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Micromolecule polypeptide and application thereof to preparation of medicines for preventing and treating Parkinson's disease

A technology of medicine and composition, which is applied in the field of application of small molecule peptides in the preparation of drugs for the prevention or treatment of Parkinson's syndrome. Good, non-toxic and side effects, high synthetic purity

Active Publication Date: 2019-07-23
HUAZHONG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In 2015, there were 6.2 million Parkinson's patients in the world, and 117,400 patients died. However, the current treatment methods for Parkinson's syndrome are very limited, and the existing drug treatment and surgical treatment cannot be effectively cured, so most patients can only Symptomatic treatment

Method used

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  • Micromolecule polypeptide and application thereof to preparation of medicines for preventing and treating Parkinson's disease
  • Micromolecule polypeptide and application thereof to preparation of medicines for preventing and treating Parkinson's disease
  • Micromolecule polypeptide and application thereof to preparation of medicines for preventing and treating Parkinson's disease

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Artificial synthesis of TAT-pSyn

[0032] The sequence of TAT-pSyn is shown in SEQ ID NO.1, artificially synthesized by Jiangsu Qiangyao Biotechnology Co., Ltd., the synthesis report is shown below, and the chromatogram is shown as figure 1 Shown.

[0033] TAT-pSyn synthetic HPLC report

[0034]

[0035] The synthetic TAT-pSyn polypeptide has a purity of 95.79%, 1 mg per tube, is a white powder, completely soluble in water, and stored at -20°C in a sealed and dark place. Before use, dilute it with the injection saline according to the specified concentration and prepare it for immediate use.

[0036] The control of TAT-pSyn is TAT-scramble-pSyn (TAT-s-pSyn), and its sequence is as follows:

[0037] Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Pro-Glu-Met-Ser-Tyr-Gly-Glu-Gln-Tyr-Glu-Asp(YGRKKRRQRRR-PEMSYGEQYED), also Synthesized for the company.

Embodiment 2

[0039] TAT-pSyn blocks the binding of DAPK1 to alpha-synuclein and inhibits the hyperphosphorylation and abnormal aggregation of alpha-synuclein.

[0040] Culture neurofibroma blast cells (N2a) in vitro, transfect the eukaryotic expression alpha-synuclein plasmid, and give 0uM, 5uM, 25uM, 50uM TAT-pSyn polypeptide or control TAT- to the cells co-transfected with DAPK1 plasmid. Incubate with s-pSyn polypeptide or vehicle. After 90 minutes, cell protein was extracted. The results showed that after 25uM TAT-pSyn was given, the protein amount of alpha-synuclein and phosphorylated alpha-synuclein was reduced ( figure 2 ). It suggests that TAT-pSyn blocks the interaction between DAPK1 and alpha-synuclein, thereby inhibiting the hyperphosphorylation and abnormal aggregation of alpha-synuclein.

Embodiment 3

[0042] Application of TAT-pSyn in a transgenic mouse model of Parkinson's syndrome

[0043] (1) Establishment of a mouse model of Parkinson's syndrome

[0044] A transgenic mouse of Alpha-synuclein (A53T) No. 004479 was purchased from Jackson Lab in the United States for breeding. The transgenic mouse expresses human-derived A53T mutant synuclein (alpha-synuclein, full length 140 amino acids). Mouse prion protein promoter. At eight months, some homozygous mice gradually showed severe movement disorders. The phenotype manifests for an average of 14-15 months. Manifestations include sagging skin, weight loss and dyskinesia that precedes dyskinesias, paralysis of some limbs, tremors, and inability to stand. Immunohistochemical analysis of mutant mice aged 8-12 months revealed that synuclein content aggregates in the spinal cord, brainstem, cerebellum, and striatum. The malignant aggregation of synuclein is synchronized with the development of movement disorders. We use 12-month-o...

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Abstract

The invention discloses micromolecule polypeptide TAT-PSYN and an application thereof to preparation of medicines for preventing or treating Parkinson's disease. Through synthesizing a TAT protein transduction domain and combining and restraining fusion protein TAT-pSyn of protein polypeptide of alpha-synuclein (alpha-synuclein), pSyn protein polypeptide carried through TAT passes through blood-brain barriers through blood transportation and is taken in by nerve cells. The polypeptide is applied to an Alpha-synuclein(A53T) transgenic Parkinson mouse model, so that the effect of the polypeptidefor blocking combination of alpha-synuclein (alpha-synuclein) and death associated protein kinase 1 (DAPK1) can be effectively exerted, loss of dopaminergic neurons and nerve projection, caused by alpha-synuclein phosphorylation and abnormal gathering can be restrained, the dyskinesia of the Parkinson model is reduced, and a molecular target is provided for medicines for clinical treatment of theParkinson's disease.

Description

Technical field [0001] The invention belongs to the field of medicine and biotechnology, and relates to drugs for preventing and treating Parkinson's syndrome, and specifically relates to the application of small molecular polypeptides in the preparation of drugs for preventing or treating Parkinson's syndrome. Background technique [0002] In 1817, British doctor James Parkinson first gave a detailed description of Parkinson’s syndrome. Its clinical manifestations mainly include resting tremor, bradykinesia, muscle rigidity and postural and gait disorders. At the same time, patients may be accompanied by depression, constipation and sleep disorders. Non-motor symptoms. The prominent pathological changes of Parkinson’s disease are the degeneration and death of dopamine (DA) neurons in the substantia nigra of the midbrain, the significant reduction of DA content in the striatum, and the appearance of eosinophilic inclusion bodies in the cytoplasm of the substantia nigra residual n...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00A61K38/16A61P25/16
CPCA61K38/00C07K14/00
Inventor 朱铃强邓曼菲刘丹周雅帆谢傲吉
Owner HUAZHONG UNIV OF SCI & TECH
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