Classifications

• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • 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
• • A—HUMAN NECESSITIES
  • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
  • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
  • 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
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/05—Dipeptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
  • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
• • 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 preventing or improving cognitive decline, and a composition for inhibiting ⁇ -secretase, etc.
• Amyloid beta is a type of protein produced in the brain. When A ⁇ aggregates and becomes oligomerized or fibrillated, it exhibits neurotoxicity. In addition, aggregated A ⁇ accumulates without being excreted from the brain, and is thought to trigger the onset of Alzheimer's disease. A ⁇ is generated by two-step cleavage of amyloid precursor protein (APP) by ⁇ -secretase (BACE1) and ⁇ -secretase. It has been reported that the activity and expression of BACE1 are elevated in the brains of patients with mild cognitive impairment (MCI) and Alzheimer's disease (Non-Patent Document 1).
• MCI mild cognitive impairment
• Non-Patent Document 1 Non-Patent Document 1
• Non-Patent Document 2 It has also been reported that inhibition of BACE1 suppresses the accumulation of A ⁇ at the early stage of accumulation of A ⁇ (Non-Patent Document 2). Therefore, inhibiting BACE1 and suppressing the production and accumulation of A ⁇ are thought to be effective in, for example, suppressing the decline in cognitive function and preventing Alzheimer's disease.
• Patent Document 1 discloses an agent for suppressing and/or improving decline in cognitive function of a subject, which contains Cyclo(Gly-Pro).
• Patent Document 2 discloses a composition for preventing neurological diseases, which contains a heat-treated animal or plant peptide as an active ingredient.
• Patent Document 3 discloses a composition for preventing neurological diseases, which contains a cyclic dipeptide having amino acids as constituent units or a salt thereof as an active ingredient, and discloses cyclolysyl lysine [Cyclo(Lys-Lys)] as a specific cyclic dipeptide.
• cyclolysyl lysine Cyclo(Lys-Lys
• the present invention aims to provide a novel composition for preventing or improving cognitive decline, and a novel composition for inhibiting ⁇ -secretase.
• the present inventors have found that the cyclic dipeptides Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys) or salts thereof inhibit ⁇ -secretase. They have also found that the above cyclic dipeptides or salts thereof inhibit the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
• the inventors also discovered that the cyclic dipeptides Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn) or salts thereof inhibit ⁇ -secretase, thereby suppressing the production and/or accumulation of amyloid ⁇ and are effective in suppressing or improving the decline in cognitive function, thus completing the present invention.
• the present invention relates to the following compositions for suppressing or improving cognitive decline, although the present invention is not limited thereto.
• a composition for inhibiting or improving a decline in cognitive function comprising at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp) and Cyclo(Trp-Asn), or a salt thereof.
• a composition for inhibiting ⁇ -secretase comprising at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), or a salt thereof.
• composition according to any one of [1] to [7] above which is a food or drink or an oral medicine.
• the present invention provides a novel composition for preventing or improving cognitive decline and a novel composition for inhibiting ⁇ -secretase.
• the composition for inhibiting or improving cognitive decline of the present invention (also referred to as the "first composition of the present invention”) comprises at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp) and Cyclo(Trp-Asn), or a salt thereof.
• the composition of the first invention generally contains the above-mentioned cyclic dipeptide or a salt thereof as an active ingredient.
• the composition of the first invention preferably further contains at least one cyclic dipeptide or a salt thereof selected from the group consisting of Cyclo(Hyp-Ala) and Cyclo(Leu-Lys).
• the ⁇ -secretase inhibiting composition of the present invention (also referred to as the "second composition of the present invention") comprises at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), or a salt thereof.
• the composition of the second invention generally contains the above-mentioned cyclic dipeptide or a salt thereof as an active ingredient.
• Cyclo(Arg-Phe) (cycloarginylphenylalanine), Cyclo(Arg-Tyr) (cycloarginyltyrosine), Cyclo(Glu-Leu) (cycloglutamate-leucine), Cyclo(His-Phe) (cyclohistidinylphenylalanine), Cyclo(Phe-Trp) (cyclophenylalanyltryptophan), Cyclo(Trp-Asn) (cyclotryptophanyl asparagine), Cyclo(Hyp-Ala) (cyclohydroxyprolinylalanine) and Cyclo(Leu-Lys) (cycloleucinyllysine) are all cyclic dipeptides.
• cyclic dipeptide refers to a compound that is characterized by having amino acids as constituent units and has a diketopiperazine structure formed by dehydration condensation of the amino group of the N-terminal amino acid and the carboxyl group of the C-terminal amino acid. Note that, as used herein, as long as the amino acid composition of the cyclic dipeptide is the same, the order in which they are described does not matter, and for example, Cyclo(Arg-Phe) and Cyclo(Phe-Arg) (cyclophenylalanyl arginine) represent the same cyclic dipeptide. Each of the above cyclic dipeptides may be in the form of a salt.
• the salt of the cyclic dipeptide is not particularly limited as long as it is a pharmacologically acceptable salt or a salt acceptable for food and beverages, and may be either an acidic salt or a basic salt.
• acidic salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, and phosphate; and organic acid salts such as acetate, citrate, maleate, malate, oxalate, lactate, succinate, fumarate, and propionate.
• Examples of basic salts include alkali metal salts such as sodium salt and potassium salt; and alkaline earth metal salts such as calcium salt and magnesium salt.
• the above-mentioned cyclic dipeptides may be incorporated into the composition using a protein hydrolysate or its heat-treated product containing the cyclic dipeptide, or may be incorporated into the composition using a concentrate, dry powder, or a product with a high degree of purification of the protein hydrolysate or its heat-treated product.
• the first and second compositions of the present invention may contain, for example, a protein hydrolysate or its heat-treated product, and the above-mentioned cyclic dipeptides may be a part of the protein hydrolysate or its heat-treated product.
• the above-mentioned cyclic dipeptides may be commercially available products.
• the salt of the cyclic dipeptide may be easily prepared by a person skilled in the art by any method known in the art.
• the first and second compositions of the present invention preferably inhibit the production and/or accumulation of amyloid ⁇ .
• a ⁇ is a peptide that is sometimes called amyloid ⁇ protein, amyloid ⁇ peptide, or ⁇ amyloid.
• a ⁇ is usually a peptide consisting of about 40 amino acids, and examples of A ⁇ include amyloid ⁇ 1-38, amyloid ⁇ 1-40, and amyloid ⁇ 1-42.
• amyloid ⁇ is preferably at least one selected from the group consisting of amyloid ⁇ 1-38, amyloid ⁇ 1-40, and amyloid ⁇ 1-42.
• the first and second compositions of the present invention can be used to prevent or ameliorate the above conditions or diseases.
• prevention of a condition or disease includes preventing onset, delaying onset, reducing the incidence, reducing the risk of onset, etc.
• Amelioration of a condition or disease includes recovering a subject from a condition or disease, alleviating the symptoms of a condition or disease, ameliorating the symptoms of a condition or disease, delaying or preventing the progression of a condition or disease, etc.
• Recovery includes partial recovery.
• the first and second compositions of the present invention can be used for the prevention or improvement of conditions or diseases associated with cognitive decline.
• the ⁇ -secretase (BACE1) inhibited by the ⁇ -secretase inhibiting composition of the second invention is an aspartyl protease that plays a major role in generating amyloid beta (A ⁇ ) peptide from amyloid precursor protein (APP). Therefore, by inhibiting the action of ⁇ -secretase, it is possible to suppress the production and/or accumulation of amyloid beta.
• the second composition of the present invention can be used to inhibit ⁇ -secretase in the brain, and the first composition of the present invention can also be used to inhibit ⁇ -secretase in the brain.
• the first and second compositions of the present invention preferably suppress the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
• the first and second compositions of the present invention can be used to suppress the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase in the brain.
• the first and second compositions of the present invention preferably inhibit ⁇ -secretase to suppress the production and/or accumulation of amyloid ⁇ , thereby suppressing or ameliorating the decline in cognitive function.
• the first and second compositions of the present invention can be used to suppress the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase in the brain, and thus suppress or improve the decline in cognitive function.
• the first and second compositions of the present invention can be applied for either therapeutic (medical) or non-therapeutic (non-medical) uses.
• Non-therapeutic is a concept that does not include medical procedures, i.e., surgery, treatment or diagnosis of humans.
• the first and second compositions of the present invention can be provided in the form of an agent, for example, but are not limited to this form.
• the agent can be provided as a composition as it is, or as a composition containing the agent.
• the first composition of the present invention can be referred to as an agent for suppressing cognitive decline or an agent for improving cognitive decline.
• the second composition of the present invention can be referred to as a ⁇ -secretase inhibitor.
• the first and second compositions of the present invention can be referred to as an agent for suppressing amyloid ⁇ production or an agent for suppressing amyloid ⁇ accumulation, respectively.
• the first and second compositions of the present invention may be either oral or parenteral.
• the first and second compositions of the present invention are preferably oral compositions.
• the first and second compositions of the present invention may be in the form of, for example, food and drink, medicine, quasi-drug, feed, etc., and are preferably food and drink or medicine, and more preferably food and drink or oral medicine.
• the composition of the present invention may also be added to food and drink, medicine, quasi-drug, feed, etc.
• the form of the composition of the present invention is not particularly limited, and may be any of a solid form (e.g., powder, granules, tablet, etc.), liquid, paste, etc.
• the first and second compositions of the present invention may further contain various diluents, acidulants, antioxidants, stabilizers, preservatives, flavorings, emulsifiers, colorants, seasonings, pH adjusters, nutritional enhancers, etc. that are permitted as additives to foods, beverages, medicines, etc.
• ingredients that can be used in food and beverage products can be blended with the above-mentioned cyclic dipeptide or its salt contained in the first and second compositions of the present invention to produce various food and beverage products.
• the food and beverage products are not particularly limited, and examples thereof include general food and beverage products, health foods, functional foods, foods for specified health uses, dietary supplements, foods for the sick, etc.
• the above-mentioned health foods, functional foods, foods for specified health uses, dietary supplements, etc. can be used in various formulation forms, such as liquids, fine granules, tablets, granules, powders, capsules, chewable agents, dry syrups, and liquid diets.
• a pharmacologically acceptable carrier an additive added as necessary, etc. can be added to the above-mentioned cyclic dipeptide or its salt contained in the first and second compositions of the present invention to produce a drug or quasi-drug in various dosage forms.
• Such carriers, additives, etc. may be any pharmacologically acceptable carriers that can be used in drugs or quasi-drugs, and examples of such carriers, additives, etc. include one or more of excipients, binders, disintegrants, lubricants, antioxidants, colorants, etc.
• the administration (ingestion) form of the drug or quasi-drug may be oral or parenteral (percutaneous, permucosal, enteral, injection, etc.) administration form.
• parenteral percutaneous, permucosal, enteral, injection, etc.
• dosage forms for oral administration include liquids, tablets, powders, fine granules, granules, sugar-coated tablets, capsules, suspensions, emulsions, chewables, etc.
• dosage forms for parenteral administration include injections, drops, ointments, lotions, patches, suppositories, nasal preparations, pulmonary preparations (inhalants), etc.
• Pharmaceuticals may be medicines for non-human animals.
• feed also includes feed additives.
• feed include livestock feed for cows, pigs, chickens, sheep, horses, etc.; small animal feed for rabbits, rats, mice, etc.; and pet food for dogs, cats, small birds, etc.
• the method of production is not particularly limited, and they can be produced by a general method using the above-mentioned cyclic dipeptide or a salt thereof contained in the first and second compositions of the present invention.
• the first and second compositions of the present invention are preferably liquid compositions, and more preferably beverages.
• the beverage may be, for example, a functional beverage.
• the form of the beverage is not particularly limited, and may be a packaged beverage.
• the container for the packaged beverage is not particularly limited, and any container of any form and material may be used, and any commonly used container may be used, for example, metal containers such as aluminum cans and steel cans; resin containers such as PET bottles; paper containers such as paper cartons; glass containers such as glass bottles; and wooden containers such as barrels.
• a packaged beverage is obtained by filling and sealing such a container with the beverage.
• the total content of at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys) contained in the second composition of the present invention is not particularly limited and can be set according to the form of the composition, etc.
• the content of Cyclo(Arg-Tyr) or a salt thereof in the first and second compositions of the present invention may be, for example, 0.0005% by weight or more, preferably 0.001% by weight or more, more preferably 0.005% by weight or more, and preferably 5% by weight or less, more preferably 1% by weight or less, and even more preferably 0.5% by weight or less, in terms of the free cyclic dipeptide.
• the content of Cyclo(Arg-Tyr) or a salt thereof in the first and second compositions of the present invention is, for example, preferably 0.0005 to 5% by weight, in terms of the free cyclic dipeptide. More preferably, it is 0.001 to 1% by weight, and even more preferably 0.005 to 0.5% by weight.
• the content of Cyclo(Glu-Leu) or a salt thereof is not particularly limited and can be set depending on the form, etc.
• the content of Cyclo(Glu-Leu) or a salt thereof in the composition of the first and second inventions of the present invention may be, for example, 0.001% by weight or more, preferably 0.005% by weight or more, more preferably 0.01% by weight or more, and preferably 20% by weight or less, more preferably 10% by weight or less, and even more preferably 5% by weight or less, in terms of the free cyclic dipeptide.
• the content of Cyclo(Glu-Leu) or a salt thereof in the composition of the first and second inventions of the present invention is, for example, preferably 0.001 to 20% by weight, in terms of the free cyclic dipeptide. More preferably, it is 0.005 to 10% by weight, and even more preferably 0.01 to 5% by weight.
• the content of Cyclo(His-Phe) or a salt thereof in the composition of the first and second inventions is, for example, preferably 0.0005 to 5% by weight, in terms of the free cyclic dipeptide, in the composition of the first and second inventions. More preferably, it is 0.001 to 1% by weight, and even more preferably 0.005 to 0.5% by weight.
• compositions of the first and second aspects of the present invention contain Cyclo(Phe-Trp) or a salt thereof
• the content thereof is not particularly limited and can be set depending on the form, etc.
• the content of Cyclo(Phe-Trp) or a salt thereof in the composition of the first and second inventions of the present invention may be, for example, 0.0001% by weight or more, preferably 0.0005% by weight or more, more preferably 0.001% by weight or more, and preferably 5% by weight or less, more preferably 1% by weight or less, and even more preferably 0.1% by weight or less, in terms of the free cyclic dipeptide.
• the content of Cyclo(Phe-Trp) or a salt thereof in the composition of the first and second inventions of the present invention is, for example, preferably 0.0001 to 5% by weight, more preferably 0.0005 to 1% by weight, and even more preferably 0.001 to 0.1% by weight, in terms of the free cyclic dipeptide.
• compositions of the first and second aspects of the present invention contain Cyclo(Trp-Asn) or a salt thereof
• the content thereof is not particularly limited and can be set depending on the form, etc.
• the content of Cyclo(Trp-Asn) or a salt thereof in the first and second compositions of the present invention may be, for example, 0.0001% by weight or more, preferably 0.0005% by weight or more, more preferably 0.001% by weight or more, and preferably 5% by weight or less, more preferably 1% by weight or less, and even more preferably 0.1% by weight or less, in terms of the free cyclic dipeptide.
• the content of Cyclo(Trp-Asn) or a salt thereof in the first and second compositions of the present invention is, for example, preferably 0.0001 to 5% by weight, in terms of the free cyclic dipeptide, in the first and second compositions of the present invention. More preferably, it is 0.0005 to 1% by weight, and even more preferably 0.001 to 0.1% by weight.
• compositions of the first and second aspects of the present invention contain Cyclo(Hyp-Ala) or a salt thereof
• the content thereof is not particularly limited and can be set depending on the form, etc.
• the content of Cyclo(Hyp-Ala) or a salt thereof in the composition of the first and second inventions of the present invention may be, for example, 0.0001% by weight or more, preferably 0.0005% by weight or more, more preferably 0.001% by weight or more, and preferably 5% by weight or less, more preferably 1% by weight or less, and even more preferably 0.1% by weight or less, in terms of the free cyclic dipeptide.
• the content of Cyclo(Hyp-Ala) or a salt thereof in the composition of the first and second inventions of the present invention is, for example, preferably 0.0001 to 5% by weight, more preferably 0.0005 to 1% by weight, and even more preferably 0.001 to 0.1% by weight, in terms of the free cyclic dipeptide.
• the content of Cyclo(Leu-Lys) or a salt thereof in the first and second compositions of the present invention may be, for example, 0.001% by weight or more, preferably 0.005% by weight or more, more preferably 0.01% by weight or more, and preferably 20% by weight or less, more preferably 10% by weight or less, and even more preferably 5% by weight or less, in terms of the free cyclic dipeptide.
• the content of Cyclo(Leu-Lys) or a salt thereof in the first and second compositions of the present invention is, for example, preferably 0.001 to 20% by weight, in terms of the free cyclic dipeptide. More preferably, it is 0.005 to 10% by weight, and even more preferably 0.01 to 5% by weight.
• the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn) and salts thereof in the composition of the first invention is not particularly limited and can be set depending on the form, etc.
• the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), and salts thereof, calculated as the free cyclic dipeptide may be, for example, 0.0001% by weight or more, preferably 0.0005% by weight or more, more preferably 0.001% by weight or more, and even more preferably 0.01% by weight or more, and is preferably 50% by weight or less, more preferably 30% by weight or less, even more preferably 20% by weight or less, and even more preferably 10% by weight or less.
• the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn) and salts thereof, calculated as a free cyclic dipeptide may be, for example, 0.0001 to 50% by weight in the composition of the first invention, preferably 0.0005 to 30% by weight, more preferably 0.001 to 20% by weight, and even more preferably 0.01 to 10% by weight.
• composition of the first invention further contains at least one cyclic dipeptide selected from the group consisting of Cyclo(Hyp-Ala) and Cyclo(Leu-Lys) or a salt thereof
• the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys), and salts thereof in the composition of the first and second inventions is not particularly limited and can be set depending on the form, etc.
• the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys) and their salts in the first and second compositions of the present invention may be, for example, 0.0001% by weight or more, preferably 0.0005% by weight or more, more preferably 0.001% by weight or more, even more preferably 0.01% by weight or more, and preferably 50% by weight or less, more preferably 30% by weight or less, even more preferably 20% by weight or less, and even more preferably 10% by weight or less, calculated based on the free cyclic dipeptide.
• the total content of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys) and salts thereof, calculated as a free cyclic dipeptide may be, for example, 0.0001 to 50% by weight in the composition of the first invention, preferably 0.0005 to 30% by weight, more preferably 0.001 to 20% by weight, and even more preferably 0.01 to 10% by weight.
• Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys) and salts thereof can be quantified by a known method, for example, liquid chromatography mass spectrometry (LC-MS/MS).
• LC-MS/MS liquid chromatography mass spectrometry
• an Agilent 1290 binary LC coupled with AB Sciex 5600+ TripleTOF system can be used.
• LC column CORTECS T3 Column, 120 ⁇ , 1.6 ⁇ m, 2.1 mm ⁇ 100 mm (Waters Corporation) Sample injection volume: 5 ⁇ L Column temperature: 40°C (LC Chromatography Conditions)
• Mobile phase Solution A: Water containing 0.1% formic acid Solution B: Acetonitrile containing 0.1% formic acid Gradient (Solution B concentration): 0 to 1 min: 1% solution B 1-8.5 minutes: B liquid 1% ⁇ 40% 8.5-13 minutes: B liquid 40% ⁇ 90% 13-15.5 minutes: B liquid 90% ⁇ 100% 15.5-17.8 minutes: B liquid 100% 17.8-18 minutes: B liquid 100% ⁇ 1% 18-20 minutes: B liquid 1%
• the first and second compositions of the present invention are preferably taken orally (orally administered).
• the dosage (which can also be referred to as the intake amount) of the first and second compositions of the present invention is not particularly limited.
• the dosage of the first composition of the present invention may be an amount that can obtain an effect of suppressing or improving cognitive function decline, for example, an amount that can obtain an effect of suppressing or improving cognitive function decline by suppressing the production and/or accumulation of amyloid ⁇ .
• an amount that can obtain an effect of suppressing or improving cognitive function decline by inhibiting ⁇ -secretase and suppressing the production and/or accumulation of amyloid ⁇ may be an amount that can obtain an effect of suppressing or improving cognitive function decline.
• the dosage of the second composition of the present invention may be an amount that provides an inhibitory effect on ⁇ -secretase, for example, an amount that provides an effect of suppressing the production and/or accumulation of amyloid ⁇ by inhibiting ⁇ -secretase.
• it may be an amount that provides an effect of suppressing or improving cognitive function decline by inhibiting ⁇ -secretase and suppressing the production and/or accumulation of amyloid ⁇ .
• the amount that provides these effects may be appropriately set depending on the administration form, administration method, subject weight, etc.
• the dosage is, in terms of the total dosage (in terms of free cyclic dipeptide) of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp) and Cyclo(Trp-Asn) and their salts, preferably 0.001 mg or more, more preferably 0.01 mg or more, even more preferably 0.1 mg or more, and also preferably 5000 mg or less, more preferably 3000 mg or less, even more preferably 2000 mg or less per day.
• the total dosage of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn) and their salts (calculated as free cyclic dipeptides) is preferably 0.001 to 5000 mg, more preferably 0.01 to 3000 mg, and even more preferably 0.1 to 2000 mg per day.
• composition of the first invention when the composition of the first invention further contains at least one cyclic dipeptide selected from the group consisting of Cyclo(Hyp-Ala) and Cyclo(Leu-Lys) or a salt thereof, the dosage of the composition of the first invention when ingested or administered to a human (adult) can be as follows.
• the dosage is, in terms of the total dosage (based on the free cyclic dipeptide) of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys) and salts thereof, preferably 0.001 mg or more, more preferably 0.01 mg or more, even more preferably 0.1 mg or more, and also preferably 5000 mg or less, more preferably 3000 mg or less, even more preferably 2000 mg or less per day.
• the total dosage of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), and Cyclo(Leu-Lys) and salts thereof is preferably 0.001 to 5000 mg, more preferably 0.01 to 3000 mg, and even more preferably 0.1 to 2000 mg per day. It is preferable to ingest or administer the above amount once or more times a day, for example, once a day or divided into several times (e.g., 2 to 3 times).
• the first and second compositions of the present invention may be oral compositions for ingesting or administering the above amount of the cyclic dipeptide or a salt thereof per 60 kg of body weight per day to a human.
• compositions of the first and second aspects of the present invention are preferably ones that are continuously ingested or administered.
• a higher effect can be obtained by continuously ingesting or administering at least one cyclic dipeptide or a salt thereof selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp) and Cyclo(Trp-Asn).
• the first and second compositions of the present invention are preferably taken or administered continuously for at least one week, more preferably at least four weeks, and even more preferably at least eight weeks.
• the above-mentioned cyclic dipeptides or salts thereof can be ingested as foods, beverages, etc., and from the viewpoint of safety, it is considered that there are few problems with long-term intake, for example.
• the subject to which the first and second compositions of the present invention are ingested or administered is not particularly limited, and is preferably a human or a non-human mammal, more preferably a human.
• the subjects to which the compositions of the first and second inventions of the present invention are administered include subjects who need or wish to inhibit or improve cognitive decline, subjects who need or wish to prevent or improve a condition or disease associated with cognitive decline, subjects who need or wish to inhibit ⁇ -secretase, subjects who need or wish to prevent or improve a condition or disease associated with ⁇ -secretase production, subjects who need or wish to inhibit the production and/or accumulation of amyloid ⁇ , subjects who need or wish to prevent or improve a condition or disease associated with the production and/or accumulation of amyloid ⁇ , and the like.
• the subjects to which the compositions of the first and second inventions of the present invention are administered include middle-aged and elderly people.
• Middle-aged and elderly people include elderly people.
• Middle-aged and elderly people may be, for example, humans aged 40 years or older.
• elderly people are preferred as subjects.
• Elderly people may be, for example, humans aged 60 years or older or 65 years or older.
• the subjects to which the compositions of the first invention of the present invention are administered may be healthy individuals.
• the subject to which the second composition of the present invention is administered may be a healthy individual.
• it can be used in healthy individuals for the purpose of inhibiting ⁇ -secretase in the brain, inhibiting the production and/or accumulation of amyloid ⁇ in the brain, preventing the production and/or accumulation of amyloid ⁇ in the brain, preventing Alzheimer's disease, mild cognitive (functional) impairment, or aging-related cognitive (functional) impairment, or the like.
• composition of the first invention may be labeled with a function exhibited by suppressing or improving cognitive function decline.
• composition of the second invention may be labeled with a function exhibited by ⁇ -secretase inhibition. Such a label is also called a functional label.
• the above label that may be attached to the compositions of the first and second inventions is not particularly limited.
• labels include "enhance cognitive function,””suppress cognitive function decline,””maintain good cognitive function,””enhancememory,””suppress memory decline,””maintain good memory,””enhance memory accuracy,””prevent memory impairment,””improve memory impairment,””maintain memory, which is part of cognitive function,””function suitable for those who are concerned about memory decline,””improve memory accuracy and judgment accuracy, which are part of cognitive function,””improve memory retention or integration,””maintain cognitive function enhancement,””improve executive function,””promote attention and concentration,””improve learning ability,””maintain or improve orientation,””delay cognitive decline associated with aging,””strengthen short-term and long-term memory,””promote verbal and visuospatial memory,””maintain or improve logical thinking ability,” and labels or functional labels that can be viewed as equivalent thereto.
• the first and second compositions of the present invention are preferably foods and beverages to which one or more of the above-mentioned indications are attached.
• the above-mentioned indications may be an indication that the above-mentioned composition is used to obtain the above-mentioned functions.
• the indications may be attached to the composition itself, or to a container or packaging of the composition.
• a method for suppressing or improving a decline in cognitive function comprising administering at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp) and Cyclo(Trp-Asn), or a salt thereof.
• At least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp) and Cyclo(Trp-Asn), or a salt thereof, for inhibiting or improving cognitive function decline.
• a method for inhibiting ⁇ -secretase comprising administering at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), or a salt thereof.
• cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), or a salt thereof, for inhibiting ⁇ -secretase.
• the method may be a therapeutic or non-therapeutic method.
• the use may be a therapeutic or non-therapeutic use.
• the subject ingest or administer the above-mentioned cyclic dipeptide or a salt thereof at least once a day, for example, once to several times a day (for example, 2 to 3 times).
• the above-mentioned use is preferably for use in a human or a non-human mammal, more preferably for use in a human.
• Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn) or a salt thereof can be used to prevent or improve a condition or disease associated with a decline in cognitive function.
• Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys) or a salt thereof can be used to prevent or ameliorate conditions or diseases for which inhibition of ⁇ -secretase is effective in preventing or ameliorating.
• Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys) or salts thereof can be used to prevent or improve conditions or diseases associated with the production and/or accumulation of amyloid beta.
• the present invention also includes a method for preventing or improving conditions or diseases associated with cognitive decline, a method for preventing or improving conditions or diseases for which inhibition of beta-secretase is effective in preventing or improving, and a method for preventing or improving conditions or diseases associated with the production and/or accumulation of amyloid beta, which involves administering each of the above cyclic dipeptides or salts thereof.
• the above-mentioned cyclic dipeptide or its salt may be used in an amount (which may be called an effective amount) that can achieve the effect of suppressing or improving the decline in cognitive function, the effect of inhibiting ⁇ -secretase, or the effect of suppressing the production and/or accumulation of amyloid ⁇ .
• the preferred dosage, administration method, and administration target of the above-mentioned cyclic dipeptide or its salt are the same as those of the above-mentioned first and second compositions of the present invention.
• the above-mentioned cyclic dipeptide or its salt may be ingested or administered as it is, or may be ingested or administered as a composition containing it.
• the first or second composition of the present invention may be ingested or administered.
• Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn) or a salt thereof can be used for the production of foods and beverages, pharmaceuticals, quasi-drugs, feeds, and the like used for suppressing or improving cognitive function decline.
• the present invention also encompasses the use of at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), and Cyclo(Trp-Asn), or a salt thereof, in the manufacture of a composition for preventing or improving a decline in cognitive function.
• Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala), Cyclo(Leu-Lys) or a salt thereof can be used for the production of foods and beverages, medicines, quasi-drugs, feeds and the like that are used for inhibiting ⁇ -secretase or suppressing the production and/or accumulation of amyloid ⁇ .
• the present invention also encompasses the use of at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), or a salt thereof, in the manufacture of a composition for inhibiting ⁇ -secretase or a composition for suppressing the production and/or accumulation of amyloid ⁇ .
• at least one cyclic dipeptide selected from the group consisting of Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys), or a salt thereof, in the manufacture of a composition for inhibit
• a numerical range expressed by a lower limit and an upper limit includes the lower limit and the upper limit.
• a range expressed by "1 to 2" means 1 or more and 2 or less, including 1 and 2.
• the upper limit and the lower limit may be in any combination. All academic and patent literature cited herein is hereby incorporated by reference.
• Example 1 Each cyclic dipeptide was evaluated for its ⁇ -secretase (BACE1) inhibitory activity.
• Reagents BACE1 Inhibitor Screening Kit (Fluorometric) was obtained from Abcam. Each cyclic dipeptide (Cyclo(Arg-Phe), Cyclo(Arg-Tyr), Cyclo(Glu-Leu), Cyclo(His-Phe), Cyclo(Phe-Trp), Cyclo(Trp-Asn), Cyclo(Hyp-Ala) and Cyclo(Leu-Lys)) was purchased from Axil Scientific Pte. Other reagents were purchased from Sigma-Aldrich.
• B. BACE1 Inhibition Assay The BACE1 inhibitory activity of each cyclic dipeptide was evaluated using the BACE1 Inhibitor Screening Kit (Fluorometric). The BACE1 inhibition assay was carried out according to the kit manufacturer's protocol. Each cyclic dipeptide was dissolved in dimethyl sulfoxide (DMSO) at a high stock concentration of 100 times (100x), and then diluted in assay buffer to twice (2x) the test concentration. The resulting dilutions of each cyclic dipeptide were used in the following experiments. BACE1 enzyme assay mix was prepared by diluting the stock enzyme (25x) with assay buffer.
• DMSO dimethyl sulfoxide
• IC50 IC50
• each cyclic dipeptide had the effect of inhibiting BACE1.
• the IC50 ( ⁇ g/mL) of each cyclic dipeptide is shown in Table 1.
• BACE1 is an aspartyl protease that plays a key role in generating amyloid beta (A ⁇ ) peptides from the amyloid precursor protein.
• a ⁇ amyloid beta
• the results of the BACE1 inhibition assay showed that each cyclic dipeptide could inhibit BACE1 with IC50 values ranging from 28.2 to 430.8 ⁇ g/mL (Table 1).
• Reference 1 Naslund et al. , JAMA 2000, 283(12), 1571-1577
• Reference 2 Fukumoto et al. , Arch. Neurol. 2002, 59(9), 1381-9.

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