WO2023186062A1 - Utilisation d'un peptide dans le traitement d'une maladie neurodégénérative ou l'amélioration de la fonction cognitive - Google Patents

Utilisation d'un peptide dans le traitement d'une maladie neurodégénérative ou l'amélioration de la fonction cognitive Download PDF

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WO2023186062A1
WO2023186062A1 PCT/CN2023/085334 CN2023085334W WO2023186062A1 WO 2023186062 A1 WO2023186062 A1 WO 2023186062A1 CN 2023085334 W CN2023085334 W CN 2023085334W WO 2023186062 A1 WO2023186062 A1 WO 2023186062A1
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amino acid
peptide
disease
acid sequence
seq
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PCT/CN2023/085334
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English (en)
Chinese (zh)
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刘承鑫
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首创生物技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • 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
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids

Definitions

  • the present invention relates to the treatment of neurodegenerative diseases and cognitive impairment; and the improvement and enhancement of cognitive function.
  • the present invention relates to the use of peptides for the prevention or treatment of neurodegenerative diseases and cognitive disorders, preferably Alzheimer's disease and Parkinson's disease.
  • the invention also relates to the use of peptides for improving or enhancing cognitive function in a subject.
  • Neurodegenerative disease or neurodegenerative disease is a disease directly caused by the gradual degeneration of neurons. Degenerative processes may involve progressive loss of neuronal structure, progressive loss of neuronal function, or progressive neuronal cell death. This progressive neurodegeneration often leads to physical disability and mental deterioration. Many neurodegenerative diseases are severe, progressive and ongoing diseases with few treatments. Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most important neurodegenerative diseases.
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • Neurocognitive Disorder also known as Dementia
  • Dementia is a type of brain disease that causes long-term and gradual deterioration of thinking ability and memory, and affects a person's daily life activities.
  • the most common type of dementia is Alzheimer's disease, which accounts for 50 to 70 percent of all dementia patients.
  • Dementia affects 36 million people worldwide. About 10% of the population will develop the disease during their lifetime.
  • Dementia is closely related to age (aging), with approximately 3% of the population developing dementia between the ages of 65 and 74, another 19% between the ages of 75 and 84, and nearly half of the population over the age of 85 developing dementia. .
  • AD Alzheimer's disease
  • the most common early symptom is loss of short-term memory.
  • symptoms may gradually appear, including language difficulties, disorientation, mood swings, loss of motivation, inability to care for oneself, and many behavioral problems.
  • patients often become disconnected from family or society, gradually lose physical function, and eventually die.
  • the course of the disease varies from person to person, the average life expectancy after diagnosis is about three to nine years.
  • AD Alzheimer's disease
  • a ⁇ beta-amyloid
  • microglial activation is involved in the spread of tau tangles in the neocortex in Alzheimer's disease, which in turn leads to the occurrence of cognitive dysfunction in Alzheimer's disease patients (see Tharick A .Pascoal et al., Microglial activation and tau propagate jointly across Braak stages, Nature Medicine, 27, pages 1592–1599 (2021 August)).
  • Microglial activation is part of the immune response in the human brain and is a key factor associated with the development of Alzheimer's disease. Excessive activation of microglia is not only an epiphenomenon of inflammation, but also a key upstream mechanism that is crucial to the development of AD.
  • Parkinson's disease is a chronic neurodegenerative disease affecting the central nervous system, mainly affecting the motor nervous system. Its symptoms usually appear slowly over time. The most obvious early symptoms are tremor, limb stiffness, reduced motor function and abnormal gait. Cognitive and behavioral problems may also be present. Dementia is quite common in severely ill patients.
  • Selegiline is a monoamine oxidase (MAO)-B inhibitor (MAOI).
  • MAOI monoamine oxidase
  • WO2013/173941 and CN104321337A disclose an analgesic peptide with 11 to 14 amino acid residues, which matches the fragment of rabbit ⁇ 1-antiprotease through sequence alignment.
  • WO2016/165101 discloses that the peptide can effectively inhibit HCV replication.
  • WO2016/165102 and CN107847550A disclosed that the peptide is used to treat stroke (an acute cerebrovascular disease), verified that the peptide can pass through the brain-blood barrier, and verified the effect of the peptide on PC12 cells through in vitro cell experiments. Protection from glutamate- and hydrogen peroxide-induced cytotoxicity.
  • the PC12 cells tested in WO2016/165102 are a type of pheochromocytoma derived from rat adrenal medulla that exhibit certain characteristics of ganglion cells and are particularly useful in establishing a model of cellular hypoxic injury, thereby simulating acute cerebrovascular disease. rapid hypoxic and toxic states.
  • Alzheimer's disease and Parkinson's disease are chronic diseases that are not caused by acute cerebral hypoxia and toxicity caused by cerebral blood vessel embolism or rupture.
  • the prior art does not mention the possibility of using said peptides to treat AD or PD.
  • the object of the present invention includes providing drugs for treating neurodegenerative diseases and cognitive impairment, as well as providing active ingredients or compositions for improving or enhancing the cognitive function of subjects. It is also an object of the present invention to provide medicaments for the treatment of Alzheimer's disease and Parkinson's disease.
  • One of the technical problems of the present invention is solved by providing the peptides of the present invention and compositions comprising said peptides.
  • the present invention relates to a peptide having the amino acid sequence of SEQ ID NO: 1 or 2 or a variant or fragment thereof.
  • “Variant” and “fragment” mean a peptide that has certain amino acid residue changes compared to the peptide of the invention and substantially retains the same or similar biological function or activity as the peptide.
  • a variant of an amino acid sequence may be a variant of an amino acid sequence that has at least a certain percent identity with the amino acid sequence, or a variant of an amino acid sequence that has at least one or more amino acid mutations compared with the amino acid sequence.
  • the variant may be at least 70% identical to the amino acid sequence of SEQ ID NO: 1 or 2.
  • the variant may have 0 to 4 amino acid mutations in the amino acid sequence of SEQ ID NO: 1 or 2.
  • a fragment of an amino acid sequence may be an amino acid sequence having one or more deletions at the C-terminus and/or N-terminus compared to the amino acid sequence.
  • the deletions may be 1-5, such as 1, 2, 3, 4 or 5.
  • Fragments of the amino acid sequence may be 8 to 20 amino acids in length, such as 10 to 15 amino acids, such as 10, 11, 12, 13, 14 or 15 amino acids.
  • the peptide of the invention is selected from:
  • a peptide comprising an amino acid sequence having 0 to 4 amino acid mutations in DEAQETAVSSHEQD (SEQ ID NO: 2).
  • the peptides of the invention comprise at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 1 sexual amino acid sequence.
  • the peptide of the invention is comprised in or has 0 to 4 amino acid mutations relative to SEQ ID NO: 1, such as 0 to 3, such as 1 to 3, such as 0, 1, 2, Amino acid sequence with 3 or 4 amino acid mutations.
  • the peptides of the invention comprise at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:2 sexual amino acid sequence.
  • the peptide of the invention is comprised in or has 0 to 4 amino acid mutations relative to SEQ ID NO: 2, such as 0 to 3, such as 1 to 3, such as 0, 1, 2, Amino acid sequence with 3 or 4 amino acid mutations.
  • Amino acid mutations can be selected from additions, deletions or substitutions of amino acids.
  • the addition can be the insertion of an amino acid between two amino acid residues in the amino acid sequence, or the addition of an amino acid at the C-terminus or N-terminus of the amino acid sequence.
  • the deletion can be the deletion of an amino acid between two amino acid residues in the amino acid sequence, or the deletion of the C-terminus or N-terminus of the amino acid sequence.
  • the substitution may be of any amino acid residue in the amino acid sequence.
  • the addition, deletion or substitution of amino acids occurs at the C-terminus or N-terminus of the sequence. Substitutions may be conservative substitutions.
  • Conservative substitution refers to the substitution between amino acid molecules with similar properties, including the ionicity, hydrophobicity and molecular weight of the molecule.
  • Amino acids with similar properties can be classified as follows: aliphatic amino acids (such as glycine, alanine, valine, leucine, isoleucine); hydroxyl-containing or sulfur-containing amino acids (such as serine, cysteine, threonine).
  • amino acids methionine
  • cyclic amino acids such as proline
  • aromatic amino acids such as phenylalanine, tyrosine, tryptophan
  • basic amino acids such as histidine, lysine
  • arginine acidic or amide amino acids (such as aspartic acid, glutamic acid, asparagine, glutamine).
  • Amino acid mutations may be located at the C-terminus and/or N-terminus of the amino acid sequence.
  • the peptide may have 1, 2 or 3 amino acid additions at the C-terminus or N-terminus of SEQ ID NO: 1.
  • the peptide may have 1, 2 or 3 amino acid deletions at the C-terminus or N-terminus of SEQ ID NO:2.
  • the peptides of the invention may be from 8 to 20 amino acids in length, preferably from 10 to 18 amino acids in length, more preferably from 11 to 14 amino acids in length.
  • the peptide may be 10, 11, 12, 13, 14, 15, 16, 17 or 18 amino acids in length.
  • the peptides of the invention may be selected from
  • a peptide comprising, consisting essentially of, or represented by the amino acid sequence of SEQ ID NO: 1; or
  • a peptide of the invention consists of the amino acid sequence of SEQ ID NO: 1.
  • the peptide of the invention consists of the amino acid sequence of SEQ ID NO:2.
  • the invention relates to the use of a peptide described herein in the preparation of a composition for preventing, treating or ameliorating a neurodegenerative disease in a subject in need thereof.
  • the invention relates to peptides for use in preventing, treating or ameliorating neurodegenerative diseases in a subject in need thereof.
  • the invention relates to a method of preventing, treating or ameliorating a neurodegenerative disease in a subject in need thereof, comprising administering an effective amount of a peptide to the subject in need thereof.
  • Neurodegenerative diseases can include cognitive impairment.
  • the neurodegenerative disease is a chronic neurodegenerative disease.
  • the invention relates to the use of a peptide described herein for the preparation of a composition for preventing, treating or ameliorating dementia in a subject in need thereof.
  • the invention relates to peptides for use in preventing, treating or ameliorating dementia in a subject in need thereof.
  • the invention relates to a method of preventing, treating or ameliorating dementia in a subject in need thereof, comprising administering an effective amount of a peptide to the subject in need thereof.
  • Dementia can be caused by neurodegenerative diseases. Alternatively, dementia can accompany neurodegenerative diseases.
  • the neurodegenerative disease or cognitive disorder is selected from Alzheimer's disease or Parkinson's disease. Therefore, the peptides of the present invention can be used to prevent, treat or improve Alzheimer's disease. In addition, the peptide of the present invention can be used to prevent, treat or improve Parkinson's disease.
  • Cognition can be the intelligent processing process by which the body recognizes and acquires knowledge, involving a series of random, psychological and social behaviors such as learning, memory, language, thinking, spirit, and emotion.
  • Cognitive impairment can include abnormalities in the brain's high-level intelligent processing related to the above-mentioned learning, memory, and thinking judgment, causing severe learning and memory impairments, accompanied by pathological processes such as aphasia, apraxia, agnosia, or aphasia.
  • the invention relates to the use of a peptide described herein in the preparation of a composition for improving, enhancing or restoring cognitive function or cognitive ability in a subject in need thereof.
  • the invention relates to peptides for use in improving, enhancing or restoring cognitive function or cognitive ability in a subject in need thereof.
  • the invention relates to a method of improving, enhancing or restoring cognitive function or cognitive ability in a subject in need thereof, comprising administering to the subject in need thereof an effective amount of a peptide.
  • cognitive function or cognitive ability includes perceptual ability, logical thinking ability, memory ability, language ability, learning ability, emotional control ability, social ability or attention.
  • the subject has a cognitive function or cognitive ability decline, such as a cognitive function or cognitive ability decline caused by or accompanying aging.
  • the subject may suffer from cognitive impairment or a neurodegenerative disease, preferably a cognitive impairment caused by a neurodegenerative disease, more preferably Alzheimer's disease or Parkinson's disease.
  • dementia is characterized or manifested by communication difficulties, poor judgment, difficulty performing simple tasks, missing or misplacing objects, language impairment, personality changes, reduced behavioral abilities, confused sense of time and space, and reduced comprehension. , decreased problem-solving ability, decreased concentration, decreased social skills, sensory impairment, logical thinking disorder or memory impairment.
  • the neurodegenerative disease or cognitive disorder is Alzheimer's disease.
  • Alzheimer's disease is characterized by beta-amyloid (A ⁇ ) deposition, neuroinflammation, and/or glial cell abnormalities or activation in the brain, particularly the hippocampus.
  • a ⁇ beta-amyloid
  • Prevention, treatment or improvement of Alzheimer's disease is achieved by reducing or alleviating beta-amyloid (A ⁇ ) deposition, neuroinflammation and/or glial cell abnormalities or activation in the brain.
  • the invention relates to the use of the peptides described herein in the preparation of a method for reducing or alleviating beta-amyloid (A ⁇ ) deposition, neuroinflammation and/or glial abnormality or activation in the brain of a subject, particularly in the hippocampus.
  • a ⁇ beta-amyloid
  • the subject may be a neurodegenerative disease patient or a cognitive impairment patient, preferably an Alzheimer's disease patient.
  • the peptides described herein can be effective in reducing or alleviating A ⁇ or A ⁇ plaque deposition in a subject's brain, such as the hippocampus.
  • the peptide can reduce or alleviate the expression or levels of inflammatory factors in the subject's brain, such as the hippocampus or cortex.
  • the inflammatory factor can be selected from IL-1 ⁇ , IL-6 or TNF- ⁇ .
  • the peptides may also reduce or alleviate glial cell abnormalities or activation in the brain's hippocampus. Glial cells can also be called glial cells and can be selected from astrocytes or microglia, with microglia being preferred.
  • the neurodegenerative disease or cognitive disorder is Parkinson's disease.
  • Parkinson's disease is characterized by abnormality or damage to neurons in the substantia nigra of the brain.
  • the prevention, treatment or improvement of Parkinson's disease is achieved by reducing or alleviating neuronal abnormalities or damage in the substantia nigra of the brain.
  • the present invention relates to the use of a peptide described herein in the preparation of a composition for reducing or alleviating abnormality or damage to neurons in the substantia nigra of the brain of a subject.
  • the subject may be a neurodegenerative disease patient or a cognitive impairment patient, preferably a Parkinson's disease patient.
  • the subject or patient is a mammal.
  • the subject or patient is a human, such as a middle-aged or elderly person, preferably an elderly person.
  • Middle-aged people can be people between 40 and 59 years old or people between 45 and 59 years old.
  • An elderly person can be a person over 60, over 65, over 70, over 75 or over 80.
  • the subject may be a subject with cognitive function or cognitive ability decline, such as cognitive function or cognitive ability decline caused by or accompanying aging.
  • the decline generally refers to chronic decline.
  • compositions of the invention comprise peptides described herein.
  • the composition of the present invention may also contain pharmaceutical excipients, solvents or carriers; or pharmaceutical excipients, solvents or carriers acceptable to the human body.
  • the composition may be a pharmaceutical composition or a nutritional composition.
  • the pharmaceutical composition may be a drug.
  • the nutritional composition may be in the form of a nutritional supplement, nutritional supplement, dietary supplement, dietary supplement, nutraceutical, nutraceutical, nutraceutical or health food.
  • compositions as described herein may generally include substances or formulations that improve or enhance the health condition of a subject (eg, a human) or treat a disease in the subject.
  • Nutritional composition as described herein may refer to meeting at least part of the nutrient requirements of a subject (such as a human), regulating the body functions of the subject, regulating the physiological functions of the subject, and/or improving the health status of the subject Substances or formulations that may be taken.
  • the nutritional composition may be a nutraceutical, functional food, dietary supplement, nutraceutical or health food that activates, modulates or improves cognitive function or cognitive ability.
  • a "pharmaceutical composition” may refer to an ingestible substance or formulation for preventing, treating, alleviating, ameliorating, conditioning, or modulating a disease, disorder, symptom, or condition in a subject (eg, a human).
  • pharmaceutical compositions may be in the form of pharmaceuticals, including oral medications, such as tablets, pills, capsules, and the like.
  • compositions for oral administration may be formulated in dosages suitable for oral administration using carriers, vehicles or excipients known in the art.
  • Such carriers enable the compositions to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a subject.
  • the polypeptide or composition of the present invention can be prepared as an injection, such as intramuscular injection, intraperitoneal injection, intraperitoneal injection, subcutaneous injection or intravenous injection.
  • Injections may be in the form of solutions, emulsions, or suspensions, as well as powders or concentrated solutions for solution or suspension before use.
  • solvents such as water, isotonic agents, buffers, preservatives, co-solvents, solubilizers, suspending agents and emulsifiers.
  • the term "effective amount” or “therapeutically effective amount” refers to an amount of a peptide or composition of the invention that is effective in treating a disease or disorder or ameliorating or enhancing the health condition of a subject. Improving or improving one's health includes improving or improving cognitive functions or abilities.
  • the peptide of the present invention can be used at 0.01mg/kg to 10mg/kg, 0.02mg/kg to 8mg/kg, 0.04mg/kg to 5mg/kg, 0.05mg/kg to 1mg/kg, 0.1mg/kg to 0.8mg/kg. kg or 0.2 mg/kg to 0.5 mg/kg is administered to the subject.
  • the peptide of the invention can be administered to a subject in an amount of 0.04 mg/kg, 0.16 mg/kg or 0.64 mg/kg.
  • a therapeutically effective amount may be these doses.
  • the peptide or composition of the invention may be administered at once daily intervals for at least 1 week, for example 1 to 4 weeks.
  • compositions of the invention may comprise such combinations of peptides.
  • the peptide combination includes a first peptide having the amino acid sequence of SEQ ID NO: 1 or a variant thereof and a second peptide having the amino acid sequence of SEQ ID NO: 2 or a variant thereof.
  • FIG. 1 Effects of combined administration of PKT101, PKT002 and PKT101/PKT002 on short-term working memory, conditioned fear memory and social ability of APP/PS1 mice.
  • A Statistical chart showing the percentage of time mice in the control group (Con), PKT101, PKT002 and PKT101/PKT002 combined treatment groups entered the novel arm in the Y maze experiment.
  • B In the new object recognition experiment, the statistical chart of the new object recognition cognitive index of the four groups of mice.
  • C Statistical chart of freezing time of mice in four groups during the conditioned fear memory experiment.
  • FIG. 1 Effects of combined administration of PKT101, PKT002 and PKT101/PKT002 on A ⁇ plaque deposition in the hippocampus and cortex of APP/PS1 mice.
  • A Fluorescence images of thioflavin S staining of mice in the control group (Con), PKT101, PKT002 and PKT101/PKT002 combined treatment groups. Scale bar is 200 ⁇ m.
  • B Immunofluorescence experiment shows fluorescence images of 6E10 expression in the cortex and hippocampus of four groups of mice. Scale bar is 200 ⁇ m.
  • C Quantitative statistical diagram of Thioflavin S-positive A ⁇ plaques in the cortex and hippocampus of four groups of mice.
  • FIG. 3 Effects of combined administration of PKT101, PKT002 and PKT101/PKT002 on glial cell activation around hippocampal A ⁇ plaques in APP/PS1 mice.
  • A Immunofluorescence experiment shows fluorescence images of Iba1, GFAP and 6E10 expression in the hippocampus of mice in the control group (Con), PKT101, PKT002 and PKT101/PKT002 combined treatment groups. Scale bar is 50 ⁇ m.
  • (B) Statistical chart of the percentage of positive expression areas of Iba1 and GFAP in the hippocampus of four groups of mice. The results are expressed as mean ⁇ standard error, n 4-5 per group, and the statistical graph uses one-way analysis of variance. Positive area of Iba1+: the positive area of Iba1+; Positive area of GFAP+: the positive area of GFAP+.
  • FIG. 4 Effects of combined administration of PKT101, PKT002 and PKT101/PKT002 on glial cell activation around cortical A ⁇ plaques in APP/PS1 mice.
  • A Immunofluorescence experiment shows fluorescence images of Iba1, GFAP and 6E10 expression in the cortex of mice in the control group (Con), PKT101, PKT002 and PKT101/PKT002 combined treatment groups. Scale bar is 50 ⁇ m.
  • (B) Statistical chart of the percentage of positive expression areas of Iba1 and GFAP in the cortex of four groups of mice. The results are expressed as mean ⁇ standard error, n 5 per group, and the statistical graph uses one-way analysis of variance. Positive area of Iba1+: the positive area of Iba1+; Positive area of GFAP+: the positive area of GFAP+.
  • FIG. 5 Effects of combined administration of PKT101, PKT002 and PKT101/PKT002 on the contents of IL-1 ⁇ , IL-6 and TNF- ⁇ in the hippocampus and cortex of APP/PS1 mice.
  • A ELISA detects the expression of inflammatory factors IL-1 ⁇ , IL-6 and TNF- ⁇ in the hippocampus of mice in the control group (Con), PKT101, PKT002 and PKT101/PKT002 combined treatment groups.
  • (B) ELISA detects the expression of inflammatory factors IL-1 ⁇ , IL-6 and TNF- ⁇ in the cortex of four groups of mice. The results are expressed as mean ⁇ standard error, n 5 per group, and the statistical graph uses one-way analysis of variance.
  • Cortext cortex; Hippocampus: hippocampus; Relative expression of IL-1 ⁇ : relative expression of IL-1 ⁇ ;; Relative expression of IL-6: relative expression of IL-6;; Relative expression of TNF- ⁇ : TNF- ⁇ Relative expression.
  • FIG. 7 Effects of PKT101 and PKT002 on the total movement distance of mice in the mine field experiment after the MPTP subacute model (1, 3, 7 and 14 days). *** p ⁇ 0.001, ** p ⁇ 0.01vs.Sham; ### p ⁇ 0.001, ## p ⁇ 0.01, # p ⁇ 0.05vs.MPTP.
  • FIG. 8 Effects of PKT101 and PKT002 on T-Turn in the pole climbing experiment of mice after the MPTP subacute model (1, 3, 7 and 14 days). ***p ⁇ 0.001,**p ⁇ 0.01vs.Sham; ###p ⁇ 0.001,##p ⁇ 0.01,#p ⁇ 0.05vs.MPTP.
  • FIG. 9 Effects of PKT101 and PKT002 on T-TLA in the pole climbing experiment of mice after the MPTP subacute model (1, 3, 7 and 14 days). ***p ⁇ 0.001vs.Sham; ###p ⁇ 0.001,##p ⁇ 0.01,#p ⁇ 0.05vs.MPTP.
  • FIG. 10 Effects of PKT101 and PKT002 on the latency period (1, 3, 7 and 14 days) of mice in the rotarod experiment after the subacute model of MPTP. ***p ⁇ 0.001vs.Sham; ###p ⁇ 0.001vs.MPTP.
  • Figure 17 Effects of PKT001 and PKT002 pretreatment on LPS-induced apoptosis of HT22 cells.
  • FIG. 18 Effects of PKT001 and PKT002 pretreatment on LPS-induced apoptosis of SK-N-SH cells.
  • Example 1 Study on the neuroprotective effect of the peptide of the present invention on the Alzheimer's disease model animal APP/PS1 mice
  • PKT101 peptide DEAQETAVSSHEQD(SEQ ID NO:2)
  • PKT002 peptide DEAQETAVSSH (SEQ ID NO:1)
  • mice Sixty 5-month-old APP/PS1 male mice were randomly divided into 4 groups, 15 in each group. They were intraperitoneally injected with normal saline, PKT101 (8mg/kg), PKT002 (8mg/kg) and PKT101/PKT002 ( 8 mg/kg) for 4 weeks. The final volume of intraperitoneal injection in each group was 80 ⁇ L. After weekly administration, 20-35 mice were randomly taken out and measured for weight measurement. The average weight was used as an important basis for the next week's dosage.
  • mice were tested for short-term learning and memory (Y maze and new object recognition), conditioned fear memory and social behavior, and the plaque deposition in the cerebral cortex and hippocampus was detected through thioflavin staining and 6E10 immunofluorescence staining; through immunofluorescence staining Observe the activation of microglia and astrocytes in the cortex and hippocampus; detect the inflammatory factors interleukin-1 ⁇ (IL-1 ⁇ ), interleukin-6 (IL-6) and tumors using enzyme-linked immunosorbent assay (ELISA) Necrosis factor (TNF- ⁇ ) content.
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-6 interleukin-6
  • ELISA enzyme-linked immunosorbent assay
  • the Y maze device used in this experiment has an angle of 120 degrees between the three arms, which are connected to each other.
  • the three arms are the same size, 29cm long, wide and high 29cm x 8cm x 15cm.
  • Different patterns are affixed to the inside of the arms to represent mice.
  • As visual markers name the starting arm, novelty arm and other arms respectively.
  • the experimental process is divided into two parts, the adaptation phase and the testing phase, with an interval of 1-2 hours. Adaptation is to separate the novel arms with baffles. Mice can only move freely in the starting arm and other arms.
  • the adaptation time of each mouse is 5 minutes.
  • the test phase is to open the novel arms after 1-2 hours. The mice can move freely within the three arms, and the test time for each mouse is 5 minutes.
  • Topscan software was used to record the time and number of times the mice entered the novel arm in real time. After each experiment, the experimental equipment must be cleaned with 75% alcohol to remove the mouse odor.
  • mice Before testing this device, the mice must be eliminated from any sense of strangeness and the mice must be stroked every day to avoid irritation to the mice during operation.
  • the mice In the first stage (familiarization period), put two identical objects (AB, make sure the objects have no smell and are not pushed) into the device. The objects are 10cm away from both sides of the walls. Put the mouse into the device from the middle of the two objects.
  • the mouse is put into the device from the middle of the two objects, and the number, time and distance of the mouse's exploration of the old and new objects within 5 minutes are recorded, that is, the number, time and distance of the mouse's activities around the old and new objects, and the cognitive status of the mouse is detected.
  • the experimental equipment needs to be cleaned with 75% alcohol. If the mouse has poor cognitive ability, there will be no difference in the exploration of new and old objects; if the mouse has normal cognitive ability, the exploration time of new objects will be longer than that of old objects.
  • mice On the first day of this experiment, the mice were put into the box (the bottom of the box is a copper fence that can be powered). After adapting for 3 minutes, the mice were allowed to stay in the box for another 6 minutes. During this period, a single frequency sound was given at the same time every 2 minutes. Stimulation (1.0 KHZ, 70 db, 30 s) and inescapable foot shock (0.8 mA, 2 s) were performed three times in total. The total time of sound and electric shock-induced freezing behavior of the mice within 6 min was recorded, and then placed back in the cage. After each experiment, wipe the bottom of the box with 75% alcohol.
  • mice with established fear were placed in the original box, and the same intensity of sound stimulation (1.0KHZ, 70db, 30s) was immediately given, and the sound-induced freezing behavior of the mice was recorded within 3 minutes.
  • Catalepsy was defined as no movement other than breathing. Percentage of environmentally and sound-induced freezing time was recorded.
  • mice were placed in the behavioral testing room to adapt for 0.5 h, and the tested rectangular box was equally divided into three areas: Empty, Center and Stranger-1. Mice of the same sex, background, and age were placed into the metal cage in the Stranger-1 area, and the metal cage on the other side of the box was empty. Put the test mouse into the center box so that the test mouse can move freely in the three boxes for 5 minutes. Photograph and record relevant parameters: the duration of entering each box. When the mouse's head and four paws enter a box, it is considered to be in that box.
  • mice of the same sex and background and different ages were placed in an empty metal cage, and then recorded for 5 minutes to observe the time the test mice spent in the Stranger-1 and Stranger-2 areas.
  • the OCT resin-embedded brain tissue was sliced coronally using a Leica freezing microtome, with a thickness of 10 ⁇ m, and collected in PBS for immunofluorescence staining and A ⁇ histopathological analysis.
  • the sections were blocked with 10% fetal bovine serum PBS solution for 1 h at room temperature. Discard the blocking solution, add mouse-derived 6E10 antibody, chicken-derived glial fibrillary acidic protein antibody, and rabbit-derived calcium ion binding receptor molecule 1 (inized calcium binding adapter molecule 1, Iba1) antibody, and incubate overnight at 4°C. The next day, the primary antibody was washed away and washed 3 times with PBS for 5 minutes each time. Add secondary antibodies of corresponding species (goat anti-chicken IgG-488; donkey anti-rabbit IgG-488; donkey anti-mouse IgG-647) and incubate at room temperature in the dark for 1 hour. Discard the secondary antibody, wash 3 times with PBS, 5 minutes each time, stain with DAPI for 10 minutes at room temperature, discard DAPI, and wash 3 times with PBS. Anti-fluorescence quenching agent sealing, Take pictures under fluorescence microscope.
  • Thioflavin S can mark A ⁇ core plaques on brain slices. Dewaxed and hydrated tissue sections can be stained with 1% thioflavin for 5 minutes, washed with running water for 1 minute, separated with 70% alcohol for 30 seconds, and then quenched with anti-fluorescence. The slides were sealed with agent and photographed under a fluorescence microscope.
  • Immunofluorescence-stained tissue sections were photographed using a Leica microscope, and ImageJ software was used to use grayscale threshold analysis to count the percentage of positive areas for GFAP, Iba1, 6E10, and thioflavin. There were 5 mice in each group, and 3 sections were selected for each mouse. , take its average value as the statistical result of this group.
  • mice were anesthetized, they were killed by decapitation, the skin on the neck and head was peeled off, the skull was exposed, the skull was cut along the sagittal suture, and the brain tissue was removed after the skull was separated. Put the cortical tissue and hippocampal tissue into marked centrifuge tubes, quickly freeze them in liquid nitrogen, and transfer them to a -80°C refrigerator for storage.
  • IL-1 ⁇ interleukin-1 ⁇
  • IL-6 interleukin-6
  • TNF- ⁇ tumor necrosis factor- ⁇
  • 3 pro-inflammatory indicators add at least two wells to each sample, 45 ⁇ L of standard and sample in each well, then add 50 ⁇ L of biotinylated antibody working solution to the sample and standard wells, seal the reaction well plate with sealing paper, and place Incubate at room temperature for 2 hours (use micro shaker, frequency, 300 rpm). Prepare the enzyme-binding substrate 30 minutes in advance and store it at room temperature away from light.
  • Washing method absorb the reaction solution in the wells, add the washing solution to the well plate, and leave it for 2 minutes with slight shaking. Add 100 ⁇ L of enzyme-bound substrate working solution to each well except the blank well, and incubate at room temperature for 1 hour (use a micro shaker, frequency, 300 rpm). Discard the liquid in the wells and pat dry on absorbent paper. Wash 5 times. Add 100 ⁇ L of chromogenic substrate working solution to each well except the blank wells, and place at room temperature in the dark for 15 minutes. Add 100 ⁇ L of stop solution to each well except the blank well to stop the reaction, and measure the experimental results within 20 minutes.
  • the Y maze test was used to evaluate the short-term memory of mice in each group.
  • the results showed that compared with the control group APP/PS1 mice, the time for APP/PS1 mice in the PKT101 treatment group to enter the novel arm increased, while PKT002 and PKT101/PKT002
  • the time for APP/PS1 mice in the combination treatment group to enter the novel arm was significantly increased (Figure 1A).
  • the new object recognition experiment was used to evaluate the short-term memory of mice in each group.
  • the results showed that compared with the control group, the index of APP/PS1 mice in the above three treatment groups to recognize new objects increased significantly (Figure 1B).
  • Conditioned fear memory was used to evaluate the fear memory of mice in each group.
  • Thioflavin staining and 6E10 immunofluorescence staining were used to evaluate the fibrous and diffuse A ⁇ plaque deposition in the cortex and hippocampus of mice in each group.
  • the results of thioflavin staining showed that compared with the control group, PKT101, PKT002 and PKT101/PKT002 combined
  • the A ⁇ plaques in the hippocampus of APP/PS1 mice in the treatment group were significantly reduced, and there was no effect on the deposition of A ⁇ plaques in the cortex ( Figure 2A, C).
  • PKT101 and PKT002 treatment alone and PKT101/PKT002 combined treatment can improve short-term cognitive impairment, reduce hippocampal A ⁇ load deposition, glial cell activation and inflammatory factors in APP/PS1 mice to varying degrees.
  • PKT101 peptide DEAQETAVSSHEQD(SEQ ID NO:2)
  • PKT002 peptide DEAQETAVSSH (SEQ ID NO:1)
  • MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) was used to establish a subacute Parkinson's disease mouse model. After the mice were weighed and recorded, 20 mg/kg MPTP was injected subcutaneously into the back of the neck once a day for 5 consecutive days. Following-up experiments were conducted on days 1, 3, 7 and 14 after the last administration.
  • Selegiline Selegiline, Imidopyr
  • mice in the MPTP model group were given an equal volume of physiological saline (0.1mL/10g).
  • the mice in the Sham group were only given an equal volume of physiological saline (0.1mL/10g).
  • the open field test was used to evaluate the voluntary movement ability of mice.
  • the open field device is made of opaque blue plastic and measures 60cm ⁇ 60cm ⁇ 45cm. During the test, each mouse was placed into the box from the central area, and at the same time, the movement trajectory of each mouse within 5 minutes was recorded, and the total movement distance was calculated using software (Clever Sys Inc., VA, USA). After each mouse test, use 75% ethanol to wipe the open area to prevent the smell of the previous mouse from affecting the next mouse.
  • the pole climbing test was used to evaluate the motor coordination function of mice.
  • the pole used has a diameter of 1cm and a height of 50cm.
  • a wooden ball with a diameter of 1.2cm is fixed on the top of the pole.
  • the pole is wrapped with anti-slip tape to prevent mice from slipping. Place the mouse's head upward on the top of the pole.
  • start the timer Record the time it takes for the mouse to move over the top of the pole (T-Turn) and the time it takes for the mouse to climb to the bottom of the four paws.
  • Time to Landing T-TLA).
  • each mouse needs to be trained three times consecutively. During the test, three consecutive measurements are required, and the shortest time is chosen.
  • the rotarod test was used to evaluate the motor balance ability and limb coordination of mice. Place the mouse on the drum of the rotarod tester, and set the rotation speed to increase from 5rpm/min to 25rpm/min at a constant speed within 2 minutes. When the mouse falls from the drum to the sensing area below, an infrared sensor will receive the signal and record it. Time for mice to move on the instrument roller. Before formal testing, each mouse needs to be trained three times consecutively. During the test, three consecutive measurements are required to calculate the average drop time (latency period).
  • mice from each group were taken, anesthetized with 4% chloral hydrate, and perfused with physiological saline + 4% PFA to obtain brain tissue.
  • Nissl bodies are basophilic substances in the cytoplasm that are widely found in various neurons and are used to count the number of brain neurons. Stain according to Nissl staining kit.
  • TH mainly labels dopaminergic neurons in the substantia nigra pars compacta, and TH-positive neurons in this brain area will be significantly reduced after MPTP modeling.
  • DAB diaminobenzidin
  • Immunohistochemistry-positive cells were counted using a Stereo Investigator (MBF bioscience) counting system to count the number of Nissl body-positive cells and TH + cells in the substantia nigra pars compacta. Cell counting was performed under a ⁇ 20 objective lens.
  • mice showed a decrease in the total movement distance in the open field test at 1, 3, 7, and 14 days after modeling, indicating a decrease in autonomous activity ability.
  • the positive control drug Selegiline can significantly improve MPTP-induced decrease in total exercise distance on days 1, 3, 7 and 14.
  • PKT101 and PKT002 also had significant improvement within 14 days.
  • the low, medium and high doses of PKT101 alone increased to 221.1%, 253.9% and 255.3% of the model group; PKT002 alone increased to 213.0% of the model group; the combined administration of PKT101 and PKT002 increased to the model group 214.8%.
  • mice showed prolonged T-Turn and T-TLA times in the pole climbing test at 1, 3, 7 and 14 days after modeling, indicating movement coordination. Decline in ability.
  • the positive control drug Selegiline can significantly improve MPTP-induced T-Turn and T-TLA time extension on days 1, 3, 7 and 14.
  • PKT101 and PKT002 also had significant improvement within 14 days.
  • mice showed a shortening of the falling latency in the rotarod test at 1, 3, 7, and 14 days after modeling, indicating a decrease in motor balance ability.
  • the positive control drug Selegiline can significantly improve the shortening of MPTP-induced latency time on days 1, 3, 7 and 14. Both PKT101 and PKT00 had significant improvement within 14 days.
  • the incubation period of low, medium and high doses of PKT101 alone was prolonged to 121.7, 119.9% and 118.3% of the model group respectively; the latency of PKT002 alone was prolonged to 120.3% of the model group; the combined administration of PKT101 and PKT002 was prolonged to 121.7%, 119.9% and 118.3% of the model group. 120.9% of the model group.
  • mice showed a decrease in the number of Nissl stain-positive neurons in the substantia nigra pars compacta 7 and 14 days after modeling, indicating the death of neurons in this brain area.
  • the positive control drug Selegiline could significantly improve the MPTP-induced decrease in the number of Nissl stain-positive neurons in the substantia nigra pars compacta on both 7 and 14 days.
  • PKT101 and PKT002 also had significant improvement effects at 7 and 14 days.
  • the number of Nissl-positive cells treated with low, medium and high doses of PKT101 alone increased to 120.9%, 124.0% and 130.9% of the model group, respectively; 124.5%; the number of Nissl-positive cells after combined administration of PKT101 and PKT002 increased to 128.0% of the model group.
  • the number of Nissl-positive cells treated with low, medium and high doses of PKT101 alone increased to 124.9%, 130.9% and 141.1% of the model group, respectively; 128.5%; the number of Nissl-positive cells after combined administration of PKT101 and PKT002 increased to 141.5% of the model group.
  • mice showed a decrease in the number of TH-positive neurons in the substantia nigra pars compacta 7 and 14 days after modeling, indicating the death of dopaminergic neurons in this brain area.
  • the positive control drug Selegiline could significantly improve the MPTP-induced decrease in the number of TH-stained positive neurons in the substantia nigra pars compacta on both 7 and 14 days.
  • PKT101 and PKT002 also had significant improvement effects at 7 and 14 days.
  • the number of TH-positive cells after single administration of low, medium and high doses of PKT101 increased to 114.5%, 124.9% and 129.7% of the model group respectively; the number of TH-positive cells after single administration of PKT002 increased to 129.9% of the model group. ;
  • the number of TH-positive cells treated with PKT101 and PKT002 combined increased to 130.3% of that in the model group.
  • the number of TH-positive cells after single administration of PKT101 at low, medium and high doses increased to 125.6%, 136.0% and 137.5% of the model group respectively; the number of TH-positive cells after single administration of PKT002 increased to 128.1% of the model group. ;
  • the number of TH-positive cells after combined administration of PKT101 and PKT002 increased to 137.7% of that in the model group.
  • Example 3 Preliminary study on the protective effect of the peptide of the present invention on damage to glial cells and neurons in neurodegenerative disease models
  • GL261 mouse glioblastoma cells culture medium: DMEM+10% FBS+1% P/S;
  • WERI-RB-1 human retinal glioma cells culture medium RPMI-1640+10% FBS+1% P/S;
  • SK-N-SH human neuroblastoma cells culture medium: MEM (containing NEAA) + 10% FBS + 1% P/S;
  • HT22 mouse hippocampal neuron cells culture medium: DMEM+10% FBS+1% P/S;
  • N2A neuro-2a mouse brain neuroma cells, culture medium: MEM (containing NEAA) + 10% FBS + 1% P/S;
  • the cells used in the experiment were all in logarithmic growth phase.
  • Cell passage and plating Take the normally cultured cells, aspirate the original culture medium, add PBS to wash, add trypsin for digestion for 1-3 minutes, then terminate the digestion, pipette into single cells with a pipette, and centrifuge the cell suspension at 200g for 5 minutes. , resuspend with culture medium, add 20 ⁇ l of cell suspension to 20 ⁇ l of trypan blue for counting, plate at 3*10 5 cells/well (6-well plate), 3 duplicate wells, 5% CO 2 , and culture at 37°C overnight.
  • the drugs were first administered for 24 hours, followed by LPS induction treatment for 48 hours, and then related tests were conducted.

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Abstract

La présente invention concerne l'utilisation d'un peptide dans le traitement d'une maladie neurodégénérative ou l'amélioration d'une fonction cognitive. La présente invention concerne le traitement de maladies neurodégénératives et de troubles cognitifs, et l'amélioration des fonctions cognitives. En particulier, la présente invention concerne l'utilisation d'un peptide dans la prévention ou le traitement d'une maladie neurodégénérative ou d'un trouble cognitif, de préférence la maladie d'Alzheimer et la maladie de Parkinson. La présente invention concerne en outre l'utilisation d'un peptide dans l'amélioration d'une fonction cognitive chez un sujet.
PCT/CN2023/085334 2022-04-01 2023-03-31 Utilisation d'un peptide dans le traitement d'une maladie neurodégénérative ou l'amélioration de la fonction cognitive WO2023186062A1 (fr)

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WO2021009288A1 (fr) * 2019-07-16 2021-01-21 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Combinaison comprenant de l'alpha-1 antitrypsine pour une utilisation dans le traitement de l'ischémie chez un sujet

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JP2020063311A (ja) * 2020-01-31 2020-04-23 プライム・バイオ‐ドラッグ・ディヴェロップメント・リミテッドＰｒｉｍｅ Ｂｉｏ‐Ｄｒｕｇ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ 脳血管疾患用治療ペプチド

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WO2006028586A2 (fr) * 2004-07-22 2006-03-16 Duke University Biomarqueurs et cibles therapeutiques pour declin cognitif
WO2008031190A1 (fr) * 2006-09-15 2008-03-20 Osta Biotechnologies Inc. Alpha-1-antitrypsine comme indicateur de diagnostic/pronostic pour des maladies neuro-dégénératives
CN101934071A (zh) * 2009-06-30 2011-01-05 基立福有限公司 α-1-抗胰蛋白酶在制备用于治疗慢性疲劳综合症的药物中的用途
WO2012029061A2 (fr) * 2010-08-31 2012-03-08 Uri Wormser Polypeptides dérivés d' α-1 antitrypsine et leurs procédés d'utilisation
CN104321337A (zh) * 2012-05-25 2015-01-28 永林有限公司 肽及其用途
CN107847550A (zh) * 2015-04-16 2018-03-27 首创生物药品发展有限公司 用于脑血管疾病的治疗肽
CN107849091A (zh) * 2015-04-16 2018-03-27 医诺生药开发有限公司 能够在人脂肪衍生的干细胞和肝细胞中抑制丙肝病毒复制的肽及其衍生物
WO2021009288A1 (fr) * 2019-07-16 2021-01-21 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Combinaison comprenant de l'alpha-1 antitrypsine pour une utilisation dans le traitement de l'ischémie chez un sujet

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