is a synthetic amylin analog, which replaces alanine at position 25, serine at position 28 and position 29 of amylin with proline, fully retaining amylin The physiological effect of human amylin changes the physical properties of human amylin, which is easy to aggregate, and avoids the formation of amyloid deposits. Pramlintide (structure as shown in formula I) was first developed by Amylin Company of the United States, and was approved by FDA in March 2005. It is suitable for adjuvant therapy for patients with poor blood sugar control who use insulin. [0003] [0004] Formula Ⅰ [0005] With the improvement ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/575A61K38/22A61P3/10A61P3/04C07K1/06C07K1/04
CPCA61K38/00C07K14/575
Inventor 朱日成陈军宓鹏程陶安进袁建成
Owner HYBIO PHARMA
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