WO2020227876A1 - Utilisation d'acide oligo-guluronique dans un médicament pour la prévention et le traitement de maladies liées la protéine tau - Google Patents

Utilisation d'acide oligo-guluronique dans un médicament pour la prévention et le traitement de maladies liées la protéine tau Download PDF

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Publication number
WO2020227876A1
WO2020227876A1 PCT/CN2019/086562 CN2019086562W WO2020227876A1 WO 2020227876 A1 WO2020227876 A1 WO 2020227876A1 CN 2019086562 W CN2019086562 W CN 2019086562W WO 2020227876 A1 WO2020227876 A1 WO 2020227876A1
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WIPO (PCT)
Prior art keywords
tau protein
tau
guluronic acid
endoplasmic reticulum
acid
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PCT/CN2019/086562
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English (en)
Chinese (zh)
Inventor
续旭
李梅婷
毕德成
蔡楠
杨朋
姚丽君
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深圳大学
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Priority to PCT/CN2019/086562 priority Critical patent/WO2020227876A1/fr
Publication of WO2020227876A1 publication Critical patent/WO2020227876A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention belongs to the technical field of biomedicine, and specifically relates to the application of an oligomeric guluronic acid in the prevention and treatment of Tau protein diseases.
  • the Tau protein gene can be encoded into 6 Tau proteins of different lengths by post-transcriptional shearing.
  • the intact Tau protein contains an N-terminal protruding region, a proline-rich region and a C-terminal microtubule binding site.
  • the C-terminus mainly contains four microtubule binding repeat sequences: R1, R2, R3 and R4.
  • Tau protein can be divided into three types, including soluble non-phosphorylated Tau, abnormal phosphorylated Tau, and insoluble double helix filamentous Tau.
  • the main physiological function of Tau protein is to promote the assembly of tubulin into microtubules, maintain the stability of microtubules and normal axon transport.
  • Tau protein is a phosphoprotein associated with microtubules in neurons. Under physiological conditions, each Tau protein molecule contains 1-3 phosphate groups. Tau protein can regulate the assembly and assembly of microtubules through the level of autophosphorylation. Stable and regulate the phosphorylation level of Tau protein mainly depends on glycogen synthase kinase 3 ⁇ (GSK-3 ⁇ ) and cyclin-dependent kinase 5 (CDK5). But in the brain of patients with Tau protein disease, the phosphorylation level of Tau protein is 3-4 times that of normal Tau protein. The hyperphosphorylation of Tau protein dissociates from the microtubules and loses its regulation and control effect on the microtubules, making the normal assembly of microtubules impossible.
  • GSK-3 ⁇ glycogen synthase kinase 3 ⁇
  • CDK5 cyclin-dependent kinase 5
  • the hyperphosphorylated Tau protein dissociated from the microtubules will aggregate by themselves to form insoluble double-helical filamentous Tau, and finally form neurofibrillary tangles, causing neurons to lose their basic morphology, and the Tau protein also accumulates in the process of self-aggregation. Will produce neurotoxicity.
  • Endoplasmic reticulum stress is an adaptive mechanism in cells. Continuous or excessive endoplasmic reticulum stress induces cell apoptosis and causes tissue damage. Endoplasmic reticulum stress is the pathophysiological basis of many diseases and plays an important role in the development of neurodegenerative diseases.
  • the endoplasmic reticulum is one of the important subcellular organelles in eukaryotic cells, and it is an important place for the correct folding and processing of membrane proteins and secreted proteins. When a large amount of unfolded or misfolded protein accumulates, excessive accumulation of normal protein, and disruption of intracellular calcium ion balance, it can trigger endoplasmic reticulum stress.
  • the accumulation of a large amount of Tau protein in the cell promotes its harmful interaction with the endoplasmic reticulum membrane and its related proteins, thereby inducing strong endoplasmic reticulum stress.
  • the treatment of Tau protein disease is generally based on the type of Tau protein disease to administer drugs and implement treatment programs.
  • related therapeutic drugs developed according to various therapeutic mechanisms of specific neurodegenerative diseases can be specifically divided into: antioxidants, anti-inflammatory agents, and anti-apoptotic agents.
  • antioxidants include edaravone, reduced glutathione, vitamin E, acetylcysteine, selegiline, rasagiline, etc., anti-inflammatory agents, non-steroidal anti-inflammatory drugs NSAIDs, selegiline Coxib and others, anti-apoptotic agents include p53 inhibitors and so on.
  • Sodium alginate is a water-soluble polysaccharide derived from the cell wall of brown algae. It is a linear acidic polysaccharide formed by connecting D-mannuronic acid and L-guluronic acid through 1®4 glycosidic bonds. Macromolecule sodium alginate (algin) has anti-tumor, anti-virus and immune-enhancing activities. Many brown algae polysaccharides have important pharmacological effects on many major and difficult human diseases, but because of their large molecular weight and high viscosity, for example, the viscosity of a 1% alginate solution can reach 10 to 2000. cps, and its viscosity increases with the increase of concentration, which brings great limitations to the research and application of biological activity.
  • the purpose of the present invention is to overcome the above-mentioned shortcomings of the prior art and provide an application of oligomeric guluronic acid as a Tau protein disease-related inhibitor or drug to solve the clinical efficacy of existing drugs for the treatment of Tau protein disease. Undesirable technical issues.
  • one aspect of the present invention provides an application method of oligoguluronic acid.
  • the oligomeric guluronic acid is used as an inhibitor of Tau protein phosphorylation at positions 396 and 404 of serine.
  • the oligomeric guluronic acid is used as an inhibitor of endoplasmic reticulum stress activity induced by thapsigargin.
  • the degree of polymerization of the oligomeric guluronic acid is 2-8.
  • Another aspect of the present invention provides the application of oligomeric guluronic acid in the preparation of medicines, functional foods or health products for preventing/treating Tau protein diseases.
  • a medicine for preventing/treating Tau disease in another aspect of the present invention, includes an effective dose of oligoguluronic acid.
  • a method for inhibiting hyperphosphorylation of Tau protein includes the step of contacting an effective dose of oligoguluronic acid or a drug for preventing/treating Tau protein disease with cells expressing Tau protein or Tau protein.
  • the method for inhibiting the aggregation of Tau protein includes the step of contacting the Tau protein with an effective dose of oligoguluronic acid or the drug for preventing/treating Tau protein disease.
  • the invention also provides a method for inhibiting the stress activity of the endoplasmic reticulum.
  • the method for inhibiting the stress activity of the endoplasmic reticulum includes the step of contacting the cells with an effective dose of oligoguluronic acid or the drug for preventing/treating Tau disease.
  • the oligomeric guluronic acid of the present invention has the following beneficial effects:
  • the oligomeric guluronic acid has relatively strong functions such as inhibiting the expression level of total Tau, phosphorylation of Tau protein, and endoplasmic reticulum stress activity.
  • Acid as an inhibitor of at least any one of the expression level of total Tau, Tau protein hyperphosphorylation, and endoplasmic reticulum stress activity, can effectively inhibit the expression level of total Tau, inhibit Tau protein hyperphosphorylation and endoplasmic Net stress activity and other effects.
  • the application of the oligomeric guluronic acid of the present invention in the preparation of drugs, functional foods or health products for preventing/treating Tau protein diseases and the drugs, functional foods or health products for preventing/treating Tau diseases prepared based on the application can be used In order to inhibit the overexpression of Tau protein in the corresponding cells, it also inhibits the hyperphosphorylation of Tau protein, which ultimately plays a role in the prevention/treatment of Tau protein diseases. At the same time, it can inhibit the endoplasmic reticulum stress activity. In addition, because the oligomeric guluronic acid is non-toxic, it has good curative effect and small side effects.
  • the biological scaffold of the present invention is formed by 3D direct printing using the biological ink of the present invention, the biological scaffold has high precision and the loaded bioactive components have high activity. Therefore, the biological scaffold has high biological activity.
  • Figure 1 is an electrophoresis diagram of GOS inhibiting the expression of total Tau protein in HEK293/Tau cells in Example 2;
  • Figure 2 is an electrophoresis diagram of GOS inhibiting Tau protein phosphorylation in HEK293/Tau cells in Example 2;
  • Figure 3 is an electrophoresis diagram of GOS inhibiting the occurrence of endoplasmic reticulum stress in HEK293/Tau cells in Example 3.
  • Tau protein A phosphoprotein. Under physiological conditions, each Tau protein molecule contains 1-3 phosphate groups. It is a microtubule-associated protein. The main member of the proteins, MAP) family is highly soluble and is encoded by a single gene on the long arm of chromosome 17. Tau protein can regulate the assembly and stability of microtubules through the level of autophosphorylation. Regulating the phosphorylation level of Tau protein mainly depends on glycogen synthase kinase 3 ⁇ (GSK-3 ⁇ ) and cyclin-dependent kinase 5 (CDK5).
  • GSK-3 ⁇ glycogen synthase kinase 3 ⁇
  • CDK5 cyclin-dependent kinase 5
  • Tau protein disease It is a general term for the abnormal disease of Tau protein of microtubule binding protein. It is a common neurodegenerative disease and a type of pathology in the human brain due to neurofibrillary tangles (NFT)) Neurodegenerative diseases caused by aggregation.
  • NFT neurofibrillary tangles
  • Endoplasmic reticulum stress manifested by the accumulation of misfolded and unfolded proteins in the endoplasmic reticulum lumen and the disorder of calcium ion balance, which can activate the unfolded protein response, the endoplasmic reticulum overload response and caspase-12 mediated Signal pathways such as apoptosis pathway can induce glucose regulated protein (glucose regulated protein) Protein 78 kD, GRP78), GRP94 and other endoplasmic reticulum molecular chaperones expressed to produce protective effects, and can also independently induce cell apoptosis.
  • glucose regulated protein glucose regulated protein
  • Protein 78 kD, GRP78 Protein 78 kD, GRP78
  • GRP94 endoplasmic reticulum molecular chaperones expressed to produce protective effects, and can also independently induce cell apoptosis.
  • oligomeric guluronic acid has relatively strong ability to inhibit the expression of total Tau, phosphorylation of Tau protein, and endoplasmic reticulum stress. Based on this, the embodiments of the present invention provide The application of oligomeric guluronic acid in the following related aspects.
  • the embodiments of the present invention provide the use of oligomeric guluronic acid as an inhibitor of at least any one of total Tau expression, Tau protein hyperphosphorylation, and endoplasmic reticulum stress.
  • the oligomeric guluronic acid can effectively inhibit the hyperphosphorylation of Tau protein and the expression level of total Tau, and can also inhibit endoplasmic reticulum stress.
  • the oligomeric guluronic acid has the function of inhibiting the phosphorylation of Tau protein at serine 396 and 404, such as inhibiting the Tau protein at serine 396, 404 in cells that can express Tau protein.
  • the function of site phosphorylation. Therefore, the oligomeric guluronic acid can be used as an inhibitor of Tau protein phosphorylation at serine 396 and 404, and specifically can be used as Tau protein phosphorylation at serine 396 and 404 in cells expressing Tau protein.
  • the application of chemical inhibitors can be used to prepare related drugs that inhibit the phosphorylation of Tau protein, such as inhibiting the phosphorylation of Tau protein at serine 396 and 404, thereby effectively inhibiting the phosphorylation of Tau protein, such as avoiding hyperphosphorylation of Tau protein , Thereby avoiding its dissociation from the microtubules, ensuring the regulation of the microtubules, allowing the normal assembly of the microtubules, thereby achieving the prevention and treatment of Tau protein disease.
  • the oligomeric guluronic acid is used as an inhibitor of endoplasmic reticulum stress activity induced by thapsigargin.
  • the oligomeric guluronic acid can be used as an endoplasmic reticulum stress activity inhibitor, and further can be used to prepare drugs that inhibit the endoplasmic reticulum stress activity, thereby effectively inhibiting the endoplasmic reticulum stress activity, Furthermore, avoiding the accumulation of a large amount of Tau protein in the cell promotes its harmful interaction with the endoplasmic reticulum membrane and its related proteins, thereby reducing the apoptosis rate of the corresponding cells.
  • the above-mentioned cells expressing Tau protein include HEK293/Tau cells.
  • the Tau protein may be a Tau protein including HEK293/Tau cells.
  • the endoplasmic reticulum stress may also be an endoplasmic reticulum stress including HEK293/Tau cells, for example, avoiding HEK293
  • HEK293/Tau cells for example, avoiding HEK293
  • the oligomeric guluronic acid having the function and effect of inhibiting at least any one of the expression level of total Tau, Tau protein phosphorylation, and endoplasmic reticulum stress activity
  • the oligomeric guluronic acid can be used to prepare medicines, functional foods or health care products for the prevention/treatment of Tau protein diseases.
  • the oligomeric guluronic acid is used to inhibit the expression level of total Tau, Tau protein phosphorylation and endoplasmic reticulum stress activity At least any one of the effective ingredients, so as to achieve the prevention/treatment of Tau disease.
  • the embodiments of the present invention also provide a A drug for preventing/treating Tau protein disease.
  • the medicine includes an effective dose of active ingredients for preventing/treating Tau disease.
  • the active ingredient includes oligomeric guluronic acid.
  • the active ingredient may also include at least any one of related properties that can effectively inhibit the expression level of total Tau, phosphorylation of Tau protein, and endoplasmic reticulum stress activity.
  • the "effective” mentioned here refers to the ingredients that have clinical effects in the prevention or treatment of Tau protein disease alone, or can be combined with oligoguluronic acid to increase oligoguluronic acid Components that have clinical effects in preventing or treating Tau protein diseases.
  • the "effective dose” refers to an effective amount capable of preventing or treating Tau proteinopathy, and refers to an amount of oligoguluronic acid sufficient to show benefits or clinical significance to an individual.
  • the effective dose of the oligoguluronic acid may be 1 mg/mL.
  • the medicine for preventing/treating Tau disease may further include a pharmaceutically acceptable carrier component of oligoguluronic acid.
  • the carrier component of the pharmaceutically acceptable oligomeric guluronic acid can be a corresponding carrier of a corresponding dosage form prepared according to the administration mode of the Tau protein disease drug.
  • the carrier includes but not only at least one of flavoring agents, excipients and natural polymer compounds. As long as it is a carrier that can support the oligomeric guluronic acid and is beneficial to its stability and absorption and meets the medical requirements, it is within the scope of the present invention. Therefore, the drug for the prevention/treatment of Tau disease can be selected according to the needs of clinical administration, and the corresponding carrier type can be selected to present a corresponding dosage form, for example, it can be a granule, tablet, pill, etc.
  • Tau protein diseases described in the foregoing embodiments include at least one of traumatic brain injury, frontotemporal dementia, progressive supranuclear palsy, Pick's disease, Alzheimer's disease, and the like.
  • the drug for the prevention/treatment of Tau protein disease contains the above-mentioned oligoguluronic acid, so that the drug can effectively inhibit the expression of total Tau protein, Tau protein hyperphosphorylation, and endoplasmic reticulum stress. Activation of at least any one of the other effects, thereby giving the preventive/therapeutic drug effective prevention/treatment of Tau disease.
  • the oligoguluronic acid is an oligosaccharide, it has good curative effect, small toxic and side effects, and is safe.
  • the embodiment of the present invention provides a method for inhibiting Tau protein hyperphosphate Method.
  • the method includes the step of contacting an effective dose of the oligoguluronic acid or the drug for preventing/treating Tau protein disease as described above with cells or Tau protein expressing Tau protein.
  • the method can effectively inhibit the phosphorylation of Tau protein, especially the hyperphosphorylation of Tau protein, specifically, inhibit the phosphorylation of Tau protein at serine 396 and 404 to prevent it from dissociating from microtubules.
  • the cells expressing Tau protein may be HEK293/Tau cells as described above.
  • the embodiment of the present invention provides a method for inhibiting aggregation of Tau protein.
  • the method includes the step of contacting Tau protein with an effective dose of the oligoguluronic acid or the drug for preventing/treating Tau disease described above.
  • the method can effectively inhibit the excessive aggregation of Tau protein, thereby avoiding the formation of insoluble double helix filamentous Tau due to the excessive aggregation of Tau protein, and finally forming neurofibrillary tangles.
  • the embodiment of the present invention also provides a method for inhibiting the stress activity of the endoplasmic reticulum.
  • the method includes the step of contacting cells with an effective dose of the oligoguluronic acid or the drug for preventing/treating Tau disease described above, so as to inhibit endoplasmic reticulum stress at the cellular level.
  • the cells are HEK293/Tau cells with overexpression of Tau protein induced by thapsigargin. The method can effectively inhibit the activation of endoplasmic reticulum stress in cells, thereby improving the survival rate of cells.
  • the above-mentioned oligoguluronic acid can be prepared according to the existing conventional methods.
  • the algin can be fractionated to obtain homo-guluronic acid (PG), and the oligoguluronic acid (PG) can be obtained by enzymatic hydrolysis of PG.
  • Uronic acid (GOS) Specifically, the oligoguluronic acid can be prepared according to the method in Example 1 below.
  • the degree of polymerization of the oligomeric guluronic acid in the above embodiments is 2-8.
  • oligoguluronic acid for inhibiting total Tau expression, phosphorylation, and endoplasmic reticulum stress activity will be further explained in detail.
  • Sodium alginate and heparin in this experiment were purchased from Sigma; DMEM medium, penicillin, and streptomycin were purchased from Hyclone, USA; fetal bovine serum was purchased from BI; cell lysate was purchased from Shanghai Bocai Biotechnology Company; Tau5, p -Tau monoclonal antibody was purchased from CST, Germany; the developer and fixing solution were purchased from Thermo Fisher Scientific.
  • This example provides a preparation method of oligoguluronic acid, and the specific preparation method is as follows:
  • Example 1 Take the GOS prepared in Example 1 to prepare a solution with a concentration of 1 mg/mL, dissolve it in 50% MeOH and 1 mM NH 4 OH, and use LCMS-IT-TOF mass spectrometer to detect.
  • the detection conditions of the LCMS-IT-TOF mass spectrometer are set as follows: Flowrate: 7.5 ⁇ l/min; Interface: -3.5 kV; Nebulizer gas: 0.5 l/min; CDL temperature (CDL temperature) ): 200°C.
  • the chemical structure of GOS was determined by LC/MS-IT-TOF mass spectrometer as shown in the above-mentioned structural formula (a) of GOS.
  • the GOS can effectively inhibit the expression level of total Tau and phosphorylation of Tau protein, thereby inhibiting the formation of neurofibrillary tangles.
  • the GOS can reduce HEK293/Tau cells.
  • the GOS can also inhibit and reduce the endoplasmic reticulum stress activity, specifically, it inhibits the endoplasmic reticulum stress activity function induced by thapsigargin, thereby reducing damage to cells and improving cell survival rate. Based on this function of the GOS, the GOS can prevent the pathological process of Tau disease, indicating that GOS may be used as a new anti-Tau disease drug for the treatment of neurodegenerative diseases.

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Abstract

L'invention concerne un acide oligo-guluronique en tant qu'inhibiteur d'au moins l'une de l'expression de la protéine Tau totale, de l'hyperphosphorylation de la protéine Tau et de l'activité de stress du réticulum endoplasmique, ainsi que son utilisation dans la préparation de médicaments. L'acide oligo-guluronique présente les fonctions d'inhibition efficace du niveau d'expression de la protéine Tau totale, de la phosphorylation de la protéine Tau, de l'activité de stress du réticulum endoplasmique, etc., et ainsi empêchant le processus pathologique de maladies liées à la protéine Tau. De plus, étant donné que l'acide oligo-guluronique n'est pas toxique, il peut être utilisé comme médicament contre les maladies liées à la protéine Tau pour le traitement de maladies neurodégénératives.
PCT/CN2019/086562 2019-05-13 2019-05-13 Utilisation d'acide oligo-guluronique dans un médicament pour la prévention et le traitement de maladies liées la protéine tau WO2020227876A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1562050A (zh) * 2004-03-24 2005-01-12 中国海洋大学 褐藻酸寡糖在抗痴呆、抗糖尿病中的应用
CN101301310A (zh) * 2007-05-08 2008-11-12 首都医科大学 褐藻多糖硫酸酯在预防和治疗帕金森病中的用途
CN106344593A (zh) * 2015-07-17 2017-01-25 上海绿谷制药有限公司 褐藻胶寡糖及其衍生物在治疗血管性痴呆中的应用

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1562050A (zh) * 2004-03-24 2005-01-12 中国海洋大学 褐藻酸寡糖在抗痴呆、抗糖尿病中的应用
CN101301310A (zh) * 2007-05-08 2008-11-12 首都医科大学 褐藻多糖硫酸酯在预防和治疗帕金森病中的用途
CN106344593A (zh) * 2015-07-17 2017-01-25 上海绿谷制药有限公司 褐藻胶寡糖及其衍生物在治疗血管性痴呆中的应用

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