Long-acting oxyntomodulin (oxm) hybrid peptide, its preparation method and its use as medicine

A compound and drug technology, applied in the field of medicinal chemistry, can solve the problems of short half-life and weak hypoglycemic activity

Active Publication Date: 2021-08-06
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Compared with pure GLP-1R agonists, OXM has a better effect in intervening body weight, regulating lipid metabolism, and improving glucose tolerance, but its hypoglycemic activity is relatively weak and its half-life is short

Method used

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  • Long-acting oxyntomodulin (oxm) hybrid peptide, its preparation method and its use as medicine
  • Long-acting oxyntomodulin (oxm) hybrid peptide, its preparation method and its use as medicine
  • Long-acting oxyntomodulin (oxm) hybrid peptide, its preparation method and its use as medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0089] His-Gly-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Met-Asp-Cys-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 (SEQ.ID NO.1)

[0090] solid phase synthesis

[0091] (1) Swelling of the resin

[0092] Weigh 50mg of Fmoc-Rink amide-MBHA Resin (degree of substitution: 0.4mmol / g), swell with 7mL of DCM for 30min, filter to remove DCM, then swell with 10mL of NMP for 30min, rinse with NMP and 7mL of DCM respectively.

[0093] (2) Removal of Fmoc protecting group

[0094] Put the swollen resin into the reactor, add 25% piperidine / NMP (V / V) solution containing 0.1M HOBt to the resin to remove Fmoc, and wash it with NMP after the reaction. A resin free of the initially attached Fmoc protecting group is obtained.

[0095] (3) Synthesis of Fmoc-Ser(tBu)-Rink amide-MBHA Resin

[0096] Fmoc-Ser(tBu)-OH (15.4 mg, 0.04 mmol), HBTU (15.1 mg, 0.04 mmol), HOBt (5.4 mg, 0.04 mmol) and DIPEA (13.9 μL, 0.08 mmol) were dissolved in N...

Embodiment 2

[0102] His-Gly-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Glu-Cys-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 (SEQ.ID NO.2)

[0103] The synthesis method was the same as in Example 1, and the collected solution was lyophilized to obtain 29.2 mg of the pure product. The theoretical relative molecular mass is 4269.7. ESI-MS m / z: Calcd.[M+3H] 3+ 1424.2, [M+4H] 4+ 1068.4; Found[M+3H] 3+ 1424.8, [M+4H] 4+ 1068.1.

Embodiment 3

[0105] His-Gly-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Cys-Glu-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH 2 (SEQ.ID NO.3)

[0106] The synthesis method was the same as in Example 1, and the collected solution was lyophilized to obtain 27.6 mg of the pure product. The theoretical relative molecular mass is 4228.6. ESI-MS m / z: Calcd.[M+3H] 3+ 1410.5, [M+4H] 4+ 1058.2; Found[M+3H] 3+ 1410.0, [M+4H] 4+ 1058.2.

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Abstract

The present invention relates to a kind of long-acting oxyntomodulin (OXM) hybrid peptide and its application and synthesis method. By modifying OXM and hybridizing with the peptide sequence of Exenatide, the OXM hybrid peptide with longer pharmacological action time and better weight loss effect is obtained. The synthesis of the target polypeptide is quickly realized through the solid-phase synthesis method of the orthogonal protection strategy. The crude product is purified and freeze-dried to obtain the OXM hybrid peptide.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to long-acting oxyntomodulin (OXM) hybrid peptide, its preparation method and its application as medicine. Background technique [0002] The cause of metabolic syndrome is abnormal metabolism of various substances such as protein, fat and carbohydrates. Overnutrition and reduced physical activity can lead to obesity and obesity-related diseases such as diabetes. In recent years, the incidence of type 2 diabetes and dyslipidemia has been increasing day by day. [0003] Oxyntomodulin (OXM) is a polypeptide composed of 37 amino acids secreted by small intestinal L cells, including the entire 29 amino acid sequence of glucagon and the 8 amino acid part of the C-terminal extension, which is similar to glucagon Peptide-1 (GLP-1) has 50% homology, and the peptide sequence is: HSQGTFTSDYSKYLDSRRAQDFVQWLMNTKRNRNNIA. OXM can simultaneously activate glucagon-like peptide-1 receptor (GLP-1...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K19/00A61K38/22A61K38/26A61P3/10A61P3/04A61P3/06A61P1/16
CPCA61P1/16A61P3/04A61P3/06A61P3/10C07K14/57563C07K14/605A61K38/00C07K2319/00
Inventor 钱海黄文龙蔡星光刘春霞毕昕洲戴雨轩周洁
Owner CHINA PHARM UNIV
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