WO2023120405A1 - COMPOSITION FOR MINIMIZING PRODUCTION AND/OR ACCUMULATION OF AMYLOID β - Google Patents

COMPOSITION FOR MINIMIZING PRODUCTION AND/OR ACCUMULATION OF AMYLOID β Download PDF

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WO2023120405A1
WO2023120405A1 PCT/JP2022/046359 JP2022046359W WO2023120405A1 WO 2023120405 A1 WO2023120405 A1 WO 2023120405A1 JP 2022046359 W JP2022046359 W JP 2022046359W WO 2023120405 A1 WO2023120405 A1 WO 2023120405A1
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composition
amyloid
memory
cyclo
leu
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PCT/JP2022/046359
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French (fr)
Japanese (ja)
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翔太 野中
義 古元
嘉宏 中尾
シャンメイ ヨン
シャージャン リン
グレース カー ヤン チャン
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サントリーホールディングス株式会社
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Publication of WO2023120405A1 publication Critical patent/WO2023120405A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/12—Cyclic peptides with only normal peptide bonds in the ring

Definitions

  • the present invention relates to a composition for suppressing production and/or accumulation of amyloid ⁇ , and the like.
  • Amyloid ⁇ (A ⁇ ) is a type of protein produced in the brain. When amyloid ⁇ aggregates to oligomerize or fibrillate, it exhibits neuronal toxicity. In addition, aggregated amyloid ⁇ accumulates without being discharged from the brain, and is thought to trigger the onset of Alzheimer's disease. Therefore, suppressing the production or accumulation of amyloid ⁇ is considered effective, for example, in preventing Alzheimer's disease or in suppressing progression of the disease.
  • Acetylcholinesterase inhibitors are known as drugs that improve symptoms of Alzheimer's disease. Inhibition of acetylcholinesterase increases the amount of acetylcholine in the brain and is effective in suppressing the progression of cognitive decline. However, acetylcholinesterase inhibition cannot suppress the production of amyloid ⁇ or remove accumulated amyloid ⁇ . There is a demand for a substance that can be ingested on a daily basis as food or drink, etc., and that can suppress the production or accumulation of amyloid ⁇ .
  • Patent Document 1 describes an agent for suppressing and/or improving cognitive function decline containing Cyclo (Gly-Pro).
  • An object of the present invention is to provide a composition for suppressing the production and/or accumulation of amyloid ⁇ .
  • the present inventors have made intensive studies in view of the above problems, and found that cyclic dipeptides cycloleucylphenylalanine (Cyclo(Leu-Phe)) and cycloleucyllysine (Cyclo(Leu-Lys)) are amyloid ⁇ found to be effective in suppressing the production and/or accumulation of
  • the present invention relates to, but is not limited to, the following compositions for suppressing production and/or accumulation of amyloid ⁇ .
  • a composition for suppressing the production and/or accumulation of amyloid ⁇ comprising as an active ingredient at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof.
  • the composition of [1] above which suppresses the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
  • composition "enhances cognitive function”, “suppresses decline in cognitive function”, “maintains good cognitive function”, “enhances memory”, “suppresses decline in memory”, “improves memory “maintaining good memory”, “improving memory accuracy”, “preventing memory impairment”, “improving memory impairment”, “maintaining memory as a part of cognitive function”, and “preventing memory loss” functions that are suitable for people to become,””improve memory accuracy and judgment accuracy, which are part of cognitive function”, “improve memory retention or consolidation”, “maintain enhanced cognitive function”, “improves executive function”, “promotes attention and concentration”, “improves learning ability”, “maintains and improves orientation”, “delays age-related cognitive decline", “ labeled with one or more functions selected from the group consisting of "strengthening short-term and long-term memory”, “promoting verbal and visuospatial memory” and “maintaining/improving logical thinking ability”
  • the composition according to any one of [1] to
  • compositions for suppressing the production and/or accumulation of amyloid ⁇ can be provided.
  • the composition of the present invention can be used as foods, beverages, pharmaceuticals, etc. for suppressing the production and/or accumulation of amyloid ⁇ .
  • FIG. 1 is a graph showing the ⁇ -secretase (BACE) inhibitory activity of the test compound-free group (Control), Cyclo(Leu-Ala) (Comparative Example 1) and Cyclo(Leu-Phe) (Examples 1 to 4).
  • FIG. 2 is a graph showing the ⁇ -secretase (BACE) inhibitory activity of the test compound-free group (Control), Cyclo(Leu-Ala) (Comparative Example 1) and Cyclo(Leu-Lys) (Example 5). .
  • the composition for suppressing production and/or accumulation of amyloid ⁇ of the present invention contains at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof.
  • the composition for suppressing production and/or accumulation of amyloid ⁇ of the present invention contains at least one selected from the group consisting of Cyclo (Leu-Phe), Cyclo (Leu-Lys) and salts thereof as an active ingredient. .
  • the composition for suppressing the production and/or accumulation of amyloid ⁇ of the present invention is sometimes referred to as the composition of the present invention.
  • the composition of the present invention is used to suppress the production of amyloid ⁇ and/or the accumulation of amyloid ⁇ .
  • Cyclo (Leu-Phe) (cycloleucylphenylalanine) and Cyclo (Leu-Lys) (cycloleucyllysine) used in the present invention are cyclic having a structure in which leucine and phenylalanine, leucine and lysine are condensed, respectively. It is a dipeptide.
  • Cyclo(Leu-Phe) and Cyclo(Leu-Lys) are sometimes referred to as CLF and CLK, respectively.
  • cyclic dipeptide is characterized by having amino acids as constituent units, and is a diketopiperazine structure produced by dehydration condensation between the amino group of the N-terminal side amino acid and the carboxyl group of the C-terminal side amino acid.
  • a compound having In this specification as long as the amino acid constitution of the cyclic dipeptides is the same, it does not matter which order they are listed.
  • Leucine represents the same cyclic dipeptide.
  • Cyclo(Leu-Lys) and Cyclo(Lys-Leu) (cyclolysylleucine) represent the same cyclic dipeptide.
  • Salts of CLF and CLK are not particularly limited as long as they are pharmacologically acceptable salts or salts acceptable for food and drink, and may be either acidic salts or basic salts.
  • Acid salts include, for example, inorganic salts such as hydrochlorides, sulfates, nitrates, phosphates; Examples include organic acid salts such as acid salts and propionate salts.
  • Examples of basic salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; Salts of cyclic dipeptides can be readily prepared by those skilled in the art by any method known in the art.
  • CLF, CLK and salts thereof are not particularly limited.
  • CLF, CLK or salts thereof can be produced according to known methods.
  • CLF, CLK and salts thereof may be derived from natural products, may be artificially synthesized, may be produced by an enzymatic method or a microbial fermentation method, and may be produced by a linear dipeptide. It may be synthesized by dehydration and cyclization.
  • protein hydrolysates such as collagen hydrolysates can be heated to obtain heat-treated peptides rich in cyclic dipeptides such as CLF and CLK.
  • CLF, CLK and salts thereof may be incorporated into compositions using protein hydrolysates containing them or heat treated products thereof, or concentrates, dry powders or purified protein hydrolysates or heat treated products thereof. Higher degrees may be used and incorporated into the composition.
  • the composition of the present invention contains, for example, a protein hydrolyzate or heat-treated product thereof, and CLF, CLK and salts thereof may be part of the protein hydrolyzate or heat-treated product thereof. Commercially available products can also be used for CLF, CLK and salts thereof.
  • Amyloid- ⁇ is a peptide sometimes referred to as amyloid- ⁇ protein, amyloid- ⁇ peptide or ⁇ -amyloid.
  • Amyloid ⁇ is usually a peptide consisting of around 40 amino acids, and includes amyloid ⁇ 1-42 , amyloid ⁇ 1-40 and the like. Unassociated amyloid- ⁇ is sometimes referred to as amyloid- ⁇ monomer.
  • Amyloid ⁇ may form an aggregate with two or more positions.
  • Amyloid ⁇ may form, for example, a soluble aggregate (amyloid ⁇ oligomer) in which two or more (eg, 2 to 50) amyloid ⁇ aggregates.
  • Amyloid ⁇ oligomers include amyloid ⁇ 1-42 oligomers, amyloid ⁇ 1-40 oligomers, and the like.
  • Amyloid ⁇ in the present invention includes non-aggregated amyloid ⁇ and amyloid ⁇ forming aggregates such as oligomers.
  • Amyloid ⁇ is produced by the two-step cleavage of amyloid ⁇ precursor protein (APP) by ⁇ -secretase and ⁇ -secretase.
  • APP amyloid ⁇ precursor protein
  • ⁇ -Secretase is the rate-limiting enzyme for amyloid ⁇ production, and its cleavage regulates the total amyloid ⁇ production. Therefore, by inhibiting ⁇ -secretase, the production of amyloid ⁇ can be suppressed, and the accumulation of amyloid ⁇ can be suppressed.
  • CLF, CLK and salts thereof have ⁇ -secretase inhibitory action.
  • the composition of the present invention can be used to suppress the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
  • CLF, CLK and salts thereof are useful as active ingredients for ⁇ -secretase inhibition.
  • the present invention also includes a ⁇ -secretase inhibitory composition containing at least one selected from the group consisting of CLF, CLK and salts thereof.
  • the composition of the present invention may contain Cyclo(Leu-Phe) or a salt thereof as an active ingredient.
  • the composition of the present invention may contain Cyclo(Leu-Lys) or a salt thereof as an active ingredient.
  • composition of the present invention can be used to suppress the production and/or accumulation of amyloid ⁇ in the brain.
  • the composition of the present invention can be used to suppress the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
  • the composition of the present invention can be used for the prevention or amelioration of a condition or disease associated with amyloid ⁇ accumulation, preferably a condition or disease associated with amyloid ⁇ accumulation in the brain.
  • conditions or diseases include conditions or diseases associated with or caused by amyloid- ⁇ accumulation.
  • Conditions or diseases associated with or resulting from accumulation of amyloid ⁇ in the brain include, for example, Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment, and the like.
  • the composition of the present invention can be used to prevent or ameliorate the above conditions or diseases, and can be preferably used for the prevention of the above conditions or diseases.
  • prevention of a condition or disease includes preventing onset, delaying onset, reducing the rate of onset, reducing risk of onset, and the like.
  • Ameliorating a condition or disease includes ameliorating the subject from the condition or disease, alleviating symptoms of the condition or disease, ameliorating symptoms of the condition or disease, slowing progression of the condition or disease, preventing the condition or disease. etc.
  • Cognitive function is known to decline in Alzheimer's disease and mild cognitive impairment.
  • Symptoms of cognitive decline in Alzheimer's disease and mild cognitive impairment include, for example, memory loss, memory impairment (forgetfulness), aphasia (difficult to name things), apraxia, agnosia (walking in familiar places). (e.g., getting lost), decreased orientation (the ability to correctly recognize one's own situation, such as place, time, name of person, etc.), decreased verbal and non-verbal learning ability, decreased auditory and visual processing, executive function executive dysfunction (inability to plan and do things), decreased ability to concentrate, decreased attention, decreased judgment, decreased spatial awareness, decreased cognitive flexibility, decreased information processing speed, etc.
  • a preventive effect on cognitive function decline or an improving effect on cognitive function for example, an effect on preventing or improving the above symptoms can be obtained.
  • compositions of the present invention can be applied for either therapeutic use (medical use) or non-therapeutic use (non-medical use).
  • Non-therapeutic is a concept that does not involve medical intervention, i.e. human surgery, treatment or diagnosis.
  • the composition for suppressing production and/or accumulation of amyloid ⁇ of the present invention can be provided in the form of an agent as an example, but is not limited to this form.
  • the agent itself can be provided as a composition, or a composition containing the agent can be provided.
  • the composition for suppressing the production and/or accumulation of amyloid ⁇ of the present invention can also be said to be an agent for suppressing the production and/or accumulation of amyloid ⁇ .
  • a ⁇ -secretase inhibitory composition can also be referred to as a ⁇ -secretase inhibitor.
  • compositions of the invention may be either oral or parenteral.
  • the compositions of the invention are preferably oral compositions.
  • the composition of the present invention can be in the form of, for example, foods, beverages, pharmaceuticals, quasi-drugs, feeds, etc. Foods, beverages, or pharmaceuticals are preferred.
  • the composition of the present invention can also be used by adding it to foods and beverages, pharmaceuticals, quasi-drugs, feeds, and the like.
  • the form of the composition of the present invention is not particularly limited, and may be solid (for example, powder, granule, tablet, etc.), liquid, paste, or the like.
  • composition of the present invention contains at least one selected from the group consisting of CLF, CLK, and salts thereof, and various diluents, acidulants, acidulants, Antioxidants, stabilizers, preservatives, fragrances, emulsifiers, pigments, seasonings, pH adjusters, nutritional enhancers and the like may be added.
  • composition of the present invention when used as a food or drink, at least one selected from the group consisting of CLF, CLK and salts thereof may be added to ingredients that can be used for food and drink (e.g., food materials, if necessary food additives, etc.) can be blended into various foods and drinks.
  • Food and drink are not particularly limited, and examples thereof include general food and drink, health food, food with function claims, food for specified health use, health supplement, and food for the sick.
  • Health foods, foods with function claims, foods for specified health uses, health supplements, etc. are various formulations such as liquids, fine granules, tablets, granules, powders, capsules, chewable formulations, dry syrups, and liquid diets. Can be used as a form.
  • composition of the present invention When the composition of the present invention is used as a drug or quasi-drug, it is added to at least one selected from the group consisting of CLF, CLK and salts thereof, a pharmacologically acceptable carrier, and if necessary It is possible to prepare pharmaceuticals or quasi-drugs in various dosage forms by blending additives and the like. Such carriers, additives, etc. may be those that can be used for pharmaceuticals or quasi-drugs and are pharmacologically acceptable. One or more of antioxidants, coloring agents and the like can be mentioned. Examples of administration (ingestion) forms of pharmaceuticals or quasi-drugs include oral or parenteral (transdermal, transmucosal, enteral, injection, etc.) forms of administration.
  • composition of the present invention When used as a drug or quasi-drug, it is preferably an oral drug or oral quasi-drug.
  • Dosage forms for oral administration include, for example, liquids, tablets, powders, fine granules, granules, dragees, capsules, suspensions, emulsions, chewables and the like.
  • Dosage forms for parenteral administration include, for example, injections, drops, ointments, lotions, patches, suppositories, nasal preparations, pulmonary preparations (inhalants) and the like.
  • the pharmaceutical may be a non-human veterinary pharmaceutical.
  • Feed also includes feed additives.
  • feeds include livestock feeds for cows, pigs, chickens, sheep, horses, etc.; small animal feeds for rabbits, rats, mice, etc.; pet foods for dogs, cats, small birds, etc.;
  • the composition of the present invention when used as a food or drink, a drug, a quasi-drug, a feed, etc., the production method is not particularly limited, and at least one selected from the group consisting of CLF, CLK and salts thereof It can be produced by a general method using seeds.
  • the composition of the present invention is preferably a liquid composition, more preferably a beverage.
  • the beverage may be, for example, a functional beverage.
  • the form of the beverage is not particularly limited, and may be a packaged beverage.
  • Containers for packaged beverages are not particularly limited, and containers of any shape and material may be used. For example, metal containers such as aluminum cans and steel cans; resin containers such as PET bottles; Containers; glass containers such as glass bottles; and wooden containers such as barrels. Any of commonly used containers can be used.
  • a packaged beverage is obtained by filling and sealing such a container with a beverage.
  • the total content of CLF, CLK and salts thereof contained in the composition of the present invention is not particularly limited, and can be set according to its form and the like.
  • the total content of CLF, CLK and salts thereof in the composition of the present invention may be, for example, 0.00001% by weight or more, preferably 0.0001% by weight or more, and 0.001% by weight. % or more, more preferably 0.01 wt% or more, particularly preferably 0.1 wt% or more, and preferably 50 wt% or less.
  • the total content of CLF, CLK and salts thereof may be, for example, 0.00001 to 25% by weight, preferably 0.0001 to 10% by weight, and 0 0.001 to 5% by weight is more preferred, 0.01 to 5% by weight is even more preferred, and 0.1 to 1% by weight is particularly preferred.
  • CLF, CLK and salts thereof can be quantified by known methods, for example, liquid chromatography mass spectrometry (LC/MS).
  • composition of the present invention contains CLF or a salt thereof
  • its content is not particularly limited, but is preferably 0.000001 to 20% by weight, for example. More preferably 0.00001 to 10% by weight, still more preferably 0.0001 to 5% by weight, still more preferably 0.001 to 2% by weight, particularly preferably 0.01 to 1% by weight is.
  • CLK or a salt thereof is contained in the composition of the present invention, its content is not particularly limited, but is preferably 0.00001 to 20% by weight, for example. More preferably 0.0001 to 10% by weight, still more preferably 0.001 to 5% by weight, still more preferably 0.01 to 2% by weight, particularly preferably 0.01 to 1% by weight is.
  • the composition of the present invention is preferably taken orally (orally administered). There is no particular limitation on the dose (which can also be referred to as intake) of the composition of the present invention.
  • the dosage of the composition of the present invention may be an amount that provides an effect of inhibiting the production and/or accumulation of amyloid ⁇ , and may be appropriately set according to the dosage form, administration method, body weight of the subject, and the like. .
  • the dosage of the composition of the present invention is preferably such that a ⁇ -secretase inhibitory effect is obtained.
  • the dose when the composition of the present invention is ingested or administered to a human (adult) subject, the dose is the total dose of CLF, CLK and salts thereof (converted to cyclic dipeptide) per day It is preferably 0.001 mg or more, more preferably 0.01 mg or more, still more preferably 0.1 mg or more, and preferably 5000 mg or less, more preferably 1000 mg or less, and still more preferably 100 mg or less.
  • the total dose of CLF, CLK and salts thereof when the composition of the present invention is ingested or administered to humans (adults), the total dose of CLF, CLK and salts thereof is preferably 0.001 to 5000 mg, more preferably 0.001 to 5000 mg per day. is 0.01 to 1000 mg, more preferably 0.1 to 100 mg.
  • the composition of the present invention is an oral composition for ingesting or administering at least one selected from the group consisting of CLF, CLK and salts thereof in the above amount per day per 60 kg body weight to humans. It may be a composition for
  • composition of the present invention is preferably taken or administered continuously. It is expected that continuous ingestion or administration of at least one selected from the group consisting of CLF, CLK and salts thereof will result in higher effects.
  • the composition of the present invention is preferably taken or administered continuously for one week or longer, more preferably for four weeks or longer, and even more preferably for eight weeks or longer.
  • CLF, CLK and salts thereof can be ingested as foods and drinks, and from the viewpoint of safety, long-term ingestion is considered to pose little problem.
  • Subjects to whom the composition of the present invention is ingested or administered are not particularly limited. Humans or non-human mammals are preferred, and humans are more preferred.
  • the subject to which the composition of the present invention is administered is a subject who needs or desires suppression of amyloid ⁇ production and/or accumulation, and a subject who needs prevention or improvement of a condition or disease associated with amyloid ⁇ accumulation.
  • administration subjects in the present invention include middle-aged and elderly people.
  • Middle-aged and elderly people include elderly people.
  • a middle-aged person may be, for example, a person over the age of 40.
  • elderly people are preferred as subjects.
  • a senior citizen may be, for example, a human over the age of 60 or over the age of 65.
  • the subject of administration of the composition of the present invention may be a healthy subject.
  • it can be used in healthy individuals for the purpose of suppressing the production and/or accumulation of amyloid ⁇ in the brain, preventing the accumulation of amyloid ⁇ in the brain, preventing Alzheimer's disease or mild cognitive impairment, and the like.
  • composition of the present invention may be labeled with a function exerted by suppressing the production and/or accumulation of amyloid ⁇ .
  • indication is also called functionality indication.
  • the display is not particularly limited. Such indications include, for example, “increases cognitive function”, “suppresses deterioration of cognitive function”, “maintains good cognitive function”, “improves memory”, “suppresses deterioration of memory”, and “improves memory”.
  • the composition of the present invention is preferably a food or drink labeled with one or more of the above labels.
  • the above indication may be an indication that the above composition is used to obtain the above functions.
  • the label may be attached to the composition itself, or may be attached to the container or packaging of the composition.
  • the invention also includes the following methods and uses.
  • a method for suppressing production and/or accumulation of amyloid ⁇ comprising administering at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof.
  • a method for inhibiting ⁇ -secretase comprising administering at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof.
  • the method may be a therapeutic method or a non-therapeutic method.
  • the use may be therapeutic use or non-therapeutic use.
  • Cyclo(Leu-Phe), Cyclo(Leu-Lys), or salts thereof are used to suppress the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase. be able to.
  • At least one selected from the group consisting of CLF, CLK and salts thereof once or more times a day, for example, once to several times (for example, 2 to 3 times) a day preferably ingested or administered to
  • the above uses are preferably in humans or non-human mammals, more preferably in humans.
  • at least one selected from the group consisting of CLF, CLK, and salts thereof can be used to prevent or improve conditions or diseases associated with amyloid ⁇ accumulation by inhibiting ⁇ -secretase. can.
  • the present invention also encompasses a method for preventing or ameliorating a condition or disease associated with amyloid ⁇ accumulation, comprising administering at least one selected from the group consisting of CLF, CLK, and salts thereof.
  • At least one selected from the group consisting of CLF, CLK and salts thereof is used in an amount (can also be referred to as an effective amount) capable of suppressing the production and/or accumulation of amyloid ⁇ . do it.
  • the effective amount is preferably an amount that provides a ⁇ -secretase inhibitory effect.
  • Preferred doses, administration methods, administration subjects, etc. of at least one selected from the group consisting of CLF, CLK and salts thereof are the same as those of the composition of the present invention described above.
  • CLF, CLK, or salts thereof may be taken or administered as they are, or may be taken or administered as a composition containing them. For example, a composition of the invention may be ingested or administered.
  • At least one selected from the group consisting of CLF, CLK and salts thereof is used for the production of foods and drinks, pharmaceuticals, quasi-drugs, feeds, etc. used for suppressing the production and / or accumulation of amyloid ⁇ .
  • the present invention also includes use of at least one selected from the group consisting of CLF, CLK and salts thereof in the production of a composition for suppressing the production and/or accumulation of amyloid ⁇ .
  • the present invention also includes the use of CLF, CLK or salts thereof in the manufacture of compositions for inhibiting ⁇ -secretase.
  • At least one selected from the group consisting of CLF, CLK and salts thereof can be used for the production of a composition for preventing or improving conditions or diseases associated with amyloid ⁇ accumulation.
  • a range represented by “1-2” means from 1 to 2 and includes 1 and 2.
  • the upper limit and the lower limit may be any combination of ranges.
  • the ⁇ fluorescence intensity of the reaction solution (fluorescence intensity at the end of the reaction (60 minutes) ⁇ fluorescence intensity before the start of the reaction (0 minutes)) was used to evaluate the enzyme activity.
  • a group to which no test compound was added was used as a control.
  • the inhibitory activity of each test compound was evaluated with the enzyme activity ( ⁇ fluorescence intensity) of Control as 1.
  • the BACE activity shown in FIGS. 1 and 2 is a relative value of the BACE activity of the test compound ( ⁇ fluorescence intensity of the reaction solution to which the test compound was added) when the BACE activity of the control ( ⁇ fluorescence intensity of the control) is set to 1. be.

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Abstract

The purpose of the present invention is to provide a composition for minimizing the production and/or accumulation of amyloid β. The present invention relates to a composition for minimizing the production and/or accumulation of amyloid β, said composition comprising, as an active ingredient, at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys), and salts thereof.

Description

アミロイドβの産生抑制及び／又は蓄積抑制用組成物Composition for suppressing production and/or accumulation of amyloid β
本発明は、アミロイドβの産生抑制及び／又は蓄積抑制用組成物等に関する。 The present invention relates to a composition for suppressing production and/or accumulation of amyloid β, and the like.
アミロイドβ（Ａβ）は、脳内で産生されるタンパク質の一種である。アミロイドβが凝集してオリゴマー化又は線維化すると、神経細胞毒性を示す。また、凝集したアミロイドβは脳から排出されずに蓄積し、アルツハイマー病発症の引き金になると考えられている。従って、アミロイドβの産生又は蓄積を抑制することは、例えば、アルツハイマー病の予防又は病気の進行の抑制に有効であると考えられる。 Amyloid β (Aβ) is a type of protein produced in the brain. When amyloid β aggregates to oligomerize or fibrillate, it exhibits neuronal toxicity. In addition, aggregated amyloid β accumulates without being discharged from the brain, and is thought to trigger the onset of Alzheimer's disease. Therefore, suppressing the production or accumulation of amyloid β is considered effective, for example, in preventing Alzheimer's disease or in suppressing progression of the disease.
アルツハイマー病の症状を改善する医薬品として、アセチルコリンエステラーゼ阻害剤が知られている。アセチルコリンエステラーゼの阻害は、脳内におけるアセチルコリン量を増加させ、認知機能低下の進行の抑制に有効である。しかしながら、アセチルコリンエステラーゼ阻害によって、アミロイドβの産生を抑制したり、蓄積したアミロイドβを除去したりすることはできない。飲食品等として日常的に摂取することができ、アミロイドβの産生又は蓄積を抑制することができる物質が求められている。 Acetylcholinesterase inhibitors are known as drugs that improve symptoms of Alzheimer's disease. Inhibition of acetylcholinesterase increases the amount of acetylcholine in the brain and is effective in suppressing the progression of cognitive decline. However, acetylcholinesterase inhibition cannot suppress the production of amyloid β or remove accumulated amyloid β. There is a demand for a substance that can be ingested on a daily basis as food or drink, etc., and that can suppress the production or accumulation of amyloid β.
一方、環状ジペプチドが脳機能に影響を与えることが報告されている。特許文献１には、Ｃｙｃｌｏ（Ｇｌｙ－Ｐｒｏ）を含有する、認知機能の低下抑制及び／又は改善剤が記載されている。 On the other hand, cyclic dipeptides have been reported to affect brain function. Patent Document 1 describes an agent for suppressing and/or improving cognitive function decline containing Cyclo (Gly-Pro).
特開２０２０－１９６６８６号公報JP 2020-196686 A
本発明は、アミロイドβの産生抑制及び／又は蓄積抑制用組成物を提供することを目的とする。 An object of the present invention is to provide a composition for suppressing the production and/or accumulation of amyloid β.
本発明者らは、上記課題に鑑み鋭意研究した結果、環状ジペプチドであるシクロロイシルフェニルアラニン（Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ））、及び、シクロロイシルリジン（Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ））が、アミロイドβの産生抑制及び／又は蓄積抑制に有効であることを見出した。 The present inventors have made intensive studies in view of the above problems, and found that cyclic dipeptides cycloleucylphenylalanine (Cyclo(Leu-Phe)) and cycloleucyllysine (Cyclo(Leu-Lys)) are amyloid β found to be effective in suppressing the production and/or accumulation of
すなわち、本発明は、これに限定されるものではないが、以下のアミロイドβの産生抑制及び／又は蓄積抑制用組成物等に関する。
〔１〕Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種を有効成分として含む、アミロイドβの産生抑制及び／又は蓄積抑制用組成物。
〔２〕β－セクレターゼを阻害することによりアミロイドβの産生及び／又は蓄積を抑制する、上記〔１〕に記載の組成物。
〔３〕上記組成物が、経口用である、上記〔１〕又は〔２〕に記載の組成物。
〔４〕上記組成物が、飲食品又は医薬品である、上記〔１〕～〔３〕のいずれかに記載の組成物。
〔５〕上記組成物が、「認知機能を高める」、「認知機能の低下を抑える」、「認知機能を良好に保つ」、「記憶力を高める」、「記憶力の低下を抑える」、「記憶力を良好に保つ」、「記憶の精度を高める」、「記憶障害を予防する」、「記憶障害を改善する」、「認知機能の一部である記憶力を維持する」、「記憶力の低下が気になる方に適した機能」、「認知機能の一部である記憶力の精度や判断の正確さを向上させる」、「記憶の保持又は統合を改善する」、「認知機能の強化を維持する」、「遂行機能を改善する」、「注意力と集中力を促進する」、「学習能力を改善する」、「見当識を維持・改善する」「加齢に伴う認知機能低下を遅延する」、「短期及び長期記憶を強化する」、「言語的及び視空間記憶を促進する」及び「論理的思考力を維持・改善する」からなる群より選択される１又は２以上の機能の表示を付されたものである、上記〔１〕～〔４〕のいずれかに記載の組成物。
〔６〕アミロイドβの産生抑制及び／又は蓄積抑制用組成物の製造における、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種の使用。
〔７〕アミロイドβの産生抑制及び／又は蓄積抑制のための、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種の使用。 That is, the present invention relates to, but is not limited to, the following compositions for suppressing production and/or accumulation of amyloid β.
[1] A composition for suppressing the production and/or accumulation of amyloid β, comprising as an active ingredient at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof.
[2] The composition of [1] above, which suppresses the production and/or accumulation of amyloid β by inhibiting β-secretase.
[3] The composition according to [1] or [2] above, which is for oral use.
[4] The composition according to any one of [1] to [3] above, wherein the composition is a food or drink or a pharmaceutical.
[5] The composition "enhances cognitive function", "suppresses decline in cognitive function", "maintains good cognitive function", "enhances memory", "suppresses decline in memory", "improves memory "maintaining good memory", "improving memory accuracy", "preventing memory impairment", "improving memory impairment", "maintaining memory as a part of cognitive function", and "preventing memory loss" functions that are suitable for people to become,""improve memory accuracy and judgment accuracy, which are part of cognitive function", "improve memory retention or consolidation", "maintain enhanced cognitive function", "improves executive function", "promotes attention and concentration", "improves learning ability", "maintains and improves orientation", "delays age-related cognitive decline", " labeled with one or more functions selected from the group consisting of "strengthening short-term and long-term memory", "promoting verbal and visuospatial memory" and "maintaining/improving logical thinking ability" The composition according to any one of [1] to [4] above.
[6] Use of at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof in the production of a composition for inhibiting the production and/or accumulation of amyloid β.
[7] Use of at least one selected from the group consisting of Cyclo (Leu-Phe), Cyclo (Leu-Lys) and salts thereof for suppressing production and/or accumulation of amyloid β.
本発明によれば、アミロイドβの産生抑制及び／又は蓄積抑制用組成物を提供することができる。本発明の組成物は、アミロイドβの産生抑制及び／又は蓄積抑制のための飲食品、医薬品等として使用することができる。 According to the present invention, a composition for suppressing the production and/or accumulation of amyloid β can be provided. The composition of the present invention can be used as foods, beverages, pharmaceuticals, etc. for suppressing the production and/or accumulation of amyloid β.
図１は、被験化合物非添加群（Ｃｏｎｔｒｏｌ）、Ｃｙｃｌｏ（Ｌｅｕ－Ａｌａ）（比較例１）及びＣｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）（実施例１～４）のβ－セクレターゼ（ＢＡＣＥ）阻害活性を示すグラフである。FIG. 1 is a graph showing the β-secretase (BACE) inhibitory activity of the test compound-free group (Control), Cyclo(Leu-Ala) (Comparative Example 1) and Cyclo(Leu-Phe) (Examples 1 to 4). is. 図２は、被験化合物非添加群（Ｃｏｎｔｒｏｌ）、Ｃｙｃｌｏ（Ｌｅｕ－Ａｌａ）（比較例１）及びＣｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）（実施例５）のβ－セクレターゼ（ＢＡＣＥ）阻害活性を示すグラフである。FIG. 2 is a graph showing the β-secretase (BACE) inhibitory activity of the test compound-free group (Control), Cyclo(Leu-Ala) (Comparative Example 1) and Cyclo(Leu-Lys) (Example 5). .
本発明のアミロイドβの産生抑制及び／又は蓄積抑制用組成物は、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種を含む。本発明のアミロイドβの産生抑制及び／又は蓄積抑制用組成物は、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種を有効成分として含む。本明細書中、本発明のアミロイドβの産生抑制及び／又は蓄積抑制用組成物を、本発明の組成物ということもある。本発明の組成物は、アミロイドβの産生を抑制するため、及び／又は、アミロイドβの蓄積を抑制するために使用されるものである。 The composition for suppressing production and/or accumulation of amyloid β of the present invention contains at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof. The composition for suppressing production and/or accumulation of amyloid β of the present invention contains at least one selected from the group consisting of Cyclo (Leu-Phe), Cyclo (Leu-Lys) and salts thereof as an active ingredient. . In the present specification, the composition for suppressing the production and/or accumulation of amyloid β of the present invention is sometimes referred to as the composition of the present invention. The composition of the present invention is used to suppress the production of amyloid β and/or the accumulation of amyloid β.
本発明において使用されるＣｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）（シクロロイシルフェニルアラニン）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）（シクロロイシルリジン）は、それぞれ、ロイシン及びフェニルアラニン、ロイシン及びリジンが縮合結合した構造を有する環状ジペプチドである。本明細書中、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）を、それぞれ、ＣＬＦ、ＣＬＫと記載することもある。
本明細書において「環状ジペプチド」とは、アミノ酸を構成単位とすることを特徴とし、Ｎ末端側アミノ酸のアミノ基とＣ末端側アミノ酸のカルボキシル基とが脱水縮合することにより生成したジケトピペラジン構造を有する化合物をいう。なお、本明細書において、環状ジペプチドのアミノ酸構成が同じであれば、それらの記載順序はいずれが先でも構わなく、例えば、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）とＣｙｃｌｏ（Ｐｈｅ－Ｌｅｕ）（シクロフェニルアラニルロイシン）とは同じ環状ジペプチドを表す。Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）とＣｙｃｌｏ（Ｌｙｓ－Ｌｅｕ）（シクロリジルロイシン）とは同じ環状ジペプチドを表す。 Cyclo (Leu-Phe) (cycloleucylphenylalanine) and Cyclo (Leu-Lys) (cycloleucyllysine) used in the present invention are cyclic having a structure in which leucine and phenylalanine, leucine and lysine are condensed, respectively. It is a dipeptide. In this specification, Cyclo(Leu-Phe) and Cyclo(Leu-Lys) are sometimes referred to as CLF and CLK, respectively.
As used herein, the term "cyclic dipeptide" is characterized by having amino acids as constituent units, and is a diketopiperazine structure produced by dehydration condensation between the amino group of the N-terminal side amino acid and the carboxyl group of the C-terminal side amino acid. A compound having In this specification, as long as the amino acid constitution of the cyclic dipeptides is the same, it does not matter which order they are listed. Leucine) represents the same cyclic dipeptide. Cyclo(Leu-Lys) and Cyclo(Lys-Leu) (cyclolysylleucine) represent the same cyclic dipeptide.
ＣＬＦ、ＣＬＫの塩としては、薬理学的に許容される塩又は飲食品に許容される塩であれば特に限定されず、酸性塩及び塩基性塩のいずれであってもよい。酸性塩として、例えば、塩酸塩、硫酸塩、硝酸塩、リン酸塩等の無機酸塩；酢酸塩、クエン酸塩、マレイン酸塩、リンゴ酸塩、シュウ酸塩、乳酸塩、コハク酸塩、フマル酸塩、プロピオン酸塩等の有機酸塩等が挙げられる。塩基性塩として、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩等が挙げられる。環状ジペプチドの塩は、当該分野で公知の任意の方法により、当業者によって容易に調製され得る。 Salts of CLF and CLK are not particularly limited as long as they are pharmacologically acceptable salts or salts acceptable for food and drink, and may be either acidic salts or basic salts. Acid salts include, for example, inorganic salts such as hydrochlorides, sulfates, nitrates, phosphates; Examples include organic acid salts such as acid salts and propionate salts. Examples of basic salts include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; Salts of cyclic dipeptides can be readily prepared by those skilled in the art by any method known in the art.
ＣＬＦ、ＣＬＫ及びこれらの塩の由来及び製造方法は特に制限されない。ＣＬＦ、ＣＬＫ又はこれらの塩は、公知の方法に従って製造することができる。ＣＬＦ、ＣＬＫ及びこれらの塩は、天然物由来のものであってもよく、人工的に合成したものであってもよく、酵素法又は微生物発酵法により製造されてもよく、直鎖状ジペプチドを脱水及び環化させることによって合成されてもよい。例えば、コラーゲン加水分解物などのタンパク質加水分解物を加熱して、ＣＬＦ、ＣＬＫ等の環状ジペプチドを豊富に含むペプチド熱処理物を得ることができる。
ＣＬＦ、ＣＬＫ及びこれらの塩は、これを含むタンパク質加水分解物又はその熱処理物を使用して組成物に配合してもよいし、タンパク質加水分解物若しくはその熱処理物の濃縮物、乾燥粉末又は精製度を高めたものを使用して組成物に配合してもよい。本発明の組成物は、例えば、タンパク質加水分解物又はその熱処理物を含有し、ＣＬＦ、ＣＬＫ及びこれらの塩は、タンパク質加水分解物又はその熱処理物の一部であってもよい。ＣＬＦ、ＣＬＫ及びこれらの塩は、市販品を使用することもできる。 The origin and production method of CLF, CLK and salts thereof are not particularly limited. CLF, CLK or salts thereof can be produced according to known methods. CLF, CLK and salts thereof may be derived from natural products, may be artificially synthesized, may be produced by an enzymatic method or a microbial fermentation method, and may be produced by a linear dipeptide. It may be synthesized by dehydration and cyclization. For example, protein hydrolysates such as collagen hydrolysates can be heated to obtain heat-treated peptides rich in cyclic dipeptides such as CLF and CLK.
CLF, CLK and salts thereof may be incorporated into compositions using protein hydrolysates containing them or heat treated products thereof, or concentrates, dry powders or purified protein hydrolysates or heat treated products thereof. Higher degrees may be used and incorporated into the composition. The composition of the present invention contains, for example, a protein hydrolyzate or heat-treated product thereof, and CLF, CLK and salts thereof may be part of the protein hydrolyzate or heat-treated product thereof. Commercially available products can also be used for CLF, CLK and salts thereof.
アミロイドβは、アミロイドβタンパク質、アミロイドβペプチド又はβアミロイドと呼ばれることもあるペプチドである。アミロイドβは、通常、４０個前後のアミノ酸からなるペプチドであり、アミロイドβ１－４２、アミロイドβ１－４０等が挙げられる。
非会合状態のアミロイドβは、アミロイドβモノマーと呼ばれることもある。アミロイドβは、２位個以上で凝集体を形成していてもよい。アミロイドβは、例えば、アミロイドβが２個以上（例えば２～５０個）凝集した可溶性凝集体（アミロイドβオリゴマー）を形成していてもよい。アミロイドβオリゴマーとして、アミロイドβ１－４２オリゴマー、アミロイドβ１－４０オリゴマー等が挙げられる。本発明におけるアミロイドβには、非会合状態のアミロイドβ、オリゴマー等の凝集体を形成しているアミロイドβが含まれる。 Amyloid-β is a peptide sometimes referred to as amyloid-β protein, amyloid-β peptide or β-amyloid. Amyloid β is usually a peptide consisting of around 40 amino acids, and includes amyloid β 1-42 , amyloid β 1-40 and the like.
Unassociated amyloid-β is sometimes referred to as amyloid-β monomer. Amyloid β may form an aggregate with two or more positions. Amyloid β may form, for example, a soluble aggregate (amyloid β oligomer) in which two or more (eg, 2 to 50) amyloid β aggregates. Amyloid β oligomers include amyloid β 1-42 oligomers, amyloid β 1-40 oligomers, and the like. Amyloid β in the present invention includes non-aggregated amyloid β and amyloid β forming aggregates such as oligomers.
アミロイドβは、アミロイドβ前駆体タンパク質（ＡＰＰ）が、β－セクレターゼ及びγ－セクレターゼによって２段階で切断されて生成する。β－セクレターゼは、アミロイドβ産生の律速酵素であり、その切断が総アミロイドβ産生量を規定している。このため、β－セクレターゼを阻害することによって、アミロイドβの産生を抑制することができ、アミロイドβの蓄積を抑制することができる。 Amyloid β is produced by the two-step cleavage of amyloid β precursor protein (APP) by β-secretase and γ-secretase. β-Secretase is the rate-limiting enzyme for amyloid β production, and its cleavage regulates the total amyloid β production. Therefore, by inhibiting β-secretase, the production of amyloid β can be suppressed, and the accumulation of amyloid β can be suppressed.
ＣＬＦ、ＣＬＫ及びこれらの塩は、β－セクレターゼ阻害作用を有する。本発明の組成物は、β－セクレターゼを阻害することにより、アミロイドβの産生を抑制するため、及び／又は、蓄積を抑制するために使用することができる。ＣＬＦ、ＣＬＫ及びこれらの塩は、β－セクレターゼ阻害のための有効成分として有用である。ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を含む、β－セクレターゼ阻害用組成物も本発明に包含される。
一態様において、本発明の組成物は、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）又はその塩を有効成分として含むものであってよい。また、別の一態様において、本発明の組成物は、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）又はその塩を有効成分として含むものであってよい。 CLF, CLK and salts thereof have β-secretase inhibitory action. The composition of the present invention can be used to suppress the production and/or accumulation of amyloid β by inhibiting β-secretase. CLF, CLK and salts thereof are useful as active ingredients for β-secretase inhibition. The present invention also includes a β-secretase inhibitory composition containing at least one selected from the group consisting of CLF, CLK and salts thereof.
In one aspect, the composition of the present invention may contain Cyclo(Leu-Phe) or a salt thereof as an active ingredient. In another aspect, the composition of the present invention may contain Cyclo(Leu-Lys) or a salt thereof as an active ingredient.
本発明の組成物は、脳内におけるアミロイドβの産生抑制及び／又は蓄積抑制のために使用することができる。一態様において、本発明の組成物は、β－セクレターゼを阻害することにより、アミロイドβの産生を抑制及び／又は蓄積を抑制するために使用することができる。 The composition of the present invention can be used to suppress the production and/or accumulation of amyloid β in the brain. In one aspect, the composition of the present invention can be used to suppress the production and/or accumulation of amyloid β by inhibiting β-secretase.
一態様において、本発明の組成物は、アミロイドβの蓄積に関連する状態又は疾患、好ましくは、脳におけるアミロイドβの蓄積に関連する状態又は疾患の予防又は改善のために使用することができる。このような状態又は疾患として、アミロイドβの蓄積を伴う又はアミロイドβの蓄積に起因する状態又は疾患が挙げられる。脳におけるアミロイドβの蓄積を伴う又はアミロイドβの蓄積に起因する状態又は疾患として、例えば、アルツハイマー病（アルツハイマー型認知症を含む）、軽度認知障害等が挙げられる。
本発明の組成物は、上記の状態又は疾患を予防又は改善するために使用することができ、上記の状態又は疾患の予防に好適に使用することができる。
本明細書において、状態又は疾患の予防は、発症を防止すること、発症を遅延させること、発症率を低下させること、発症のリスクを軽減すること等を包含する。状態又は疾患の改善は、対象を状態又は疾患から回復させること、状態又は疾患の症状を軽減すること、状態又は疾患の症状を好転させること、状態又は疾患の進行を遅延させること、防止すること等を包含する。 In one aspect, the composition of the present invention can be used for the prevention or amelioration of a condition or disease associated with amyloid β accumulation, preferably a condition or disease associated with amyloid β accumulation in the brain. Such conditions or diseases include conditions or diseases associated with or caused by amyloid-β accumulation. Conditions or diseases associated with or resulting from accumulation of amyloid β in the brain include, for example, Alzheimer's disease (including Alzheimer's dementia), mild cognitive impairment, and the like.
The composition of the present invention can be used to prevent or ameliorate the above conditions or diseases, and can be preferably used for the prevention of the above conditions or diseases.
As used herein, prevention of a condition or disease includes preventing onset, delaying onset, reducing the rate of onset, reducing risk of onset, and the like. Ameliorating a condition or disease includes ameliorating the subject from the condition or disease, alleviating symptoms of the condition or disease, ameliorating symptoms of the condition or disease, slowing progression of the condition or disease, preventing the condition or disease. etc.
アルツハイマー病及び軽度認知障害では、認知機能が低下することが知られている。アルツハイマー病、軽度認知障害における認知機能低下の症状として、例えば、記憶力低下、記憶障害（物忘れ）、失語（ものの名前が出にくくなる）、失行、失認（よく知っているはずの場所で道に迷う等）、見当識（場所、時間、人の名前など、自分が置かれた状況を正しく認識する能力）の低下、言語及び非言語学習能力の低下、聴覚及び視覚処理の低下、遂行機能低下、遂行機能障害（計画を立てて物事を行うことができなくなる）、集中力低下、注意力低下、判断力低下、空間認識力低下、認知柔軟性低下、情報処理速度低下等が挙げられる。アミロイドβの産生又は蓄積を抑制することによって、認知機能低下の予防又は認知機能の改善効果、例えば、上記の症状の予防又は改善効果が得られることが期待できる。 Cognitive function is known to decline in Alzheimer's disease and mild cognitive impairment. Symptoms of cognitive decline in Alzheimer's disease and mild cognitive impairment include, for example, memory loss, memory impairment (forgetfulness), aphasia (difficult to name things), apraxia, agnosia (walking in familiar places). (e.g., getting lost), decreased orientation (the ability to correctly recognize one's own situation, such as place, time, name of person, etc.), decreased verbal and non-verbal learning ability, decreased auditory and visual processing, executive function executive dysfunction (inability to plan and do things), decreased ability to concentrate, decreased attention, decreased judgment, decreased spatial awareness, decreased cognitive flexibility, decreased information processing speed, etc. By suppressing the production or accumulation of amyloid β, it can be expected that a preventive effect on cognitive function decline or an improving effect on cognitive function, for example, an effect on preventing or improving the above symptoms can be obtained.
本発明の組成物は、治療的用途（医療用途）又は非治療的用途（非医療用途）のいずれにも適用することができる。非治療的とは、医療行為、すなわち人間の手術、治療又は診断を含まない概念である。
本発明のアミロイドβの産生抑制及び／又は蓄積抑制用組成物は、一例として、剤の形態で提供することができるが、本形態に限定されるものではない。当該剤をそのまま組成物として、又は、当該剤を含む組成物として提供することもできる。一態様において、本発明のアミロイドβの産生抑制及び／又は蓄積抑制用組成物は、アミロイドβの産生抑制及び／又は蓄積抑制剤ということもできる。β－セクレターゼ阻害用組成物は、β－セクレターゼ阻害剤ということもできる。 The compositions of the present invention can be applied for either therapeutic use (medical use) or non-therapeutic use (non-medical use). Non-therapeutic is a concept that does not involve medical intervention, i.e. human surgery, treatment or diagnosis.
The composition for suppressing production and/or accumulation of amyloid β of the present invention can be provided in the form of an agent as an example, but is not limited to this form. The agent itself can be provided as a composition, or a composition containing the agent can be provided. In one aspect, the composition for suppressing the production and/or accumulation of amyloid β of the present invention can also be said to be an agent for suppressing the production and/or accumulation of amyloid β. A β-secretase inhibitory composition can also be referred to as a β-secretase inhibitor.
本発明の組成物は、経口用又は非経口用のいずれであってもよい。本発明の組成物は、好ましくは経口用組成物である。本発明の組成物は、例えば、飲食品、医薬品、医薬部外品、飼料等の形態とすることができ、飲食品又は医薬品が好ましい。本発明の組成物は、飲食品、医薬品、医薬部外品、飼料等に添加して使用することもできる。本発明の組成物の形態は特に限定されず、固体状（例えば、粉末状、顆粒状、タブレット状等）、液状、ペースト状等のいずれであってもよい。 The compositions of the invention may be either oral or parenteral. The compositions of the invention are preferably oral compositions. The composition of the present invention can be in the form of, for example, foods, beverages, pharmaceuticals, quasi-drugs, feeds, etc. Foods, beverages, or pharmaceuticals are preferred. The composition of the present invention can also be used by adding it to foods and beverages, pharmaceuticals, quasi-drugs, feeds, and the like. The form of the composition of the present invention is not particularly limited, and may be solid (for example, powder, granule, tablet, etc.), liquid, paste, or the like.
本発明の組成物は、ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を含み、更に飲食品又は医薬品等への添加物として許容されている各種の希釈剤、酸味料、抗酸化剤、安定剤、保存料、香料、乳化剤、色素類、調味料、ｐＨ調整剤、栄養強化剤等が添加されていてもよい。 The composition of the present invention contains at least one selected from the group consisting of CLF, CLK, and salts thereof, and various diluents, acidulants, acidulants, Antioxidants, stabilizers, preservatives, fragrances, emulsifiers, pigments, seasonings, pH adjusters, nutritional enhancers and the like may be added.
例えば、本発明の組成物を飲食品とする場合、ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種に、飲食品に使用可能な成分（例えば、食品素材、必要に応じて使用される食品添加物等）を配合して、種々の飲食品とすることができる。飲食品は特に限定されず、例えば、一般的な飲食品、健康食品、機能性表示食品、特定保健用食品、健康補助食品、病者用食品等が挙げられる。上記健康食品、機能性表示食品、特定保健用食品、健康補助食品等は、例えば、液剤、細粒剤、錠剤、顆粒剤、散剤、カプセル剤、チュアブル剤、ドライシロップ剤、流動食等の各種製剤形態として使用することができる。 For example, when the composition of the present invention is used as a food or drink, at least one selected from the group consisting of CLF, CLK and salts thereof may be added to ingredients that can be used for food and drink (e.g., food materials, if necessary food additives, etc.) can be blended into various foods and drinks. Food and drink are not particularly limited, and examples thereof include general food and drink, health food, food with function claims, food for specified health use, health supplement, and food for the sick. Health foods, foods with function claims, foods for specified health uses, health supplements, etc. are various formulations such as liquids, fine granules, tablets, granules, powders, capsules, chewable formulations, dry syrups, and liquid diets. Can be used as a form.
本発明の組成物を医薬品又は医薬部外品とする場合、ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種に、薬理学的に許容される担体、必要に応じて添加される添加剤等を配合して、各種剤形の医薬品又は医薬部外品とすることができる。そのような担体、添加剤等は、医薬品又は医薬部外品に使用可能な、薬理学的に許容されるものであればよく、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、抗酸化剤、着色剤等の１又は２以上が挙げられる。医薬品又は医薬部外品の投与（摂取）形態としては、経口又は非経口（経皮、経粘膜、経腸、注射等）投与の形態が挙げられる。本発明の組成物を医薬品又は医薬部外品とする場合、経口用医薬品又は経口用医薬部外品とすることが好ましい。経口投与のための剤形としては、例えば、液剤、錠剤、散剤、細粒剤、顆粒剤、糖衣錠、カプセル剤、懸濁液、乳剤、チュアブル剤等が挙げられる。非経口投与のための剤形としては、例えば、注射剤、点滴剤、軟膏剤、ローション剤、貼付剤、坐剤、経鼻剤、経肺剤（吸入剤）等が挙げられる。医薬品は、非ヒト動物用医薬であってもよい。 When the composition of the present invention is used as a drug or quasi-drug, it is added to at least one selected from the group consisting of CLF, CLK and salts thereof, a pharmacologically acceptable carrier, and if necessary It is possible to prepare pharmaceuticals or quasi-drugs in various dosage forms by blending additives and the like. Such carriers, additives, etc. may be those that can be used for pharmaceuticals or quasi-drugs and are pharmacologically acceptable. One or more of antioxidants, coloring agents and the like can be mentioned. Examples of administration (ingestion) forms of pharmaceuticals or quasi-drugs include oral or parenteral (transdermal, transmucosal, enteral, injection, etc.) forms of administration. When the composition of the present invention is used as a drug or quasi-drug, it is preferably an oral drug or oral quasi-drug. Dosage forms for oral administration include, for example, liquids, tablets, powders, fine granules, granules, dragees, capsules, suspensions, emulsions, chewables and the like. Dosage forms for parenteral administration include, for example, injections, drops, ointments, lotions, patches, suppositories, nasal preparations, pulmonary preparations (inhalants) and the like. The pharmaceutical may be a non-human veterinary pharmaceutical.
本発明の組成物を飼料とする場合には、ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を飼料に配合すればよい。飼料には飼料添加剤も含まれる。飼料としては、例えば、牛、豚、鶏、羊、馬等に用いる家畜用飼料；ウサギ、ラット、マウス等に用いる小動物用飼料；犬、猫、小鳥等に用いるペットフードなどが挙げられる。 When the composition of the present invention is used as feed, at least one selected from the group consisting of CLF, CLK and salts thereof may be added to the feed. Feed also includes feed additives. Examples of feeds include livestock feeds for cows, pigs, chickens, sheep, horses, etc.; small animal feeds for rabbits, rats, mice, etc.; pet foods for dogs, cats, small birds, etc.;
本発明の組成物を、例えば、飲食品、医薬品、医薬部外品、飼料等とする場合、その製造方法は特に限定されず、ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を用いて、一般的な方法により製造することができる。 For example, when the composition of the present invention is used as a food or drink, a drug, a quasi-drug, a feed, etc., the production method is not particularly limited, and at least one selected from the group consisting of CLF, CLK and salts thereof It can be produced by a general method using seeds.
一態様において、本発明の組成物は、液状組成物であることが好ましく、飲料であることがより好ましい。飲料は、例えば、機能性飲料であってよい。飲料の形態は特に限定されず、容器詰飲料であってよい。容器詰飲料の容器は特に限定されず、いずれの形態及び材質の容器を用いてもよく、例えば、アルミ缶、スチール缶等の金属製容器；ペットボトル等の樹脂製容器；紙パック等の紙容器；ガラス瓶等のガラス製容器；樽等の木製容器等の通常用いられる容器のいずれも用いることができる。このような容器に飲料を充填及び密閉することにより、容器詰飲料が得られる。 In one aspect, the composition of the present invention is preferably a liquid composition, more preferably a beverage. The beverage may be, for example, a functional beverage. The form of the beverage is not particularly limited, and may be a packaged beverage. Containers for packaged beverages are not particularly limited, and containers of any shape and material may be used. For example, metal containers such as aluminum cans and steel cans; resin containers such as PET bottles; Containers; glass containers such as glass bottles; and wooden containers such as barrels. Any of commonly used containers can be used. A packaged beverage is obtained by filling and sealing such a container with a beverage.
本発明の組成物に含まれるＣＬＦ、ＣＬＫ及びこれらの塩の合計の含有量は特に限定されず、その形態等に応じて設定することができる。
一態様において、本発明の組成物におけるＣＬＦ、ＣＬＫ及びこれらの塩の合計の含有量は、例えば、０．００００１重量％以上であってよく、０．０００１重量％以上が好ましく、０．００１重量％以上がより好ましく、０．０１重量％以上が更に好ましく、０．１重量％以上が特に好ましく、また、５０重量％以下が好ましい。一態様において、ＣＬＦ、ＣＬＫ及びこれらの塩の合計の含有量は、例えば、本発明の組成物中に０．００００１～２５重量％であってよく、０．０００１～１０重量％が好ましく、０．００１～５重量％がより好ましく、０．０１～５重量％が更に好ましく、０．１～１重量％が特に好ましい。
ＣＬＦ、ＣＬＫ及びこれらの塩は、例えば、液体クロマトグラフィー質量分析法（ＬＣ／ＭＳ）により公知の方法で定量することが可能である。 The total content of CLF, CLK and salts thereof contained in the composition of the present invention is not particularly limited, and can be set according to its form and the like.
In one aspect, the total content of CLF, CLK and salts thereof in the composition of the present invention may be, for example, 0.00001% by weight or more, preferably 0.0001% by weight or more, and 0.001% by weight. % or more, more preferably 0.01 wt% or more, particularly preferably 0.1 wt% or more, and preferably 50 wt% or less. In one aspect, the total content of CLF, CLK and salts thereof may be, for example, 0.00001 to 25% by weight, preferably 0.0001 to 10% by weight, and 0 0.001 to 5% by weight is more preferred, 0.01 to 5% by weight is even more preferred, and 0.1 to 1% by weight is particularly preferred.
CLF, CLK and salts thereof can be quantified by known methods, for example, liquid chromatography mass spectrometry (LC/MS).
本発明の組成物にＣＬＦ又はその塩が含まれる場合、その含有量は特に制限されないが、例えば、０．０００００１～２０重量％であることが好ましい。より好ましくは０．００００１～１０重量％であり、更に好ましくは０．０００１～５重量％であり、更により好ましくは０．００１～２重量％であり、特に好ましくは０．０１～１重量％である。 When the composition of the present invention contains CLF or a salt thereof, its content is not particularly limited, but is preferably 0.000001 to 20% by weight, for example. More preferably 0.00001 to 10% by weight, still more preferably 0.0001 to 5% by weight, still more preferably 0.001 to 2% by weight, particularly preferably 0.01 to 1% by weight is.
本発明の組成物にＣＬＫ又はその塩が含まれる場合、その含有量は特に制限されないが、例えば、０．００００１～２０重量％であることが好ましい。より好ましくは０．０００１～１０重量％であり、更に好ましくは０．００１～５重量％であり、更により好ましくは０．０１～２重量％であり、特に好ましくは０．０１～１重量％である。 When CLK or a salt thereof is contained in the composition of the present invention, its content is not particularly limited, but is preferably 0.00001 to 20% by weight, for example. More preferably 0.0001 to 10% by weight, still more preferably 0.001 to 5% by weight, still more preferably 0.01 to 2% by weight, particularly preferably 0.01 to 1% by weight is.
本発明の組成物は、経口で摂取（経口投与）されることが好ましい。本発明の組成物の投与量（摂取量ということもできる）は特に限定されない。本発明の組成物の投与量は、アミロイドβの産生抑制及び／又は蓄積抑制効果が得られるような量であればよく、投与形態、投与方法、対象の体重等に応じて適宜設定すればよい。本発明の組成物の投与量は、β－セクレターゼ阻害効果が得られるような量であることが好ましい。 The composition of the present invention is preferably taken orally (orally administered). There is no particular limitation on the dose (which can also be referred to as intake) of the composition of the present invention. The dosage of the composition of the present invention may be an amount that provides an effect of inhibiting the production and/or accumulation of amyloid β, and may be appropriately set according to the dosage form, administration method, body weight of the subject, and the like. . The dosage of the composition of the present invention is preferably such that a β-secretase inhibitory effect is obtained.
一態様において、本発明の組成物をヒト（成人）を対象に摂取させる又は投与する場合、その投与量は、ＣＬＦ、ＣＬＫ及びこれらの塩の合計の投与量（環状ジペプチド換算）として、１日あたり、好ましくは０．００１ｍｇ以上、より好ましくは０．０１ｍｇ以上、さらに好ましくは０．１ｍｇ以上、また、好ましくは５０００ｍｇ以下、より好ましくは１０００ｍｇ以下、さらに好ましくは１００ｍｇ以下である。一態様において、本発明の組成物をヒト（成人）に摂取させる又は投与する場合、ＣＬＦ、ＣＬＫ及びこれらの塩の合計の投与量として、１日あたり、好ましくは０．００１～５０００ｍｇ、より好ましくは０．０１～１０００ｍｇ、さらに好ましくは０．１～１００ｍｇである。
上記量を、１日１回以上、例えば、１日１回又は数回（例えば２～３回）に分けて、摂取又は投与することが好ましい。一態様においては、上記量のＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を、経口で摂取させる又は投与することが好ましい。ヒト（成人）の場合、１日当たり体重６０ｋｇ当たり上記量のＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を摂取させる又は投与することが好ましい。一態様において、本発明の組成物は、ヒトに、体重６０ｋｇあたり、１日あたり上記量のＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を摂取させる又は投与するための経口用組成物であってよい。 In one aspect, when the composition of the present invention is ingested or administered to a human (adult) subject, the dose is the total dose of CLF, CLK and salts thereof (converted to cyclic dipeptide) per day It is preferably 0.001 mg or more, more preferably 0.01 mg or more, still more preferably 0.1 mg or more, and preferably 5000 mg or less, more preferably 1000 mg or less, and still more preferably 100 mg or less. In one aspect, when the composition of the present invention is ingested or administered to humans (adults), the total dose of CLF, CLK and salts thereof is preferably 0.001 to 5000 mg, more preferably 0.001 to 5000 mg per day. is 0.01 to 1000 mg, more preferably 0.1 to 100 mg.
It is preferable to take or administer the above amount once or more a day, for example, once a day or divided into several times (eg, 2 to 3 times). In one aspect, it is preferable to orally ingest or administer at least one selected from the group consisting of CLF, CLK and salts thereof in the above amounts. For humans (adults), it is preferable to ingest or administer at least one selected from the group consisting of CLF, CLK and salts thereof in the above amount per 60 kg body weight per day. In one embodiment, the composition of the present invention is an oral composition for ingesting or administering at least one selected from the group consisting of CLF, CLK and salts thereof in the above amount per day per 60 kg body weight to humans. It may be a composition for
本発明の組成物は、継続して摂取又は投与されるものであることが好ましい。ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を継続的に摂取させる又は投与することによって、より高い効果が得られることが期待される。一態様において、本発明の組成物は、好ましくは１週間以上、より好ましくは４週間以上、さらに好ましくは８週間以上継続して摂取又は投与されることが好ましい。
ＣＬＦ、ＣＬＫ及びこれらの塩は、飲食品などとして摂取可能であり、安全性の観点から、例えば長期摂取することにも問題が少ないと考えられる。 The composition of the present invention is preferably taken or administered continuously. It is expected that continuous ingestion or administration of at least one selected from the group consisting of CLF, CLK and salts thereof will result in higher effects. In one aspect, the composition of the present invention is preferably taken or administered continuously for one week or longer, more preferably for four weeks or longer, and even more preferably for eight weeks or longer.
CLF, CLK and salts thereof can be ingested as foods and drinks, and from the viewpoint of safety, long-term ingestion is considered to pose little problem.
本発明の組成物を摂取させる又は投与する対象（投与対象ということもできる）は、特に限定されない。好ましくはヒト又は非ヒト哺乳動物であり、より好ましくはヒトである。
一態様において、本発明の組成物の投与対象として、アミロイドβの産生抑制及び／又は蓄積抑制を必要とする又は希望する対象、アミロイドβの蓄積に関連する状態又は疾患の予防又は改善を必要とする又は希望する対象等が挙げられる。一態様において、本発明における投与対象として、中高年者が挙げられる。中高年者は、高齢者を含む。中高年者は、例えば、４０歳以上のヒトであってよい。一態様において中高年者の中でも、対象として高齢者が好ましい。高齢者は、例えば、６０歳以上又は６５歳以上のヒトであってよい。一態様において、本発明の組成物の投与対象は、健常者であってよい。例えば、脳内におけるアミロイドβの産生抑制及び／又は蓄積抑制、脳内におけるアミロイドβの蓄積予防、アルツハイマー病又は軽度認知障害の予防等を目的として、健常者に対して使用することもできる。 Subjects to whom the composition of the present invention is ingested or administered (can also be referred to as administration subjects) are not particularly limited. Humans or non-human mammals are preferred, and humans are more preferred.
In one aspect, the subject to which the composition of the present invention is administered is a subject who needs or desires suppression of amyloid β production and/or accumulation, and a subject who needs prevention or improvement of a condition or disease associated with amyloid β accumulation. The subject etc. which do or desire are mentioned. In one aspect, administration subjects in the present invention include middle-aged and elderly people. Middle-aged and elderly people include elderly people. A middle-aged person may be, for example, a person over the age of 40. In one aspect, among middle-aged and elderly people, elderly people are preferred as subjects. A senior citizen may be, for example, a human over the age of 60 or over the age of 65. In one aspect, the subject of administration of the composition of the present invention may be a healthy subject. For example, it can be used in healthy individuals for the purpose of suppressing the production and/or accumulation of amyloid β in the brain, preventing the accumulation of amyloid β in the brain, preventing Alzheimer's disease or mild cognitive impairment, and the like.
本発明の組成物には、アミロイドβの産生抑制及び／又は蓄積抑制により発揮される機能の表示が付されていてもよい。このような表示は機能性表示ともいう。上記表示は、特に限定されない。このような表示として、例えば、「認知機能を高める」、「認知機能の低下を抑える」、「認知機能を良好に保つ」、「記憶力を高める」、「記憶力の低下を抑える」、「記憶力を良好に保つ」、「記憶の精度を高める」、「記憶障害を予防する」、「記憶障害を改善する」、「認知機能の一部である記憶力を維持する」、「記憶力の低下が気になる方に適した機能」、「認知機能の一部である記憶力の精度や判断の正確さを向上させる」、「記憶の保持又は統合を改善する」、「認知機能の強化を維持する」、「遂行機能を改善する」、「注意力と集中力を促進する」、「学習能力を改善する」、「見当識を維持・改善する」、「加齢に伴う認知機能低下を遅延する」、「短期及び長期記憶を強化する」、「言語的及び視空間記憶を促進する」、「論理的思考力を維持・改善する」及び、これらと同視できる表示又は機能性表示が挙げられる。
本発明の一態様において、本発明の組成物は、上記の表示が１又は２以上付された飲食品であることが好ましい。また上記の表示は、上記の機能を得るために上記組成物を用いる旨の表示であってもよい。当該表示は、組成物自体に付されてもよいし、組成物の容器又は包装に付されていてもよい。 The composition of the present invention may be labeled with a function exerted by suppressing the production and/or accumulation of amyloid β. Such indication is also called functionality indication. The display is not particularly limited. Such indications include, for example, "increases cognitive function", "suppresses deterioration of cognitive function", "maintains good cognitive function", "improves memory", "suppresses deterioration of memory", and "improves memory". "maintaining good memory", "improving memory accuracy", "preventing memory impairment", "improving memory impairment", "maintaining memory as a part of cognitive function", and "preventing memory loss" functions that are suitable for people to become,""improve memory accuracy and judgment accuracy, which are part of cognitive function", "improve memory retention or consolidation", "maintain enhanced cognitive function", "improves executive function", "promotes attention and concentration", "improves learning ability", "maintains and improves orientation", "delays age-related cognitive decline", Examples include "strengthening short-term and long-term memory", "promoting verbal and visuospatial memory", "maintaining/improving logical thinking ability", and indications or functional indications equivalent thereto.
In one aspect of the present invention, the composition of the present invention is preferably a food or drink labeled with one or more of the above labels. Moreover, the above indication may be an indication that the above composition is used to obtain the above functions. The label may be attached to the composition itself, or may be attached to the container or packaging of the composition.
本発明は、以下の方法及び使用も包含する。
Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種を投与する、アミロイドβの産生抑制及び／又は蓄積抑制方法。
Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種を投与する、β－セクレターゼ阻害方法。
アミロイドβの産生抑制及び／又は蓄積抑制のための、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種の使用。
β－セクレターゼを阻害するための、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種の使用。
上記方法は、治療的な方法であってもよく、非治療的な方法であってもよい。上記使用は、治療的な使用であってもよく、非治療的な使用であってもよい。 The invention also includes the following methods and uses.
A method for suppressing production and/or accumulation of amyloid β, comprising administering at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof.
A method for inhibiting β-secretase, comprising administering at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof.
Use of at least one selected from the group consisting of Cyclo (Leu-Phe), Cyclo (Leu-Lys) and salts thereof for suppressing production and/or accumulation of amyloid β.
Use of at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof for inhibiting β-secretase.
The method may be a therapeutic method or a non-therapeutic method. The use may be therapeutic use or non-therapeutic use.
一態様において、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）又はこれらの塩は、β－セクレターゼ阻害によって、アミロイドβの産生を抑制するため、及び／又は、蓄積を抑制するために使用することができる。 In one aspect, Cyclo(Leu-Phe), Cyclo(Leu-Lys), or salts thereof are used to suppress the production and/or accumulation of amyloid β by inhibiting β-secretase. be able to.
上記方法及び使用においては、１日に１回以上、例えば、１日１回～数回（例えば２～３回）、ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を対象に摂取させる又は投与することが好ましい。上記の使用は、好ましくはヒト又は非ヒト哺乳動物、より好ましくはヒトにおける使用である。一態様において、ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種は、β－セクレターゼ阻害によって、アミロイドβの蓄積に関連する状態又は疾患を予防又は改善するために使用することができる。ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を投与する、アミロイドβの蓄積に関連する状態又は疾患の予防又は改善方法も本発明に包含される。 In the above method and use, at least one selected from the group consisting of CLF, CLK and salts thereof, once or more times a day, for example, once to several times (for example, 2 to 3 times) a day preferably ingested or administered to The above uses are preferably in humans or non-human mammals, more preferably in humans. In one aspect, at least one selected from the group consisting of CLF, CLK, and salts thereof can be used to prevent or improve conditions or diseases associated with amyloid β accumulation by inhibiting β-secretase. can. The present invention also encompasses a method for preventing or ameliorating a condition or disease associated with amyloid β accumulation, comprising administering at least one selected from the group consisting of CLF, CLK, and salts thereof.
上記方法及び使用においては、アミロイドβの産生抑制及び／又は蓄積抑制効果が得られる量（有効量ということもできる）のＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種を使用すればよい。上記有効量は、β－セクレターゼ阻害効果が得られるような量であることが好ましい。ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種の好ましい投与量、投与方法、投与対象等は上述した本発明の組成物と同じである。ＣＬＦ、ＣＬＫ又はこれらの塩は、そのまま摂取又は投与してもよく、これを含む組成物として摂取又は投与してもよい。例えば、本発明の組成物を摂取又は投与してもよい。 In the above method and use, at least one selected from the group consisting of CLF, CLK and salts thereof is used in an amount (can also be referred to as an effective amount) capable of suppressing the production and/or accumulation of amyloid β. do it. The effective amount is preferably an amount that provides a β-secretase inhibitory effect. Preferred doses, administration methods, administration subjects, etc. of at least one selected from the group consisting of CLF, CLK and salts thereof are the same as those of the composition of the present invention described above. CLF, CLK, or salts thereof may be taken or administered as they are, or may be taken or administered as a composition containing them. For example, a composition of the invention may be ingested or administered.
ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種は、アミロイドβの産生抑制及び／又は蓄積抑制のために使用される飲食品、医薬品、医薬部外品、飼料等の製造のために使用することができる。一態様において、本発明は、アミロイドβの産生抑制及び／又は蓄積抑制用組成物の製造における、ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種の使用、も包含する。本発明は、β－セクレターゼ阻害用組成物の製造における、ＣＬＦ、ＣＬＫ又はこれらの塩の使用、も包含する。
ＣＬＦ、ＣＬＫ及びこれらの塩からなる群より選択される少なくとも１種は、アミロイドβの蓄積に関連する状態又は疾患の予防又は改善用組成物の製造のために使用することができる。 At least one selected from the group consisting of CLF, CLK and salts thereof is used for the production of foods and drinks, pharmaceuticals, quasi-drugs, feeds, etc. used for suppressing the production and / or accumulation of amyloid β. can be used for In one aspect, the present invention also includes use of at least one selected from the group consisting of CLF, CLK and salts thereof in the production of a composition for suppressing the production and/or accumulation of amyloid β. The present invention also includes the use of CLF, CLK or salts thereof in the manufacture of compositions for inhibiting β-secretase.
At least one selected from the group consisting of CLF, CLK and salts thereof can be used for the production of a composition for preventing or improving conditions or diseases associated with amyloid β accumulation.
本明細書において下限値と上限値によって表されている数値範囲、即ち「下限値～上限値」は、それら下限値及び上限値を含む。例えば、「１～２」により表される範囲は、１以上２以下を意味し、１及び２を含む。本明細書において、上限及び下限は、いずれの組み合わせによる範囲としてもよい。 Numerical ranges represented by lower and upper limits herein, ie, "lower and upper limits", include these lower and upper limits. For example, a range represented by "1-2" means from 1 to 2 and includes 1 and 2. In this specification, the upper limit and the lower limit may be any combination of ranges.
以下、本発明を実施例によりさらに詳しく説明するが、これにより本発明の範囲を限定するものではない。 EXAMPLES The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited by these examples.
＜実施例１～５及び比較例１＞
（β－セクレターゼ阻害活性を有する化合物の評価）
材料と方法
シクロロイシルアラニン（Ｃｙｃｌｏ（Ｌｅｕ－Ａｌａ））(以下、ＣＬＡともいう。)、シクロロイシルフェニルアラニン（Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ））及びシクロロイシルリジン（Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ））のβセクレターゼ阻害活性を調べた。なお、被験化合物としてのＣｙｃｌｏ（Ｌｅｕ－Ａｌａ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）はＢａｃｈｅｍ社から、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）は株式会社ペプチド研究所から購入した。
β－セクレターゼ阻害活性の評価には、市販のキットＢｅｔａ　Ｓｅｃｒｅｔａｓｅ　（ＢＡＣＥ１）　Ａｃｔｉｖｉｔｙ　Ａｓｓａｙ　Ｋｉｔ（ａｂｃａｍ）を用いた。キットに記載の方法に従って、β－セクレターゼ酵素活性の阻害効果を評価した。
９６　Ｗｅｌｌ　Ｐｌａｔｅ（Ｃｏｒｎｉｎｇ）上でサンプル液（被験化合物溶液）と酵素液を混合した後、３７℃で１０分間プレインキュベートした。その後、基質液を添加し、３７℃で６０分間反応させた。反応開始後０分から６０分まで５分ごとに、マイクロプレートリーダー　ＦｌｅｘＳｔａｔｉｏｎ　３（Ｍｏｌｅｃｕｌａｒ　Ｄｅｖｉｃｅｓ）で、反応液の蛍光強度（ＲＦＵ）（Ｅｘ／Ｅｍ＝３３５ｎｍ／４９５ｎｍ）を測定した。ｎ＝２で反応を行い、反応液の蛍光強度の平均値を測定値とした。
評価における各被験化合物の濃度（最終濃度）は、表１の通りとして実施した。 <Examples 1 to 5 and Comparative Example 1>
(Evaluation of compounds having β-secretase inhibitory activity)
Materials and Method β-secretase inhibitory activity was examined. Cyclo (Leu-Ala) and Cyclo (Leu-Phe) as test compounds were purchased from Bachem, and Cyclo (Leu-Lys) was purchased from Peptide Institute.
A commercially available kit, Beta Secretase (BACE1) Activity Assay Kit (abcam), was used to evaluate the β-secretase inhibitory activity. The inhibitory effect on β-secretase enzymatic activity was evaluated according to the method described in the kit.
After mixing the sample solution (test compound solution) and the enzyme solution on a 96 Well Plate (Corning), the mixture was preincubated at 37°C for 10 minutes. After that, a substrate solution was added and reacted at 37° C. for 60 minutes. The fluorescence intensity (RFU) (Ex/Em=335 nm/495 nm) of the reaction solution was measured with a microplate reader FlexStation 3 (Molecular Devices) every 5 minutes from 0 to 60 minutes after the start of the reaction. The reaction was performed with n=2, and the average fluorescence intensity of the reaction solution was used as the measured value.
The concentration (final concentration) of each test compound in the evaluation was carried out as shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
酵素活性の評価には反応液のΔ蛍光強度（反応終了時の蛍光強度（６０分）－反応開始前蛍光強度（０分））を使用した。被験化合物非添加群をＣｏｎｔｒｏｌとした。各被験化合物の阻害活性は、Ｃｏｎｔｒｏｌの酵素活性（Δ蛍光強度）を１として評価を行った。 The Δ fluorescence intensity of the reaction solution (fluorescence intensity at the end of the reaction (60 minutes)−fluorescence intensity before the start of the reaction (0 minutes)) was used to evaluate the enzyme activity. A group to which no test compound was added was used as a control. The inhibitory activity of each test compound was evaluated with the enzyme activity (Δ fluorescence intensity) of Control as 1.
結果
図１、２は、被験化合物のβ－セクレターゼ（ＢＡＣＥ）阻害活性を示すグラフである。
結果は、平均±標準偏差（ｎ＝２）で示した。図１、２に示すＢＡＣＥ活性は、ＣｏｎｔｒｏｌのＢＡＣＥ活性（ＣｏｎｔｒｏｌのΔ蛍光強度）を１とした場合の、被験化合物のＢＡＣＥ活性（被験化合物を添加した反応液のΔ蛍光強度）の相対値である。
比較例１として測定したシクロロイシルアラニン（Ｃｙｃｌｏ（Ｌｅｕ－Ａｌａ））では阻害活性が確認されなかったが、シクロロイシルフェニルアラニン（Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ））（実施例１～４）及びシクロロイシルリジン（Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ））（実施例５）について、β－セクレターゼの酵素活性の低下が確認された。
以上の結果より、環状ジペプチドであるＣｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）及びＣｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）がβ－セクレターゼ阻害活性を有していることが明らかになった。

  Results FIGS. 1 and 2 are graphs showing the β-secretase (BACE) inhibitory activity of test compounds.
Results are shown as mean±standard deviation (n=2). The BACE activity shown in FIGS. 1 and 2 is a relative value of the BACE activity of the test compound (Δ fluorescence intensity of the reaction solution to which the test compound was added) when the BACE activity of the control (Δ fluorescence intensity of the control) is set to 1. be.
Inhibitory activity was not confirmed in cycloleucylalanine (Cyclo(Leu-Ala)) measured as Comparative Example 1, but cycloleucylphenylalanine (Cyclo(Leu-Phe)) (Examples 1 to 4) and cycloleucylalanine A decrease in β-secretase enzymatic activity was confirmed for silysine (Cyclo(Leu-Lys)) (Example 5).
From the above results, it was revealed that the cyclic dipeptides Cyclo(Leu-Phe) and Cyclo(Leu-Lys) have β-secretase inhibitory activity.

Claims (7)

  1. Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種を有効成分として含む、アミロイドβの産生抑制及び／又は蓄積抑制用組成物。 A composition for suppressing the production and/or accumulation of amyloid β, comprising as an active ingredient at least one selected from the group consisting of Cyclo(Leu-Phe), Cyclo(Leu-Lys) and salts thereof.
  2. β－セクレターゼを阻害することによりアミロイドβの産生及び／又は蓄積を抑制する、請求項１に記載の組成物。 The composition according to claim 1, which suppresses the production and/or accumulation of amyloid β by inhibiting β-secretase.
  3. 前記組成物が、経口用である、請求項１又は２に記載の組成物。 3. The composition according to claim 1 or 2, wherein said composition is for oral use.
  4. 前記組成物が、飲食品又は医薬品である、請求項１又は２に記載の組成物。 The composition according to claim 1 or 2, wherein the composition is a food or drink or a pharmaceutical.
  5. 前記組成物が、「認知機能を高める」、「認知機能の低下を抑える」、「認知機能を良好に保つ」、「記憶力を高める」、「記憶力の低下を抑える」、「記憶力を良好に保つ」、「記憶の精度を高める」、「記憶障害を予防する」、「記憶障害を改善する」、「認知機能の一部である記憶力を維持する」、「記憶力の低下が気になる方に適した機能」、「認知機能の一部である記憶力の精度や判断の正確さを向上させる」、「記憶の保持又は統合を改善する」、「認知機能の強化を維持する」、「遂行機能を改善する」、「注意力と集中力を促進する」、「学習能力を改善する」、「見当識を維持・改善する」「加齢に伴う認知機能低下を遅延する」、「短期及び長期記憶を強化する」、「言語的及び視空間記憶を促進する」及び「論理的思考力を維持・改善する」からなる群より選択される１又は２以上の機能の表示を付されたものである、請求項１又は２に記載の組成物。 The composition "enhances cognitive function", "suppresses decline in cognitive function", "maintains good cognitive function", "enhances memory", "suppresses decline in memory", "maintains good memory" , "Improve memory accuracy", "Prevent memory impairment", "Improve memory impairment", "Maintain memory which is a part of cognitive function", "For those who are concerned about memory decline" "improve memory accuracy and judgment accuracy", "improve memory retention or consolidation", "maintain enhanced cognitive function", "executive function" "improve attention and concentration", "improve learning ability", "maintain and improve orientation", "delay age-related cognitive decline", "short-term and long-term labeled with one or more functions selected from the group consisting of "strengthening memory," "promoting verbal and visuospatial memory," and "maintaining/improving logical thinking ability." 3. The composition of claim 1 or 2, wherein the composition is
  6. アミロイドβの産生抑制及び／又は蓄積抑制用組成物の製造における、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種の使用。 Use of at least one selected from the group consisting of Cyclo (Leu-Phe), Cyclo (Leu-Lys) and salts thereof in the production of a composition for suppressing the production and/or accumulation of amyloid β.
  7. アミロイドβの産生抑制及び／又は蓄積抑制のための、Ｃｙｃｌｏ（Ｌｅｕ－Ｐｈｅ）、Ｃｙｃｌｏ（Ｌｅｕ－Ｌｙｓ）及びこれらの塩からなる群より選択される少なくとも１種の使用。 Use of at least one selected from the group consisting of Cyclo (Leu-Phe), Cyclo (Leu-Lys) and salts thereof for suppressing production and/or accumulation of amyloid β.
PCT/JP2022/046359 2021-12-23 2022-12-16 COMPOSITION FOR MINIMIZING PRODUCTION AND/OR ACCUMULATION OF AMYLOID β WO2023120405A1 (en)

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