Drug fusant of specific binding GLP-1 (Glucagon-like peptide-1) receptor

A technology of GLP-1 and fusion, applied in the field of genetic engineering, can solve the problems of reducing therapeutic effect, decreasing biological activity, causing immunogenicity, etc.

Inactive Publication Date: 2013-03-06
HAISCO PHARMA GRP INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] However, the above-mentioned several solutions have the following potential problems: (1) PEG-modified long-acting preparations (GLP1-PEG, developed by Eli Lilly, in II Suspended during the clinical stage), its polymer is directly modified at the tail of GLP-1
Due to the larger molecular size of the polymer and GLP-1, the steric hindrance effect will affect the effective binding of GLP-1 to its receptor (GLP-1R), resulting in a significant decrease in biological activity in vivo; (2) Fc fusion The prolongation of the half-life of the polypeptide was not as significant as expected (US Patent No. 6,756,480, which is incorporated herein by reference); (3) other forms, such as human albumin fusion or microsphere entrapment, have the potential to elicit immunity in patients Risk of originality, reduced therapeutic effect

Method used

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  • Drug fusant of specific binding GLP-1 (Glucagon-like peptide-1) receptor
  • Drug fusant of specific binding GLP-1 (Glucagon-like peptide-1) receptor
  • Drug fusant of specific binding GLP-1 (Glucagon-like peptide-1) receptor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0084] This example describes the preparation method of the drug fusion named HSK-B-01 in the present invention, the X fragment sequence of the fusion is:

[0085] HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: 1),

[0086] The sequence of X' fragments is:

[0087] SPPPAGSSPGGNKLWEIFLRVAEEEMQKSLDSTFTGEGH (SEQ ID NO: 7),

[0088] Y is GGGGGCGGGGG (SEQ ID NO: 4),

[0089] Z is a molecular weight of 20,000 Daltons, the end of which is maleic imide-activated monomethoxypolyethylene glycol,

[0090] a and b do not exist, that is, the number of amino acid residues is 0, n=1.

[0091] Plasmid cloning

[0092] Cloning of plasmids expressing the following protein sequences:

[0093] HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPSGGGGGCGGGGG SPPPAGSSPGGNKLWEIFLRVAEEEMQKSLDSTFTGEGH (SEQ ID NO: 8)

[0094] Primer 5'-CATGCCATGGCCCATATGAAATACCTGCTGCCGACCGCTGC-3' (SEQ ID NO:9)

[0095] 5'-CCGAATTCTCATTAGTGGCCCTCGCCGGTGAAGGTGCTGT-3' (SEQ ID NO: 10)

[0096] The DNA sequence encodin...

Embodiment 2

[0107] Example 2 This example describes the preparation method of the drug fusion named HSK-B-02 in the present invention, the X fragment sequence of the fusion is:

[0108] HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRG (SEQ ID NO:2),

[0109] The sequence of X' fragments is:

[0110] GRGKVLWAIFEKAAQGELYSSVDSTFTGEGH (SEQ ID NO: 12),

[0111] Y is GGGSGGGCGGGSGGG (SEQ ID NO:5),

[0112] Z is a molecular weight of 30,000 Daltons, the end of which is maleic imide-activated monomethoxypolyethylene glycol,

[0113] The amino acid residue sequence of a is DKTHT,

[0114] The amino acid residue sequence of b is PAPELL, n=1.

[0115] clone

[0116] Cloning of plasmids expressing the following protein sequences:

[0117] HGEGTFTSDVSSYLEGQAAKEFIAWLVKGRGGGGSGGGCGGGSGGG GRGKVLWAIFEKAAQGELYSSVDSTFTGEGH (SEQ ID NO: 13)

[0118] Primer 5'- CATGCCATGGCCCATATGAA ATACCTGCTGCCGACCGCTGC -3' (SEQ ID NO: 14)

[0119] 5'-CCGAATTCTCATTAGTGGCCCTCACCGGTGAAGGTGCTGT-3' (SEQ ID NO: 15)

[0120] The DNA s...

Embodiment 3

[0128] This example describes the preparation method of the drug fusion body named HSK-B-03 in the present invention, the X fragment sequence of the fusion body is:

[0129] HGEGTFTSDLSKQMEEEAVALPIETWLKQGGPSSGAPPSKKKKKK (SEQ ID NO: 3),

[0130] The sequence of X' fragments is:

[0131] KKKKKKSPPAGSSPGGQKLWTEIPLAVAEEEMQKSLDSTFTGEGH (SEQ ID NO: 17),

[0132] Y is GGGGGSGGGCGGGSGGGGG (SEQ ID NO: 6),

[0133] Z is a polyethylene glycol-polylactic acid block copolymer with a molecular weight of 20,000 Daltons and activated by maleic imide at the end,

[0134] a and b do not exist, that is, the number of amino acid residues is 0, n=1.

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Abstract

The invention discloses a drug fusant of a specific binding GLP-1 (Glucagon-like peptide-1) receptor, and also discloses a preparation method of the drug fusant and applications of the medicament fusant in preparing diabetes drug by utilizing the drug fusant.

Description

technical field [0001] The invention belongs to the field of genetic engineering, and relates to a class of agonists capable of specifically binding to GLP-1 receptors and applications thereof. The present invention mainly relates to an active polypeptide fragment (X) capable of effectively binding to GLP-1 receptors by means of genetic engineering n By connecting the chain with the (X) n Polypeptide fragment (X') composed of mirror image amino acid sequence n Linked together, with any of polymer, fatty acid, and sugar modifications at the linking chain. The resulting drug fusion contains 2 inverted repeats of the polypeptide fragment sequence (X) n with (X') n . The invention also covers the application of the drug fusion body and its modified product in treating diabetes. Background technique [0002] Studies have found that endogenous glucagon-like peptide-1 (GLP-1) secretion is insufficient in patients with type 2 diabetes, so supplementing sufficient GLP-1 has bec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/48A61K38/16A61K38/26C12N15/62C12N1/15C12N1/19C12N1/21C12N5/10A61P3/10
Inventor 于鹏展
Owner HAISCO PHARMA GRP INC
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