WO2023246847A1 - Peptide bloquant b2m-glun1, composition pharmaceutique et son utilisation - Google Patents

Peptide bloquant b2m-glun1, composition pharmaceutique et son utilisation Download PDF

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WO2023246847A1
WO2023246847A1 PCT/CN2023/101626 CN2023101626W WO2023246847A1 WO 2023246847 A1 WO2023246847 A1 WO 2023246847A1 CN 2023101626 W CN2023101626 W CN 2023101626W WO 2023246847 A1 WO2023246847 A1 WO 2023246847A1
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glun1
human brain
disease
alzheimer
down syndrome
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PCT/CN2023/101626
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English (en)
Chinese (zh)
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王鑫
高月
黄莉红
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厦门大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70571—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • 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
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or 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

Definitions

  • the invention belongs to the field of biomedicine and relates to B2M-GluN1 blocking peptide, its pharmaceutical composition and uses.
  • Down syndrome also known as Trisomy 21, is one of the most common intellectual disabilities. About 1 in 800 newborns worldwide suffer from this disease. Patients with Down syndrome have one or part of chromosome 21. The increase in gene copy number on chromosome 21 leads to abnormal gene expression and ultimately causes symptoms of a variety of diseases, including developmental delay, intellectual disability, language delay, immune and endocrine systems. Abnormalities and defects in the bones, heart, and digestive system, among others. Intellectual retardation is the most prominent and serious symptom of Down syndrome. The vast majority of children have varying degrees of intellectual development disabilities. Most of the children have IQs of about 25 to 50 (normal people are above 90). It becomes more and more obvious with age, and language problems , memory, abstract thinking, etc. will be damaged.
  • Alzheimer's disease is one of the most common neurodegenerative diseases in humans. According to the World Alzheimer's Disease 2018 Report, 50 million people worldwide were suffering from Alzheimer's disease in 2018. By 2050, this number will will increase to 152 million.
  • the main pathological characteristics of the disease include amyloid deposition formed by the oligomerization of ⁇ -amyloid (A ⁇ ) produced by the cleavage of amyloid precursor protein (APP) in the brain, and abnormal phosphorylation of the intracellular microtubule-binding protein tau.
  • a ⁇ ⁇ -amyloid
  • APP amyloid precursor protein
  • NFTs Neurofibrillary tangles
  • Alzheimer's disease patients memory decline and cognitive impairment, and this decline worsens as the disease progresses, eventually leading to the loss of all memory and ability to take care of themselves until death.
  • cognitive impairment the main clinical manifestations of Alzheimer's disease patients.
  • this decline worsens as the disease progresses, eventually leading to the loss of all memory and ability to take care of themselves until death.
  • GluN1 is a component subunit of the NMDA receptor. It is encoded by the human chromosome 9 gene. It contains 938 amino acids and is a three-transmembrane protein, including the N-terminal extracellular segment, C-terminal intracellular segment, transmembrane structure and cell structure. Extracellular loop.
  • NMDA receptors are considered to be a potential pathogenic feature of a variety of neurological diseases, such as ischemic stroke, traumatic brain injury, Alzheimer's disease, epilepsy, mood disorders, and schizophrenia.
  • NMDA receptors are diverse in terms of subunit composition, biophysical and pharmacological properties, interactions and subcellular localization. developing Subunit composition varies in different CNS regions during processes and disease states.
  • NMDA receptors have always been a research hotspot and drug target in the field of neuropharmacology.
  • interest in NMDA receptor modulators as therapeutic agents has also increased significantly. Therefore, these compounds will provide new tools to study the physiology of NMDA receptor signaling, thereby revealing new therapeutic opportunities.
  • Memantine a drug currently approved by the FDA for the treatment of Alzheimer's disease, is a reversible blocker of NMDA glutamate receptors, but its mechanism and mode of action are completely different from those of the present invention.
  • B2M ⁇ 2-microglobulin
  • MHC-I Major histocompatibility complex I
  • B2M protein exists in the form of soluble monomers, but under the influence of some pathological factors, B2M will aggregate and deposit. These pathological factors include aging, long-term renal dysfunction, and inflammation.
  • B2M amyloid deposition is mainly found in bone and joint areas and eventually leads to severe arthritis, fractures and carpal tunnel syndrome.
  • the levels of B2M in serum and plasma are increased in many disease states.
  • B2M has a direct or indirect impact on the development of Down syndrome and Alzheimer's disease.
  • the inventor discovered the role of B2M in the occurrence and development of Down syndrome.
  • the inventor surprisingly found that the blocking peptide that hinders the binding of B2M and GluN1 has the potential to prevent and treat Down syndrome or The potential of drugs to treat cognitive impairment caused by Alzheimer's disease.
  • the following invention is thereby provided:
  • One aspect of the present invention relates to an isolated polypeptide, which is the polypeptide shown in SEQ ID NO: 8 or a truncated fragment of the polypeptide shown in SEQ ID NO: 8; preferably, the truncated fragment comprises SEQ ID NO: The polypeptide shown in 11.
  • the isolated polypeptide is a polypeptide represented by any one of SEQ ID NO: 11 or SEQ ID NOs: 14-32.
  • Another aspect of the invention relates to an isolated polynucleotide encoding an isolated polypeptide according to any one of the invention.
  • Yet another aspect of the invention relates to a recombinant expression vector comprising an isolated polynucleotide of the invention.
  • Yet another aspect of the invention relates to a transformed cell comprising the recombinant expression vector of the invention.
  • Yet another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more (eg 2, 3, 4 or 5) isolated polypeptides according to any one of the invention.
  • the pharmaceutical composition further contains one or more pharmaceutically acceptable excipients.
  • Another aspect of the present invention relates to the use of the isolated polypeptide according to any one of the present invention for the treatment or prevention of Down syndrome, Alzheimer's disease, or the diagnosis caused by Down syndrome or Alzheimer's disease. Use in medicines that prevent damage.
  • Another aspect of the present invention relates to the use of the isolated polypeptide according to any one of the present invention in the preparation of the following medicines: use:
  • Drugs that reduce B2M levels in the human brain drugs that reduce amyloid precursor protein levels in the human brain, drugs that inhibit the binding of GluN1 to B2M in the human brain, or drugs that repair synaptic damage caused by increased B2M in the human brain.
  • the isolated polypeptide according to any one of the present invention is used to treat or prevent Down syndrome, Alzheimer's disease, or cognitive impairment caused by Down syndrome or Alzheimer's disease.
  • the isolated polypeptide according to any one of the present invention is used to reduce the level of B2M in the human brain, reduce the level of amyloid precursor protein in the human brain, inhibit the binding of GluN1 to B2M in the human brain, or repair B2M in the human brain. Increased synaptic damage caused.
  • Yet another aspect of the present invention relates to a method for treating or preventing Down syndrome, Alzheimer's disease, or cognitive impairment caused by Down syndrome or Alzheimer's disease, comprising administering to a subject in need or with an effective amount of an isolated polypeptide of any one of the invention.
  • Yet another aspect of the present invention relates to a method for reducing B2M levels in the human brain, reducing amyloid precursor protein levels in the human brain, inhibiting the binding of GluN1 to B2M in the human brain, or repairing synaptic damage caused by increased B2M in the human brain. , comprising the step of administering an effective amount of an isolated polypeptide of any one of the invention to a subject in need thereof.
  • the method of treating or preventing Down syndrome, Alzheimer's disease, or cognitive impairment caused by Down syndrome or Alzheimer's disease or the method Methods for inhibiting the binding of GluN1 to B2M in the human brain or repairing synaptic damage caused by increased B2M in the human brain, wherein,
  • the single dosage of the isolated polypeptide according to any one of the present invention is 0.1-100 mg per kilogram of body weight, preferably 5-50 mg or 5-15 mg per kilogram of body weight;
  • it is administered every 3 days, every 4 days, every 5 days, every 6 days, every 10 days, every 1 week, every 2 weeks or every 3 weeks;
  • the administration method is intravenous drip or intravenous injection.
  • the present invention discovered for the first time that the expression of B2M in the brain tissue of patients with Down syndrome is significantly increased. Increased B2M will damage synaptic plasticity and cognitive function. Furthermore, the inventors found that there is a direct interaction between B2M and the extracellular segment of GluN1. Using a truncated GluN1 amino acid sequence as a blocking peptide can hinder the binding of B2M to GluN1 and inhibit the function of B2M from damaging NMDA receptors. In vivo experiments show that blocking The peptide can significantly inhibit the binding of B2M and GluN1 in the brain and enhance synaptic plasticity. This discovery provides a potential clinical treatment for Down syndrome Drug targets and new treatments based on these targets.
  • amino acid sequence of GluN1 is shown in SEQ ID NO: 1.
  • amino acid sequence (N-terminus to C-terminus) of rat GluN1 protein is as follows:
  • amino acid sequence (N-terminus to C-terminus) of human GluN1 protein is as follows:
  • the terms “isolated” or “isolated” refer to those obtained by artificial means from the natural state. If an "isolated" substance or ingredient occurs in nature, it may be that the natural environment in which it is located has changed, or that the substance has been separated from its natural environment, or both. For example, a certain unisolated polynucleotide or polypeptide naturally exists in a living animal, and the high purity of the same polynucleotide or polypeptide isolated from this natural state is called isolation. of.
  • isolation a certain unisolated polynucleotide or polypeptide naturally exists in a living animal, and the high purity of the same polynucleotide or polypeptide isolated from this natural state is called isolation. of.
  • the term “isolated” or “isolated” does not exclude the admixture of artificial or synthetic substances, nor does it exclude the presence of other impure substances that do not affect the activity of the substance.
  • an effective amount refers to an amount sufficient to obtain, at least in part, the desired effect.
  • an effective amount to prevent a disease is an amount sufficient to prevent, prevent, or delay the occurrence of a disease (such as Down syndrome or Alzheimer's disease); treat a disease
  • An effective amount is an amount sufficient to cure or at least partially prevent disease and its complications in a patient already suffering from the disease. Determining such effective amounts is well within the capabilities of those skilled in the art.
  • the amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall status of the patient's own immune system, the patient's general condition such as age, weight and gender, the manner in which the drug is administered, and other treatments administered concurrently etc.
  • blocking peptide refers to a protein that competitively binds to B2M with the full-length GluN1 protein, thereby inhibiting B2M binding.
  • the biological effects of GluN1 on synaptic plasticity impairment are not limited to GluN1 and fragments thereof.
  • Figure 3B Immunoprecipitation of B2M and N-terminally deleted GluN1 using anti-HA antibodies.
  • Figure 3D Immunoprecipitation of B2M and GluN1 extracellular cyclic peptides using anti-HA antibodies.
  • Figure 4D The above three short peptides without overlapping sequences were pre-incubated with Ni-NTA Agarose in PBS solution for 8 hours at 4°C, and then hB2M protein was added and incubated at 4°C overnight. Western blot detection and analysis were performed the next day.
  • Figure 5B NMDAR EPSC amplitude statistical graph.
  • the hippocampus of 3-month-old C57BL/6 mice was stereotaxically injected with 1 ⁇ l (1 ⁇ g/ ⁇ l) GluN1-P2 truncated peptide or Non-sense peptide (the left and right brains of each mouse were controlled).
  • the mice were brain-dissected.
  • the brain slices were incubated with B2M protein (concentration 10 ⁇ g/ml) and ACSF for two hours respectively, and electrophysiological recording was performed after incubation.
  • amyloid precursor protein encoded by chromosome 21 in the brain tissue of Down syndrome patients and Dp16 mice was significantly higher than that of the respective control groups.
  • Rat GluN1 N-terminal extracellular segment deletion (100% homology to human GluN1 N-terminal extracellular segment deletion)
  • Rat GluN1 extracellular cyclic peptide (100% homology with human GluN1 extracellular cyclic peptide)
  • PEI cell transfection
  • GluN1 is a three-transmembrane protein, including an N-terminal extracellular segment, a C-terminal intracellular segment, a transmembrane structure and an extracellular loop.
  • B2M Interacts with both N-terminal deletion (GluN1-N terminal deletion-myc) ( Figure 3B) and C-terminal deletion GluN1 (GluN1-C terminal deletion-myc) ( Figure 3C).
  • GluN1 with N-terminal deletion and C-terminus deletion contain a common extracellular cyclic peptide region.
  • a co-immunoprecipitation experiment was performed on the GluN1 extracellular cyclic peptide fragment and B2M. The results showed that the GluN1 extracellular cyclic peptide fragment can interact with B2M ( Figure 3D).
  • GluN1 truncated peptide can be used as a blocking peptide to prevent GluN1 from binding to B2M and prevent B2M. GluN1 acts to produce inhibition
  • Rat GluN1-S2loop-L1 (100% homology to human GluN1-S2loop-L1)
  • Rat GluN1-S2loop-L2 (100% homology to human GluN1-S2loop-L2)
  • Rat GluN1-S2loop-L3 (100% homology to human GluN1-S2loop-L3)
  • the GluN1-P2 short peptide can be used as a blocking peptide to prevent GluN1 from binding to B2M, making B2M unable to inhibit NMDA receptor function.
  • Example 5 GluN1-P2 blocking peptide blocks the binding of B2M to GluN1, thereby reducing synaptic damage
  • GluN1 is an essential subunit of NMDA receptors. Impairment of its function will severely damage synaptic plasticity. GluN1-P2 blocking peptide can prevent B2M from binding to GluN1. Therefore, it is necessary to study whether GluN1-P2 blocking peptide can prevent B2M from damaging NMDA. Receptor function in turn impairs excitatory synaptic function.
  • the hippocampus of 6-month-old Dp16 mice and control WT mice were stereotaxically injected with 1 ⁇ l (1 ⁇ g/ ⁇ l) GluN1-P2 short peptide or Non-sense peptide (the left CA1 area of each mouse was injected with the GluN1-P2 short peptide, and the right Non-sense peptide) was injected into the lateral CA1 area, and electrophysiological recording was performed one day after injection. Record the NMDAR EPSCs of the Schaeffer collateral circuit in the hippocampus.
  • the stimulating electrode is placed near the CA3 area to record the pyramidal cell current in the CA1 area. 5mM QX-314 is added to the electrode internal solution, and 50 ⁇ M PTX and 20 ⁇ M CNQX are added to the perfusion solution to block respectively.
  • GABA A receptor and AMPA receptor ion channels, clamping voltage is +40mV.
  • the hippocampus of 3-month-old C57BL/6 mice was stereotaxically injected with 1 ⁇ l (1 ⁇ g/ ⁇ l) GluN1-P2 truncated peptide or Non-sense peptide (the left and right brains of each mouse were controlled).
  • the mice were brain-dissected.
  • the brain slices were incubated with B2M protein (concentration 10 ⁇ g/ml) and ACSF for two hours respectively, and electrophysiological recording was performed after incubation. Record the NMDAR EPSC amplitude of the Schaeffer collateral loop in the hippocampus.
  • the stimulating electrode is placed near the CA3 area to record the pyramidal cell current in the CA1 area.
  • 5mM QX-314 is added to the electrode internal solution, and 50 ⁇ M PTX and 20 ⁇ M CNQX are added to the perfusate to block the current.
  • the brain tissue was quickly removed and placed in ice-cold and oxygen-saturated artificial cerebrospinal fluid (ACSF), and then transferred to a vibrating microtome for coronal sectioning.
  • the thickness of the brain slices was 400 ⁇ m.
  • the brain slices were incubated in oxygen-saturated ACSF at 32°C for 1 hour, and then transferred to room temperature for 1 hour.
  • the recording electrode was placed in the stratum radiatum of the CA1 area of the Schaffer collateral pathway, and the stimulating electrode was placed in the CA3 area.
  • the stimulation intensity was 30% of the maximum amplitude of the excitatory postsynaptic potential (fEPSP).
  • HFS high-frequency stimulation

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Abstract

L'invention concerne un médicament pour réduire le niveau de B2M dans le cerveau humain, un médicament pour réduire le niveau d'une protéine précurseur amyloïde dans le cerveau humain, un médicament pour inhiber la liaison de GluN1 et de B2M dans le cerveau humain, ou un médicament pour réparer les dommages synaptiques causés par l'augmentation de B2M dans le cerveau humain.
PCT/CN2023/101626 2022-06-24 2023-06-21 Peptide bloquant b2m-glun1, composition pharmaceutique et son utilisation WO2023246847A1 (fr)

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CN202210722699.7 2022-06-24
CN202210722699.7A CN117327168A (zh) 2022-06-24 2022-06-24 B2M-GluN1封闭肽、其药物组合物及用途

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