WO2020103889A1 - 抑郁症治疗方法和药物 - Google Patents

抑郁症治疗方法和药物

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Publication number
WO2020103889A1
WO2020103889A1 PCT/CN2019/119855 CN2019119855W WO2020103889A1 WO 2020103889 A1 WO2020103889 A1 WO 2020103889A1 CN 2019119855 W CN2019119855 W CN 2019119855W WO 2020103889 A1 WO2020103889 A1 WO 2020103889A1
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Prior art keywords
depression
polypeptide
glur2
subject
amino acid
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PCT/CN2019/119855
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English (en)
French (fr)
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王玉田
李扬
郭飞
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青岛普美圣医药科技有限公司
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Priority to US17/436,900 priority Critical patent/US20220347266A1/en
Priority to CN201980076664.7A priority patent/CN113166721A/zh
Publication of WO2020103889A1 publication Critical patent/WO2020103889A1/zh

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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
    • A61K38/16—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
    • A61K38/177—Receptors; Cell surface antigens; Cell surface determinants
    • A61K38/1787—Receptors; Cell surface antigens; Cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
    • 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
    • A61P25/24—Antidepressants
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • 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
    • 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
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

Definitions

  • the invention relates to the field of biomedicine. Specifically, the present invention discloses new depression treatment methods and medicines. More specifically, the present invention relates to the new use of GluR2-CT polypeptides in the treatment of depression, especially major depression.
  • Depression is a global and clinically common mental health disease, especially prone to stroke, neurasthenia, organ transplantation, diabetes, Parkinson's disease, neurosis, postpartum and elderly population. If the patient's condition is severe and recurrent, there will be suicidal tendency, which will affect their daily life. According to statistics from the World Health Organization, depression has become the fourth largest disease in the world. By 2020, depression may become the second largest non-self-conscious disease after ischemic heart disease. Depression is very common in clinical treatment. The disease is mainly caused by patients with severe social and emotional disorders.
  • Depression can be divided into mild / moderate depression and severe depression.
  • the clinical manifestations of mild / moderate depression include: depressed mood or several other symptoms (like changes in appetite, changes in sleep structure, depression, pessimism, inferiority, etc.) lasting more than two years; these symptoms have not reached The degree of major depression; for two months or longer, the patient was not in a normal state for one day.
  • Clinical manifestations of major depression include: weight gain or loss (without dieting); change in appetite; too much or too little sleep; restlessness; listlessness; feeling of no value, shame, and guilt; unable to concentrate, unable Make a decision; emerge the thought of wanting to die or commit suicide. If a person develops this symptom almost every day for most of the day or for two weeks or more, then it is very likely to suffer from major depression.
  • FIG. 1 Shows the evaluation results of the forced swimming experiment.
  • the left picture shows the forced swimming experiment after 1 hour of administration, and the right picture shows the forced swimming experiment after 24 hours of administration.
  • the C-terminal polypeptide of the GluR2 subunit of the AMPAR receptor has previously been shown to be associated with anxiety disorders (see EP1,687,427B1).
  • Peptides can block stress anxiety caused by emotions, and thus are used to treat anxiety disorders.
  • anxiety disorders are significantly different from depression.
  • Anxiety is an expected reaction caused by an inevitable, inevitable, and upcoming stressful event. It is mainly manifested by mental symptoms such as fear, worry, and tension, and is accompanied by palpitations, sweating, and cold hands and feet.
  • the core symptom is worry.
  • Depression is a mental illness with low mood, slow thinking, and slow behavior as the main symptoms. It can also be accompanied by physical symptoms such as reduced sleep and weight loss. Uncontrollable stress is an important reason for its occurrence, which is It is said that depressive behavior is caused by uncontrollable negative events.
  • those skilled in the art did not know whether the GluR2-CT polypeptide could be used to treat depression.
  • GluR2-CT polypeptide is a promising drug candidate for the treatment of depression.
  • the GluR2-CT polypeptide of the present invention can rapidly and significantly reduce the immobility time of forced swimming mice, and can maintain a relatively stable within 24 hours. Good antidepressant effect.
  • GluR2-C-terminal polypeptide or "GluR2-CT polypeptide” means a polypeptide derived from the C-terminus of a GluR2 polypeptide, which can inhibit NMDA-mediated excessive endocytosis of AMPAR or regulate neuronal apoptosis.
  • the GluR2-CT polypeptide may be the same as the C-terminus of the receptor GluR2 polypeptide, or it may contain one or more amino acid substitutions but retain its biological function.
  • the GluR2-CT polypeptide comprises the amino acid sequence YKEGYNVYG.
  • GluR2-CT polypeptides can also contain other polypeptide sequences in the form of fusion proteins, such as carrier polypeptide sequences that facilitate the penetration of cell membranes.
  • the carrier polypeptide may be, for example, a Tat polypeptide, which includes the amino acid sequence YGRKKRRQRRR.
  • the polypeptide is an isolated polypeptide.
  • the polypeptide is a synthetic polypeptide.
  • the polypeptide is a recombinantly produced polypeptide.
  • the present invention provides a method of treating depression in a subject, the method comprising administering to the subject a therapeutically effective amount of GluR2-CT polypeptide.
  • the GluR2-CT polypeptide comprises the amino acid sequence YKEGYNVYG.
  • the GluR2-CT polypeptide is fused with a carrier polypeptide sequence at the N-terminus.
  • the GluR2-CT polypeptide is fused at the N-terminus with the amino acid sequence YGRKKRRQRRR of the Tat carrier polypeptide.
  • the GluR2-CT polypeptide comprises the amino acid sequence YGRKKRRQRRRYKEGYNVYG.
  • subject means mammals, especially primates, especially humans.
  • GluR2-CT polypeptides have a rapid onset of effect in animal models of depression, so they are particularly suitable for the treatment of major depression relative to traditional antidepressant drugs. Therefore, in some embodiments of the method of the present invention, the depression is major depression.
  • the "depression” described in the present invention can be diagnosed and graded clinically through the Depression Symptom Rating Scale. Suitable scales include but are not limited to Hamilton Depression Scale (HAMD), Beck Depression Inventory (BDI) and Self-rating Depression (SDS).
  • HAMD Hamilton Depression Scale
  • BDI Beck Depression Inventory
  • SDS Self-rating Depression
  • a total score of ⁇ 8 points is normal, a total score of 8 to 20 points may have depression, and a total score of 20 to 35 points is diagnosed with depression, a total score of> 35 points Is suffering from major depression.
  • the GluR2-CT polypeptide of the present invention is particularly suitable for patients with severe depression with a total score of> 35 in the HAMD scale.
  • a total score of 10-15 points indicates that you may have depression; a total score greater than 15 points indicates that you already have depression; when it exceeds 25 points, it indicates severe depression.
  • the GluR2-CT polypeptide of the present invention is particularly suitable for patients with severe depression with a total score of> 25 points in the BDI questionnaire.
  • the cut-off value of the SDS standard score is 53 points, of which 53-62 points are mild depression, 63-72 points are moderate depression, and 73 points or more are severe depression.
  • the GluR2-CT polypeptide of the present invention is particularly suitable for patients with severe depression with a standard score of> 73 in the SDS scale.
  • the suicidal tendency is, for example, that the subject has prepared for suicidal behavior, or that the subject has committed suicidal behavior but has been prevented.
  • traditional antidepressant drugs usually take several weeks to take effect, so they cannot effectively prevent suicide.
  • the GluR2-CT polypeptide of the present invention can quickly take effect (for example, within 1 hour), and has a long action time (for example, a single dose lasts at least about 24 hours), which can timely reduce the suicidal tendency of patients with major depression and prevent The occurrence of suicide.
  • the depression is severe depression with a suicidal tendency.
  • the subject when the subject exhibits a suicidal tendency, the subject is administered a therapeutically effective amount of GluR2-CT polypeptide.
  • the invention provides a method of reducing suicide risk in a subject suffering from depression, the method comprising administering to the subject a therapeutically effective amount of GluR2-CT polypeptide.
  • the GluR2-CT polypeptide comprises the amino acid sequence YKEGYNVYG.
  • the GluR2-CT polypeptide is fused with a carrier polypeptide sequence at the N-terminus.
  • the GluR2-CT polypeptide is fused at the N-terminus with the amino acid sequence YGRKKRRQRRR of the Tat carrier polypeptide.
  • the GluR2-CT polypeptide comprises the amino acid sequence YGRKKRRQRRRYKEGYNVYG.
  • the depression is major depression.
  • the depression is severe depression with a suicidal tendency.
  • the subject when the subject exhibits a suicidal tendency, the subject is administered a therapeutically effective amount of GluR2-CT polypeptide.
  • the present invention provides the use of GluR2-CT polypeptide in the preparation of a medicament for treating depression in a subject.
  • the GluR2-CT polypeptide comprises the amino acid sequence YKEGYNVYG.
  • the GluR2-CT polypeptide is fused with a carrier polypeptide sequence at the N-terminus.
  • the GluR2-CT polypeptide is fused at the N-terminus with the amino acid sequence YGRKKRRQRRR of the Tat carrier polypeptide.
  • the GluR2-CT polypeptide comprises the amino acid sequence YGRKKRRQRRRYKEGYNVYG.
  • the depression is major depression.
  • the depression is severe depression with a suicidal tendency.
  • the medicament is for administration to the subject when the subject shows suicidal tendency.
  • the present invention provides the use of GluR2-CT polypeptides in the preparation of a medicament for reducing suicide risk in subjects suffering from depression.
  • the GluR2-CT polypeptide comprises the amino acid sequence YKEGYNVYG.
  • the GluR2-CT polypeptide is fused with a carrier polypeptide sequence at the N-terminus.
  • the GluR2-CT polypeptide is fused at the N-terminus with the amino acid sequence YGRKKRRQRRR of the Tat carrier polypeptide.
  • the GluR2-CT polypeptide comprises the amino acid sequence YGRKKRRQRRRYKEGYNVYG.
  • the depression is major depression.
  • the depression is severe depression with a suicidal tendency.
  • the medicament is for administration to the subject when the subject shows suicidal tendency.
  • the present invention provides a pharmaceutical composition comprising a GluR2-CT polypeptide and a pharmaceutically acceptable carrier, which is used to treat depression in a subject.
  • the GluR2-CT polypeptide comprises the amino acid sequence YKEGYNVYG.
  • the GluR2-CT polypeptide is fused with a carrier polypeptide sequence at the N-terminus.
  • the GluR2-CT polypeptide is fused at the N-terminus with the amino acid sequence YGRKKRRQRRR of the Tat carrier polypeptide.
  • the GluR2-CT polypeptide comprises the amino acid sequence YGRKKRRQRRRYKEGYNVYG.
  • the depression is major depression.
  • the depression is severe depression with a suicidal tendency.
  • the pharmaceutical composition is for administration to the subject when the subject exhibits a suicidal tendency.
  • the invention provides a pharmaceutical composition comprising a GluR2-CT polypeptide and a pharmaceutically acceptable carrier, which is used to reduce the risk of suicide in a subject suffering from depression.
  • the GluR2-CT polypeptide comprises the amino acid sequence YKEGYNVYG.
  • the GluR2-CT polypeptide is fused with a carrier polypeptide sequence at the N-terminus.
  • the GluR2-CT polypeptide is fused at the N-terminus with the amino acid sequence YGRKKRRQRRR of the Tat carrier polypeptide.
  • the GluR2-CT polypeptide comprises the amino acid sequence YGRKKRRQRRRYKEGYNVYG.
  • the depression is major depression.
  • the depression is severe depression with a suicidal tendency.
  • the medicament is for administration to the subject when the subject shows suicidal tendency.
  • the "therapeutically effective amount" of the GluR2-CT polypeptide preferably leads to a reduction in the severity of disease symptoms, an increase in the frequency and duration of the asymptomatic period of the disease, or to prevent injury or disability due to the suffering of the disease.
  • administration of a therapeutically effective amount of GluR2-CT polypeptide can result in a reduction in the subject's depression scale.
  • administration of a therapeutically effective amount of GluR2-CT polypeptide may result in a total score reduction of about 5 points, about 10 points, about 15, 20 points, or more in the HAMD scale, or a total score reduction of about 5 points in the BDI questionnaire, Approximately 10 points, approximately 15 points, approximately 20 points or more, or results in a reduction of the standard score of the SDS scale by approximately 5 points, approximately 10 points, approximately 15 points, approximately 20 points or more.
  • administration of a therapeutically effective amount of GluR2-CT polypeptide causes the subject to relieve from major depression to mild depression or no symptoms of depression.
  • administration of a therapeutically effective amount of GluR2-CT polypeptide results in a reduced suicide risk in the subject.
  • Those skilled in the art can determine the therapeutically effective amount based on factors such as the size of the subject, the severity of the subject's symptoms (such as the level of the score), and the specific composition or route of administration selected.
  • the GluR2-CT polypeptide or pharmaceutical composition of the present invention can be administered by one or more routes of administration using one or more methods known in the art. Those skilled in the art will understand that the route and / or mode of administration will vary depending on the desired result. Preferred routes of administration of the GluR2-CT polypeptides of the present invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, such as injection or infusion. Preferably, the GluR2-CT polypeptide of the present invention is administered by injection.
  • the dosage range may be about 0.0001 to 100 mg / kg, more usually 0.01 to 20 mg / kg recipient body weight.
  • the dosage may be 1 mg / kg body weight, 3 mg / kg body weight, 5 mg / kg body weight, 10 mg / kg body weight or 20 mg / kg body weight, or in the range of 1-20 mg / kg body weight.
  • an exemplary treatment regimen can be administered once a day, once every two days, once every three days, once every four days, once every five days, once every six days, weekly Once, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months, once every 3-6 months, or the initial dosing interval is slightly shorter (such as once a day to every three weeks Once) The interval of late dosing is extended (eg, once a month to once every 3-6 months).
  • the specific administration regimen can be determined by the physician based on the patient's specific symptoms.
  • the GluR2-CT polypeptide of the present invention since the GluR2-CT polypeptide of the present invention has a rapid onset of action, it can be administered when a patient has a major depression, such as a suicidal tendency, thereby quickly reducing the patient's risk of suicide. At the same time, the GluR2-CT polypeptide of the present invention has a long duration of drug effect, so the number of administrations can be significantly reduced.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral administration (eg by injection or infusion).
  • the active compound, GluR2-CT polypeptide can be encapsulated in a material to protect the compound from acids and other natural conditions that can inactivate the compound.
  • Compound PMS-001 (also known as Tat-GluR2-3Y) is a polypeptide compound that contains the amino acid sequence Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Arg-Tyr-Lys-Glu-Gly -Tyr- Asn-Val-Tyr-Gly (YGRKKRRQRRRYKEGYNVYG).
  • the amino acid sequence YGRKKRRQRRR also known as Tat peptide, is a carrier peptide that can assist the polypeptide to cross the blood-brain barrier.
  • the amino acid sequence YKEGYNVYG (also known as GluR2-3Y) is derived from the C-terminal sequence of GluR2, which has been shown to inhibit NMDA-mediated excessive endocytosis of AMPAR, thereby regulating the neural response (see EP1,687,427B1).
  • the C-terminal polypeptide of GluR2 such as YKEGYNVYG, can be used to treat depression, especially major depression.
  • the experimental animals were 6-week-old C57 mice, male. C57 mice were purchased from Shanghai Slake Experimental Animal Co., Ltd. and weighed 20.45 ⁇ 0.19g. Before the experiment, arrive at the Animal Feeding Center of Shanghai Institute of Materia Medica, Chinese Academy of Sciences (animal production license: SCXK9 [Shanghai] 2004-0002, use license: SYXK [Shanghai] 2003-0029), and adapt to animal facilities for more than 3 days, 6 Only / cage feeding.
  • the feeding environment is room temperature 23 ⁇ 0.2 ° C, and the light and dark alternate between day and night for 12/12 hours. Before the behavioral test, the animal was moved to the behavior test operation room 2 hours in advance to adapt it to the environment and reduce its nervousness.
  • the tested drugs used in this research are: HNK, PMS-001, 0.9% NaCl solution (blank control).
  • the specific information of each tested drug is shown in Table 1 below:
  • test drugs prepared freshly before each experiment: Take appropriate amounts of HNK and PMS-001 powders respectively, weigh 4 mg of the compound precisely, and fix the volume to 3 ml of 0.9% NaCl respectively, mix well and make 1 mg / ml Solution, to be used.
  • mice were randomly divided into 6 groups, with 10 animals in each group.
  • the way of administration of animals in each group is shown in Table 2.
  • mice Before being tested, mice must be acclimatized for more than 2 hours in the operating room.
  • mice were weighed and marked at the tail before adaptation.
  • mice 24 hours before dosing, the mice were placed in a cylindrical cylinder to adapt to the water environment for 10 minutes.
  • the animals were dosed once and administered intraperitoneally 1h and 24h before the behavioral test.
  • the water depth in the cylinder is 15 cm, so that the animal cannot escape from the glass cylinder, its feet and tail do not touch the bottom of the cylinder, and the water temperature is 23 °C. -25 °C.
  • the 6-minute video of the mouse after entering the water was taken. Since most animals were very active in the first two minutes, the immobility time after 4 minutes was calculated (the standard for immobility: the mouse stopped struggling in the water, immobility and balance or Floating small limb movements). The mice in each group were operated in parallel.

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Abstract

一种抑郁症治疗方法和药物。具体而言，一种GluR2-CT多肽在治疗抑郁症，特别是重度抑郁症的用途。

Description

抑郁症治疗方法和药物 技术领域
本发明涉及生物医药领域。具体而言，本发明公开了新的抑郁症治疗方法和药物。更具体而言，本发明涉及GluR2-CT多肽在治疗抑郁症，特别是重度抑郁症的新用途。
发明背景
抑郁症是一种全球性且临床常见的精神卫生疾病，特别容易发生在中风、神经衰弱、器官移植、糖尿病、帕金森病、神经官能症、产后及老年人群体中。若患者病情较严重且反复发作，则会出现自杀倾向，进而影响其日常生活。据世界卫生组织统计，抑郁症已成为目前世界第四大疾患，到2020年抑郁症可能成为仅次于局部缺血性心脏病引起的第二大非自理性疾病。抑郁症在临床治疗过程中十分常见，该病主要因患者出现严重社交及情感障碍所致。
抑郁症可以分为轻/中度抑郁症以及重度抑郁症。轻/中度抑郁症的临床表现包括：有抑郁心情或有其他几种症状(像食欲发生改变、睡眠结构发生改变，闷闷不乐、悲观厌世、自卑等)持续时间超过两年；这些症状并没达到重性抑郁症的程度；在两个月或更长的时间内，患者没有一天处于正常状态。重度抑郁症的临床表现包括：体重增加或减少(在不节食的情况下)；食欲改变；睡眠过多或过少；坐立不安；无精打采；感觉自己没有任何价值，羞愧和内疚；无法集中精力，无法做决定；浮现想死的念头或自杀。如果一个人在一天的大部分时间或两个星期或更长时间内几乎每天都出现这种症状，那么就很有可能患上了重度抑郁症。
传统抗抑郁药物虽然对抑郁症患者有一定的治疗缓解作用，但由于其缓慢的起效期阻碍了临床上的广泛应用。传统抗抑郁药物一般在服药3～4周才会发挥相应的治疗作用，这不仅增加了患者的治疗期限导致患者顺应性降低，同时极大降低了患者的生活质量和生存状态。更为严重的是，对于重度抑郁患者，由于得不到及时有效的治疗，自杀风险会显著提升，这 给患者本身以及家庭带来严重的后果。因此如何在最短的时间内发挥抗抑郁药的治疗效果，从而降低相关风险的发生一直阻碍着抗抑郁药的进一步发展。虽然目前以艾司氯胺酮为代表的在研药物解决了起效慢的问题，一定程度上缓解了重度抑郁症患者的治疗期限，但是其较强的致幻副作用阻碍了该药物的进一步临床应用。除此之外，传统抗抑郁药物还普遍存在口干、便秘、嗜睡以及体重增加和肝毒性等不良反应，这进一步阻碍了抗抑郁药物的使用。然而随着社会的发展，人们的生活压力日益增大，抑郁人群的数量也在不断增加，因此迫切需要一种快速有效安全的药物以满足市场需要。
附图简述
图1.示出强迫游泳实验评价结果。左图为给药1h后进行强迫游泳实验，右图为给药24h后进行强迫游泳实验。
发明内容
受体AMPAR的GluR2亚基的C末端多肽(GluR2-CT多肽)之前已经被证明与焦虑症相关(参见EP1,687,427B1)，例如在焦虑症的动物行为模型高架十字迷宫实验中，GluR2-CT多肽可以阻断情绪导致的应激性焦虑，从而用于治疗焦虑症。然而，焦虑症与抑郁症明显不同。焦虑是由预先知道但又不可避免的、即将发生的应激性事件引起的一种预期反应，以恐惧、担心、紧张等精神症状为主要表现，同时多伴有心悸、多汗、手脚发冷等植物神经功能紊乱，其核心症状为担忧。而抑郁症是一种以情绪低落，思维迟钝，行为迟缓为主要症状的精神疾病，同时可伴有睡眠减少，体重降低等躯体症状，不可控制的应激是其产生的重要原因，也即是说，抑郁行为是由不可控制的负性事件所产生的。在本发明之前，本领域技术人员并不知晓GluR2-CT多肽是否能够用于治疗抑郁症。
在本发明中，发明人惊奇地发现，GluR2-CT多肽是治疗抑郁症的极具前景的候选药物。如实施例所证明，在抗抑郁症经典模型—小鼠强迫性游泳实验中，本发明的GluR2-CT多肽能够快速并显著降低强迫游泳小鼠不动时间，且在24小时之内能够维持较好的抗抑郁效果。实验数据显示，与阳性抗抑郁药物HNK(氯胺酮代谢物)相比，本报道化合物具有更加明显的 抗抑郁功效，从而证明GluR2-CT多肽有望开发为快速起效的用于各类型抑郁症治疗的新型药物，特别是其快速起效的特点将极大降低重症抑郁患者的自杀风险。
在本发明中，“GluR2-C末端多肽”或“GluR2-CT多肽”意指衍生自GluR2多肽的C末端的多肽，其能够抑制NMDA介导的AMPAR过度内吞或调节神经元凋亡。所述GluR2-CT多肽可以与受体GluR2多肽的C末端相同，或者包含一或多个氨基酸取代但是保留其生物学功能。例如，所述GluR2-CT多肽包含氨基酸序列YKEGYNVYG。然而，GluR2-CT多肽还可以以融合蛋白的方式包含其它多肽序列，例如有助于透过细胞膜的载体多肽序列。所述载体多肽例如可以是Tat多肽，其包含氨基酸序列YGRKKRRQRRR。在一些实施方案中，所述多肽是分离的多肽。在一些实施方案中，所述多肽是人工合成的多肽。在一些实施方案中，所述多肽是重组产生的多肽。
因此，第一方面，本发明提供一种在对象中治疗抑郁症的方法，所述方法包括给所述对象施用治疗有效量的GluR2-CT多肽。在一些实施方案中，所述GluR2-CT多肽包含氨基酸序列YKEGYNVYG。在一些实施方案中，所述GluR2-CT多肽在N端融合有载体多肽序列。在一些实施方案中所述GluR2-CT多肽在N端融合有Tat载体多肽的氨基酸序列YGRKKRRQRRR。在一些具体实施方案中，所述GluR2-CT多肽包含氨基酸序列YGRKKRRQRRRYKEGYNVYG。
如本文所用的术语“对象”意指哺乳动物，尤其灵长类动物，尤其是人。
本发明另一重要的发现是GluR2-CT多肽在抑郁症动物模型中起效迅速，因此相对于传统抗抑郁药物，特别适合于治疗重度抑郁症。因此，在本发明方法的一些实施方案中，所述抑郁症是重度抑郁症。
本发明所述的“抑郁症”，在临床上可以通过抑郁症状评定量表来进行诊断和分级。合适的量表包括但不限于汉密尔顿抑郁分级量表(Hamilton Depression Scale，HAMD)、贝克抑郁自评问卷(Beck Depression Inventory，BDI)和抑郁自评量表(Self-rating depression scale，SDS)。
例如在HAMD量表中，总分<8分为正常，总分在8～20分为可能有抑郁症，而总分在20～35分之间被诊断为患有抑郁症，总分>35分为患有重度 抑郁症。本发明的GluR2-CT多肽特别适合于HAMD量表中总分>35分的重度抑郁症患者。
在BDI问卷中，总分10分-15分，代表可能患有抑郁症；总分大于15分，表明已有抑郁症；当大于25分时，表示重度抑郁。本发明的GluR2-CT多肽特别适合于BDI问卷中总分>25分的重度抑郁症患者。
而在SDS量表中，SDS标准分的分界值为53分，其中53-62分为轻度抑郁，63-72分为中度抑郁，73分以上为重度抑郁。本发明的GluR2-CT多肽特别适合于SDS量表中标准分>73分的重度抑郁症患者。
在重度抑郁症患者中常常会出现严重的自杀倾向，造成严重的社会问题。所述自杀倾向例如是：所述对象已经为自杀行为做出准备，或者所述对象已经实施自杀行为但已经被制止。对于此类的患者，传统的抗抑郁药物通常需要几周才能起效，因此无法有效防止患者的自杀行为。而本发明的GluR2-CT多肽能够迅速起效(例如在1小时内起效)，且作用时间长(例如一次给药持续至少大约24小时)，能够及时降低重度抑郁症患者的自杀倾向，防止自杀行为的发生。
因此，在本发明一些实施方案中，所述抑郁症是有自杀倾向的重度抑郁症。在一些实施方案中，在所述对象表现出自杀倾向时，给所述对象施用治疗有效量的GluR2-CT多肽。
在另一方面，本发明提供了一种降低患抑郁症对象自杀风险的方法，所述方法包括给所述对象施用治疗有效量的GluR2-CT多肽。在一些实施方案中，所述GluR2-CT多肽包含氨基酸序列YKEGYNVYG。在一些实施方案中，所述GluR2-CT多肽在N端融合有载体多肽序列。在一些实施方案中所述GluR2-CT多肽在N端融合有Tat载体多肽的氨基酸序列YGRKKRRQRRR。在一些具体实施方案中，所述GluR2-CT多肽包含氨基酸序列YGRKKRRQRRRYKEGYNVYG。
在一些实施方案中，所述抑郁症是重度抑郁症。
在一些实施方案中，所述抑郁症是有自杀倾向的重度抑郁症。
在一些实施方案中，在所述对象表现出自杀倾向时，给所述对象施用治疗有效量的GluR2-CT多肽。
在另一方面，本发明提供GluR2-CT多肽在制备用于在对象中治疗抑郁症的药物中的用途。在一些实施方案中，所述GluR2-CT多肽包含氨基酸序 列YKEGYNVYG。在一些实施方案中，所述GluR2-CT多肽在N端融合有载体多肽序列。在一些实施方案中所述GluR2-CT多肽在N端融合有Tat载体多肽的氨基酸序列YGRKKRRQRRR。在一些具体实施方案中，所述GluR2-CT多肽包含氨基酸序列YGRKKRRQRRRYKEGYNVYG。
在一些实施方案中，所述抑郁症是重度抑郁症。
在一些实施方案中，所述抑郁症是有自杀倾向的重度抑郁症。
在一些实施方案中，所述药物用于在所述对象表现出自杀倾向时，给所述对象施用。
在另一方面，本发明提供GluR2-CT多肽在制备用于降低患抑郁症的对象自杀风险的药物中的用途。在一些实施方案中，所述GluR2-CT多肽包含氨基酸序列YKEGYNVYG。在一些实施方案中，所述GluR2-CT多肽在N端融合有载体多肽序列。在一些实施方案中所述GluR2-CT多肽在N端融合有Tat载体多肽的氨基酸序列YGRKKRRQRRR。在一些具体实施方案中，所述GluR2-CT多肽包含氨基酸序列YGRKKRRQRRRYKEGYNVYG。
在一些实施方案中，所述抑郁症是重度抑郁症。
在一些实施方案中，所述抑郁症是有自杀倾向的重度抑郁症。
在一些实施方案中，所述药物用于在所述对象表现出自杀倾向时，给所述对象施用。
在另一方面，本发明提供一种包含GluR2-CT多肽以及药学上可接受的载体的药物组合物，其用于在对象中治疗抑郁症。在一些实施方案中，所述GluR2-CT多肽包含氨基酸序列YKEGYNVYG。在一些实施方案中，所述GluR2-CT多肽在N端融合有载体多肽序列。在一些实施方案中所述GluR2-CT多肽在N端融合有Tat载体多肽的氨基酸序列YGRKKRRQRRR。在一些具体实施方案中，所述GluR2-CT多肽包含氨基酸序列YGRKKRRQRRRYKEGYNVYG。
在一些实施方案中，所述抑郁症是重度抑郁症。
在一些实施方案中，所述抑郁症是有自杀倾向的重度抑郁症。
在一些实施方案中，所述药物组合物用于在所述对象表现出自杀倾向时，给所述对象施用。
在另一方面，本发明提供一种包含GluR2-CT多肽以及药学上可接受的载体的药物组合物，其用于降低患抑郁症的对象自杀风险。在一些实施方 案中，所述GluR2-CT多肽包含氨基酸序列YKEGYNVYG。在一些实施方案中，所述GluR2-CT多肽在N端融合有载体多肽序列。在一些实施方案中所述GluR2-CT多肽在N端融合有Tat载体多肽的氨基酸序列YGRKKRRQRRR。在一些具体实施方案中，所述GluR2-CT多肽包含氨基酸序列YGRKKRRQRRRYKEGYNVYG。
在一些实施方案中，所述抑郁症是重度抑郁症。
在一些实施方案中，所述抑郁症是有自杀倾向的重度抑郁症。
在一些实施方案中，所述药物用于在所述对象表现出自杀倾向时，给所述对象施用。
如本发明所述，GluR2-CT多肽的“治疗有效量”优选地导致疾病症状的严重性降低，疾病无症状期的频率和持续时间增加，或者防止因疾病痛苦而引起的损伤或失能。例如，施用治疗有效量的GluR2-CT多肽可以导致对象抑郁症量表的评分降低。例如，施用治疗有效量的GluR2-CT多肽可以导致HAMD量表总分降低大约5分、大约10分、大约15分、大约20分或更多，或者导致BDI问卷评分总分降低大约5分、大约10分、大约15分、大约20分或更多，或者导致SDS量表评分标准分降低大约5分、大约10分、大约15分、大约20分或更多。优选地，施用治疗有效量的GluR2-CT多肽导致对象从重度抑郁症缓解为轻度抑郁症或无抑郁症症状。或者，施用治疗有效量的GluR2-CT多肽导致对象降低的自杀风险。本领域技术人员可以根据如下因素确定治疗有效量，如对象的大小、对象症状的严重性(如评分高低)和选择的特定组合物或给药途径。
本发明的GluR2-CT多肽或药物组合物可以利用本领域公知的一种或多种方法通过一种或多种施用途径施用。本领域技术人员应当理解，施用途径和/或方式根据期望的结果而不同。本发明GluR2-CT多肽的优选施用途径包括静脉内、肌肉内、皮内、腹膜内、皮下、脊柱或其他肠胃外施用途径，例如注射或输注。优选地，本发明的GluR2-CT多肽通过注射施用。
对于本发明的GluR2-CT多肽的施用而言，剂量范围可以为约0.0001至100mg/kg，更通常为0.01至20mg/kg受者体重。例如，剂量可以是1mg/kg体重、3mg/kg体重、5mg/kg体重，10mg/kg体重或20mg/kg体重，或在1-20mg/kg体重范围内。
对于本发明的GluR2-CT多肽的施用而言，示例性的治疗方案可以每天 施用一次、每两天一次，每三天一次、每四天一次、每五天一次、每六天一次、每周一次、每两周一次、每三周一次、每四周一次、每月一次、每3个月一次、每3-6个月一次、或起始给药间隔略短(如每天一次至每三周一次)后期给药间隔加长(如每月一次至每3-6个月一次)。具体施用方案可以由医师根据患者具体症状确定。例如，如上所述，由于本发明的GluR2-CT多肽起效迅速，可以在患者出现重度抑郁症例如自杀倾向时施用，从而迅速降低患者自杀风险。同时，本发明的GluR2-CT多肽药效持续时间长，因此可以显著减少施用次数。
本文使用的“药学上可接受的载体”包括生理学相容的任何和所有的溶剂、分散介质、包衣、抗细菌剂和抗真菌剂、等渗剂和吸收延迟剂等。优选地，该载体适合于静脉内、肌肉内、皮内、腹膜内、皮下、脊柱或其他肠胃外施用(如通过注射或输注)。根据施用途径，可将活性化合物即GluR2-CT多肽包裹于一种材料中，以保护该化合物免受可使该化合物失活的酸和其他天然条件的作用。
实施例
下面将通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所描述的实施例范围中。
目前抑郁症动物模型的建立方法主要分为三类：行为绝望、习得性无助和慢性温和的不可预知性应激。
在行为绝望模型中，大鼠或小鼠的强迫性游泳是目前评价抗抑郁药作用效果最常用的抑郁动物模型。在这个模型中，动物被迫在一个有限的空间内游泳，连续多次挣扎却不能摆脱困境后动物会静止漂浮于水面，不再进行挣扎逃脱反应，这种静止不动状态被认为是行为绝望和抑郁的表现。此模型对抗抑郁药有很好的预测效度。
1、实验目的
以氯氨酮代谢产物HNK为阳性对照药，通过单次药物干预，给药1h和24h后，测试强迫游泳实验，考察化合物PMS-001对C57小鼠抑郁样行为的影响。化合物PMS-001(也称为Tat-GluR2-3Y)为多肽化合物，包含氨基酸序列Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg-Tyr-Lys-Glu-Gly-Tyr- Asn-Val-Tyr-Gly(YGRKKRRQRRRYKEGYNVYG)。其中氨基酸序列YGRKKRRQRRR，也称作Tat肽，是一种载体肽，能协助多肽穿过血脑屏障。而氨基酸序列YKEGYNVYG(也称为GluR2-3Y)衍生自GluR2的C末端序列，其已经被证明能够抑制NMDA介导的AMPAR过度内吞，从而调节神经应答(参见EP1,687,427B1)。然而，本领域未知GluR2的C末端多肽例如YKEGYNVYG能否用于治疗抑郁症，尤其是重度抑郁症。
2、实验方案
1)动物
实验动物为6周龄C57小鼠，雄性，C57小鼠购自上海斯莱克实验动物有限公司，体重20.45±0.19g。实验前到达中国科学院上海药物研究所动物饲养中心(动物生产许可证：SCXK9[沪]2004-0002，使用许可证：SYXK[沪]2003-0029)，并在动物设施中适应3天以上，6只/笼饲养。饲养环境为室温23±0.2℃，12/12小时昼夜明暗交替。行为学测试前，动物先提前2小时移至行为测试操作间，使之适应该环境，降低其紧张感。
2)药品与试剂
本研究所用受试药物有：HNK、PMS-001、0.9％NaCl溶液(空白对照)。各受试药物具体信息如下表1所示：
表1 受试药物
Figure PCTCN2019119855-appb-000001
3)仪器
1毫升带针无菌一次性注射器(购自浙江康德莱医疗器械有限公司)；透明水桶(自制，高30cm，直径20cm，水深15cm)，小鼠强迫游泳装置；高清摄像头；吉量行为分析系统(上海吉量软件科技有限公司)。
4)试验分组
表2 动物分组信息
Figure PCTCN2019119855-appb-000002
5)行为学试验
(1)实验步骤
i)供试药品配制(每次实验前新鲜配制)：分别取适量HNK、PMS-001粉末，分别精密称量化合物4mg，分别定容于3ml 0.9％NaCl，充分混匀，配成1mg/ml溶液，待用。
ii)动物随机分成6组，每组10只动物。每组动物的给药方式如表2示。
iii)受试前，小鼠须在操作间适应2小时以上。
iv)适应前小鼠称重，并尾部标记。在强迫游泳实验行为测试开始前1小时，每只动物给予药物干预，详见表2。
(2)强迫游泳实验(FST)
在给药前24小时，小鼠放入圆柱型缸内适应水中环境10min。行为测试当天，动物给药1次，分别在行为测试前1h和24h腹腔给药。将小鼠单独放入高30厘米、直径20厘米的圆柱型玻璃缸中，缸内水深为15厘米，使动物既不能逃出玻璃缸，其脚和尾部又不接触到缸底，水温23℃-25℃。拍摄小鼠入水后的6分钟视频，由于大多数动物在开始两分钟十分活跃，因此计算后4分钟不动时间(判定不动标准：小鼠在水中停止挣扎、不动和为保持平衡或呈漂浮状态的细小的肢体运动)。各组小鼠平行操作。
6)数据处理与统计方法
所有数据分析采用spss 22数据处理软件完成。使用单因素方差分析，采用post-hoc LSD法多重比较校验结果。数据用Mean±s.e.m.表示。p<0.05 时标记一个星号；p<0.01时标记两个星号；p<0.001时标记三个星号。
3、实验结果
由于经典抗抑郁药物起效慢，单次剂量给药不能产生抗抑郁作用。本实验用氯胺酮代谢产物HNK做阳性药物，之前研究表明HNK在给药后1h能快速起效，且药效可持续24h。本实验结果显示(图1)：在给药1h后，受试化合物HNK能显著地降低强迫游泳小鼠不动时间，而PMS-001能极显著地降低强迫游泳小鼠不动时间。给药24h后进行行为学测试，发现HNK能显著地降低小鼠强迫游泳不动时间，而PMS-001能极显著地降低强迫游泳小鼠不动时间。结果初步确定化合物HNK、PMS-001具有抗抑郁效果，且药效能维持到24h。
4、总结
抑郁症模型—强迫游泳实验证明，在同等剂量下，PMS-001相比于阳性对照药氯胺酮代谢物—HNK表现出更好的快速而持久的抗抑郁效果(给药1h后抗抑郁效果出现，并可维持24h)。
动物模型实验证明PMS-001可以快速起效，降低了传统已上市药物4周左右的起效时间，减少了患者的治疗期限，所以可以大大降低重度抑郁自杀的风险以及由于抑郁导致的家庭、社会问题。

Claims (9)

  1. GluR2-CT多肽在制备用于治疗抑郁症或用于降低患抑郁症的对象自杀风险的药物中的用途，所述GluR2-CT多肽包含氨基酸序列YKEGYNVYG。
  2. 权利要求1的用途，其中所述GluR2-CT多肽在N端融合有氨基酸序列YGRKKRRQRRR。
  3. 权利要求2的用途，其中所述GluR2-CT多肽包含氨基酸序列YGRKKRRQRRRYKEGYNVYG。
  4. 权利要求1-3中任一项的用途，其中所述抑郁症是重度抑郁症。
  5. 权利要求1-4中任一项的用途，其中所述对象具有总分>35分的HAMD量表评分，或具有总分>25分的BDI问卷评分，或者具有标准分>73分的SDS量表评分。
  6. 权利要求1-5中任一项的用途，其中所述抑郁症是有自杀倾向的重度抑郁症。
  7. 权利要求1-6中任一项的用途，其中所述药物用于在所述对象表现出自杀倾向时，给所述对象施用。
  8. 权利要求1-7中任一项的用途，其中所述药物包含剂量为1-20mg/kg体重的GluR2-CT多肽。
  9. 权利要求1-8中任一项的用途，其中所述药物用于注射施用。
PCT/CN2019/119855 2018-11-21 2019-11-21 抑郁症治疗方法和药物 WO2020103889A1 (zh)

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