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Endomorphin-derived peptide with blood-brain barrier permeability as well as synthesis and application of endomorphin-derived peptide

An endomorphin and blood-brain barrier technology, applied in the field of biochemistry, can solve the problems of not easily permeating the blood-brain barrier, short biological half-life, poor enzymatic hydrolysis stability, etc.

Active Publication Date: 2013-04-03
LANZHOU UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, like all small molecule peptides, endomorphins face problems such as poor enzymatic stability, short biological half-life, and difficulty in penetrating the blood-brain barrier in research. These shortcomings have seriously hindered the development of endomorphins into clinical analgesics.

Method used

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  • Endomorphin-derived peptide with blood-brain barrier permeability as well as synthesis and application of endomorphin-derived peptide
  • Endomorphin-derived peptide with blood-brain barrier permeability as well as synthesis and application of endomorphin-derived peptide
  • Endomorphin-derived peptide with blood-brain barrier permeability as well as synthesis and application of endomorphin-derived peptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Membrane-penetrating peptide-linked endomorphin-1 derivative peptide——EM1-SS-SynB3 synthesis

[0056] (1) Cysteine-containing endomorphin-1 (Tyr-Pro-Trp-Phe-Cys-NH 2 ) and the penetrating peptide SynB3 (Arg-Arg-Leu-Ser-Tyr-Ser-Arg-Arg-Arg-Phe-NH 2 ), the solid-phase synthesis of:

[0057] a. Resin pretreatment: Add Rink-Amide-MBHA resin with an amino molar mass of 0.5mmol / g into the reactor, add dichloromethane and stir for 30 min to fully swell the resin and then vacuum-drain the solvent;

[0058] b. Deprotection of F-moc: The deprotection reagent is piperidine / DMF=1:4 (V / V). Stir the deprotection reagent with the resin for 2 minutes and then drain it. Repeat 4 times to completely remove the Fmoc group. Finally, wash with DMF to remove the deprotection reagent.

[0059] c. Condensation: 0.6~0.8 mol Fmoc group-protected amino acid, N-hydroxybenzotriazole, O-benzotriazole-N,N,N',N'-tetramethylurea-hexa Dissolve fluorophosphate in DMF, add 1.2~1.6 mol of di...

Embodiment 2

[0066] Example 2: Derivative peptides of endomorphin-1 analogues linked to penetrating peptides——[D-Ala 2 ] Synthesis of EM1-SS-SynB3

[0067] (1) Cysteine-containing endomorphin-1 analogs (Tyr-D-Ala-Trp-Phe-Cys-NH 2 ) and the penetrating peptide SynB3 (Arg-Arg-Leu-Ser-Tyr-Ser-Arg-Arg-Arg-Phe-NH 2 ) of solid-phase synthesis: with embodiment 1.

[0068] (2) Synthesis of PDP-SynB3 with activated sulfhydryl group: Dissolve the peptide SynB3 (1mmol) and the activator SPDP (2mmol) in 10ml of anhydrous methanol, stir and mix well, add 6mmol of N,N-diisopropylethyl Amine (DIEA), react at room temperature for 6~8h; use C 18 Reversed-phase HPLC column purification to obtain PDP-SynB3 with activated sulfhydryl group;

[0069] (3) Synthesis of endomorphin-derived peptides: the reaction bottle was pumped and replaced with argon. Sulfhydryl-activated PDP-SynB3 (1 mmol) was combined with cysteine-containing endomorphin-1 analog [D-Ala 2 ]EM1 (1.1mmol) was dissolved in 10ml methanol / wa...

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Abstract

The invention discloses endomorphin-derived peptides with blood-brain barrier permeability. The endomorphin-derived peptides are formed by connecting cell-penetrating peptide SynB3 with the carbon terminal of EM1 (Endomorphin1) and analogue (D-A1a2) EM1 through a disulfide bond; good BBB (Blood-Brain Barrier) permeability of the SynB3 is used to mediate the EM1 and the analogue (D-A1a2) EM1 to permeate the blood-brain barrier to reach the center by means of adsorption effect; and the characteristics that the disulfide bond is stable in blood and is easily reduced to break in meninx are utilized, the disulfide bond is broken under the action of a meningeal reductase to release free endomorphin-derived peptide so that the pain killing effect of the endomorphin-derived peptide can be exerted. A pharmacodynamic experiment proves that the endomorphin-derived peptides can be peripherally administrated besides the obviously improved pain killing activity to provide a wide prospect for developing clinical application of a neuropeptide medicine.

Description

technical field [0001] The invention belongs to the field of biochemical technology, and relates to an endomorphin-derived peptide, in particular to an endomorphin-derived peptide with blood-brain barrier permeability; the invention also relates to the use of the endomorphin-derived peptide in preparing analgesic drugs Applications. Background technique [0002] The market value of global central nervous system drugs in 1998 was 3.3×10 8 US dollars, less than 1 / 2 of the global market share of cardiovascular disease drugs, but only in the United States as an example, the number of patients with central nervous system diseases is about twice that of patients with cardiovascular diseases (Drug Discov. Today, 2002, 7, 223 ). An important reason for this imbalance is that more than 98% of drugs with potential to treat diseases of the central nervous system cannot penetrate the blood-brain barrier. [0003] There are two barriers between the central nervous system and the exter...

Claims

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Application Information

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IPC IPC(8): C07K19/00A61K38/07A61K47/48A61P25/04A61K47/64
Inventor 王锐倪京满刘晖
Owner LANZHOU UNIVERSITY
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