GLP-2 compounds, formulations, and uses thereof

A technology of GLP-2 and D33E-GLP-2, which is applied in the field of new human glucagon-like peptide-2 peptide and its derivatives, can solve the problems of high clearance rate and limited use, and achieve the purpose of reducing intestinal permeability, inhibiting Effects of gastric emptying and acid secretion

Inactive Publication Date: 2005-12-07
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the high clearance limits the usefulness of this class of compounds, therefore, there is a need for improved

Method used

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  • GLP-2 compounds, formulations, and uses thereof
  • GLP-2 compounds, formulations, and uses thereof
  • GLP-2 compounds, formulations, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0702] 1. GLP-2 peptide, which contains the amino acid sequence of formula I:

[0703] His-X2-X3-Gly-X5-Phe-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-Ala-Arg-X21-Phe-Ile-X24-Trp- Leu-Ile-X28-Thr-Arg-Ile-Thr-X33 (Formula I)

[0704] Or a fragment thereof; wherein X2 is Ala, Val or Gly; X3 is Asp or Glu; X5 is Ser or Lys; X7 is Ser or Lys; X8 is Asp, Glu or Lys; X9 is Asp, Glu or Lys; X10 is Met , Lys, Leu, Ile or Norleucine; X11 is Asn or Lys; X12 is Thr or Lys; X13 is Ile or Lys; X14 is Leu or Lys; X15 is Asp or Lys; X16 is Asn or Lys; X17 is Leu or Lys; X18 is Ala or Lys; X21 is Asp or Lys; X24 is Asn or Lys; X28 is Gln or Lys; X33 is Asp, Glu or Lys.

[0705] 2. The GLP-2 peptide according to embodiment 1, consisting of the following amino acid sequence

[0706]His-X2-X3-Gly-X5-Phe-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-Ala-X20-X21-Phe-Ile-X24-Trp- Leu-Ile-X28-Thr-Arg-Ile-Thr-X33

[0707] Or a fragment thereof; wherein X2 is Ala, Val or Gly; X3 is Asp or Glu; X5 is Ser ...

Embodiment 1

[1666] Preparation of derivatives of GLP-2 peptide analogs by peptide synthesis

[1667] The peptide bound to the resin with a fully protected group is acylated, and only the epsilon-amino group to be acylated on the peptide is deprotected. Use Fmoc chemistry to synthesize resin-bound peptides with appropriate protective groups, such as:

[1668] ↓Boc-[1-33, Lys(Dde)]-resin

[1669] ↓2% hydrazine / DMF treatment to remove Dde group

[1670] ↓Use Fmoc-Glu(γ-OH)-OBu t Acylation by HOAt / DIC / DIEA / NMP

[1671]↓ Piperidine treatment to remove Fmoc group

[1672] ↓Acylation by HOAt / DIC / DIEA / NMP with C16 acid

[1673] ↓Trifluoroacetic acid deprotection

[1674] ↓High performance liquid chromatography (HPLC) purification

[1675] ↓Freeze drying

[1676] ↓Analyze by liquid chromatography-mass spectrometry (LC-MS) and analytical high performance liquid chromatography

[1677] The length of the spacer and the fatty acid chain can be different. In the case of fixed acylation positions, three spa...

Embodiment 2

[1684] Synthesis of D3E / L17K((S)-4-carboxy-4-(hexadecanoylamino)butyryl) / K30R / D33E-GLP-2(1-33)

[1685] 2.a Synthesis of peptidyl resin with protective group

[1686] According to the Fmoc strategy, using Applied Biosystems' 0.25mmol scale 431A peptide synthesizer, using the FastMoc UV test protocol provided by the company, synthesizing a peptide-based resin with protective groups, that is, using HBTU(2-(1hydro-benzotriazole) -1-yl-1,1,3,3 tetramethylurea hexafluorophosphate) mediated coupling in NMP (N-methylpyrrolidone) and deprotection of Fmoc protecting group for UV detection. The synthetic raw material resin (400mg) is (4-((2′,4′-dimethoxyphenyl)-(Fmoc-Glu(OBut)-O-p-benzyloxybenzyl resin (Wang resin)) (Novabiochem, Bad Soden, Germany, product number: 04-12-2052), displacement capacity 0.53mmol / g.

[1687] The amino acid derivatives with protective groups used are Fmoc-Ala-OH, Fmoc-Arg(Pmc)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OBut)-OH, Boc-His(Boc)- OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(O...

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Abstract

The present invention relates to novel human glucagon-like peptide-2 (GLP-2) peptides and human glucagon-like peptide-2 derivatives which have a protracted profile of action as well as polynucleotide constructs encoding such peptides, vectors and host cells comprising and expressing the polynucleotide, pharmaceutical compositions, uses and methods of treatment.

Description

Invention field [0001] The present invention relates to a new human glucagon-like peptide-2 (GLP-2) peptide and its derivatives, which have a prolonged action curve. The present invention also relates to methods for preparing and using the GLP-2 peptides and derivatives, as well as polynucleotide constructs encoding the GLP-2 peptides, and host cells containing and expressing the GLP-2 peptides, pharmaceutical compositions, and The preparation method, use and treatment method of the preparation. Background of the invention [0002] Glucagon peptide-2 (GLP-2) is a 33 amino acid residue peptide produced in intestinal L-cells and is released after nutrient intake. The amino acid sequence of the human GLP-2 peptide is shown in Figure 1. [0003] The GLP-2 peptide is the product of the proglucagon gene. Proglucagon is mainly expressed in the pancreas and intestines, and to a certain extent in specific neurons located in the brain. However, the post-translational processing of progluca...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605
Inventor L·蒂姆S·邦M·施莱因N·C·卡尔肖尔姆D·K·恩格伦德A·S·尼尔森N·L·约翰森K·马森M·曾德尔P·蒂格森
Owner NOVO NORDISK AS
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