KR101801478B1 - Composition for preventing or treating neurodegenerative disease comprising biochanin A as active ingredient - Google Patents
Composition for preventing or treating neurodegenerative disease comprising biochanin A as active ingredient Download PDFInfo
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- KR101801478B1 KR101801478B1 KR1020160096752A KR20160096752A KR101801478B1 KR 101801478 B1 KR101801478 B1 KR 101801478B1 KR 1020160096752 A KR1020160096752 A KR 1020160096752A KR 20160096752 A KR20160096752 A KR 20160096752A KR 101801478 B1 KR101801478 B1 KR 101801478B1
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- KR
- South Korea
- Prior art keywords
- biocanin
- bace1
- active ingredient
- beta
- secretase
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- 239000000203 mixture Substances 0.000 title description 11
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- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
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- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23V2200/00—Function of food ingredients
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Abstract
Description
본 발명은 비오카닌 A를 유효성분으로 포함하는 퇴행성 뇌질환의 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to a composition for preventing or treating degenerative brain diseases comprising biocanin A as an active ingredient.
최근 통계청에 따르면 2005년에는 생산가능인구 7.9명이 노인 1명을 부양하였으나, 2010년에는 6.6명, 2030년에는 2.6명, 2050년에는 1.4명, 2060년에는 1.2명으로 노인 부양부담이 증가하는 추세이다. 이는 최근 심각한 사회문제로 떠오르는 고령화 사회에 대한 실상을 보여주는 것이며 고령화 사회에 대한 대응의 필요성을 나타내고 있다(통계청, 2011).According to the National Statistical Office (NSO), 7.9 persons are able to support one elderly person in 2005, but 6.6 persons in 2010, 2.6 persons in 2030, 1.4 persons in 2050 and 1.2 persons in 2060 to be. This shows the reality of an aging society that emerges as a serious social problem in recent years, and shows the need for a response to an aging society (National Statistical Office, 2011).
알츠하이머성 치매(Alzheimer's disease)는 뇌가 위축되고 뇌실이 확장되어 있으며, 신경원섬유 변화(neurofibrillary tangle)와 노인반(senile plaque)과 같은 병리학적 특징이 동반된다. 이 중 노인반의 구성물질인 베타-아밀로이드 플라크(β-amyloid plaque, 이하 "Aβ"이라 함)는 39-43개의 아미노산으로 구성된 펩타이드이다. Aβ는 아밀로이드 전구 단백질(amyloid precursor protein, APP)의 β-site에 β-secretase와 γ-secretase의 순차적인 가수분해에 의해 생성된다(Park SH et al., 2014). 정상인의 경우 γ-secretase가 작용하기 전 α-secretase에 의해 APP의 N-말단에서 15, 16번째 아미노산이 잘린 후 γ-효소가 작용하기 때문에 독성이 없는 짧은 peptide를 세포 밖으로 유리시키지만(Efrev I et al., 2012), 치매환자의 경우 β-와γ-효소의 활성이 높아 Aβ의 생성량이 많다. 생성된 Aβ는 세포주위 혈관에 침착하여 염증반응을 동반한 병변을 이차적으로 발생시키고 그 결과 뇌기능의 광범위한 장애가 오게 된다(Kim JH, 2000).Alzheimer's disease is characterized by atrophy of the brain and enlargement of the ventricles, accompanied by pathological features such as neurofibrillary tangles and senile plaques. Among these, β-amyloid plaque (hereinafter referred to as "Aβ"), a constituent of the elderly, is a peptide composed of 39-43 amino acids. Aβ is produced by sequential hydrolysis of β-secretase and γ-secretase to the β-site of amyloid precursor protein (APP) (Park SH et al., 2014). In normal individuals, the α-secretase cleaves the 15th and 16th amino acids at the N-terminus of the APP before the action of the γ-secretase, and the γ-enzyme acts to release the short peptide that is not toxic (Efrev I et al., 2012). In patients with dementia, the production of Aβ is high due to high β- and γ-enzyme activities. The resulting Aβ deposits in the pericellular blood vessels, secondary to the inflammatory reaction, resulting in a widespread impairment of brain function (Kim JH, 2000).
알츠하이머성 치매의 치료제로는 미국 FDA에서 승인한 4개의 치료제가 있으며 acetyl-cholinesterase(AChE) 억제제가 주를 이르고 있다. 현재까지의 치료는 증상완화 또는 진행속도 지연뿐이며 질병자체를 치료하지는 못하고 있다(Lee HS, 2012). 근원적인 문제를 해결하기 위하여 Aβ의 응집저해 후보 물질이 제시되었지만 아직 검증된 치료제는 없는 실정이다(Lee MY, 2005).There are four treatments approved by the US FDA and acetylcholinesterase (AChE) inhibitors are the main treatments for Alzheimer's dementia. Until now, treatment has only been symptomatic or delayed, and the disease itself has not been treated (Lee HS, 2012). In order to solve the fundamental problem, Aβ has been suggested as a candidate substance for inhibition of aggregation, but there is no proven therapeutic agent (Lee MY, 2005).
본 발명의 목적은 비오카닌 A 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다. It is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of degenerative brain diseases comprising biocanin A or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 또다른 목적은 비오카닌 A 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환의 예방 또는 개선용 건강기능식품을 제공하는 것이다. It is still another object of the present invention to provide a health functional food for preventing or ameliorating a degenerative brain disease comprising biocanin A or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 비오카닌 A 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환의 예방 또는 치료용 약학적 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating degenerative brain diseases comprising biocanin A or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일실시예에 있어서, 상기 비오카닌 A는 하기 화학식 1의 구조를 가진 것일 수 있다. In one embodiment of the present invention, the biocanin A may have a structure represented by the following formula (1).
[화학식 1][Chemical Formula 1]
본 발명의 일실시예에 있어서, 상기 비오카닌 A는 BACE1(beta-secretase 1)의 활성을 억제하여 베타-아밀로이드 플라크의 생성을 억제하는 것일 수 있다. In one embodiment of the present invention, the biocanin A may inhibit the activity of BACE1 (beta-secretase 1) to inhibit the formation of beta-amyloid plaques.
본 발명의 일실시예에 있어서, 상기 퇴행성 뇌질환은 알츠하이머병, 헌팅턴병 또는 파킨슨병인 것일 수 있다. In one embodiment of the present invention, the degenerative brain disease may be Alzheimer's disease, Huntington's disease or Parkinson's disease.
또한, 본 발명은 비오카닌 A 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 퇴행성 뇌질환의 예방 또는 개선용 건강기능식품을 제공한다. The present invention also provides a health functional food for preventing or ameliorating a degenerative brain disease comprising biocanin A or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 일실시예에 있어서, 상기 비오카닌 A는 BACE1(beta-secretase 1)의 활성을 억제하여 베타-아밀로이드 플라크의 생성을 억제하는 것일 수 있다. In one embodiment of the present invention, the biocanin A may inhibit the activity of BACE1 (beta-secretase 1) to inhibit the formation of beta-amyloid plaques.
본 발명의 일실시예에 있어서, 상기 퇴행성 뇌질환은 알츠하이머병, 헌팅턴병 또는 파킨슨병인 것일 수 있다. In one embodiment of the present invention, the degenerative brain disease may be Alzheimer's disease, Huntington's disease or Parkinson's disease.
본 발명의 비오카닌 A는 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 산 부가염은 염산, 질산, 인산, 황산, 브롬화수소산, 요드화수소산, 아질산 또는 아인산과 같은 무기산류와 지방족 모노 및 디카르복실레이트, 페닐-치환된 알카노에이트, 하이드록시 알카노에이트 및 알칸디오에이트, 방향족 산류, 지방족 및 방향족 설폰산류와 같은 무독성 유기산으로부터 얻는다. 이러한 약학적으로 무독한 염류로는 설페이트, 피로설페이트, 바이설페이트, 설파이트, 바이설파이트, 니트레이트, 포스페이트, 모노하이드로겐 포스페이트, 디하이드로겐 포스페이트, 메타포스페이트, 피로포스페이트 클로라이드, 브로마이드, 아이오다이드, 플루오라이드, 아세테이트, 프로피오네이트, 데카노에이트, 카프릴레이트, 아크릴레이트, 포메이트, 이소부티레이트, 카프레이트, 헵타노에이트, 프로피올레이트, 옥살레이트, 말로네이트, 석시네이트, 수베레이트, 세바케이트, 푸마레이트, 말리에이트, 부틴-1,4-디오에이트, 헥산-1,6-디오에이트, 벤조에이트, 클로로벤조에이트, 메틸벤조에이트, 디니트로 벤조에이트, 하이드록시벤조에이트, 메톡시벤조에이트, 프탈레이트, 테레프탈레이트, 벤젠설포네이트, 톨루엔설포네이트, 클로로벤젠설포네이트, 크실렌설포네이트, 페닐아세테이트, 페닐프로피오네이트, 페닐부티레이트, 시트레이트, 락테이트, β-하이드록시부티레이트, 글리콜레이트, 말레이트, 타트레이트, 메탄설포네이트, 프로판설포네이트, 나프탈렌-1-설포네이트, 나프탈렌-2-설포네이트 또는 만델레이트를 포함한다.Biocanin A of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, acid addition salts formed by pharmaceutically acceptable free acids are useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.
본 발명에 따른 산 부가염은 통상의 방법, 예를 들면, 비오카닌 A를 과량의 산 수용액 중에 용해시키고, 이 염을 수혼화성 유기 용매, 예를 들면 메탄올, 에탄올, 아세톤 또는 아세토니트릴을 사용하여 침전시켜서 제조할 수 있다. 동량의 비오카닌 A 및 물 중의 산 또는 알코올을 가열하고, 이어서 이 혼합물을 증발시켜서 건조시키거나 또는 석출된 염을 흡입 여과시켜 제조할 수도 있다.The acid addition salt according to the present invention can be produced by a conventional method, for example, by dissolving biocanin A in an excess amount of an aqueous acid solution and then using this salt in a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile Followed by precipitation. By heating the same amount of biocanin A and an acid or alcohol in water, then evaporating the mixture and drying, or by suction filtration of the precipitated salt.
또한, 염기를 사용하여 약학적으로 허용 가능한 금속염을 만들 수 있다. 알칼리 금속 또는 알칼리 토금속 염은 예를 들면, 화합물을 과량의 알칼리 금속 수산화물 또는 알칼리 토금속 수산화물 용액 중에 용해하고, 비용해 화합물 염을 여과하고, 여액을 증발, 건조시켜 얻는다. 이때, 금속염으로는 나트륨, 칼륨 또는 칼슘염을 제조하는 것이 제약상 적합하다. 또한, 이에 대응하는 은 염은 알칼리 금속 또는 알칼리 토금속 염을 적당한 음염(예, 질산은)과 반응시켜 얻는다.In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).
또한, 본 발명의 비오카닌 A는 약학적으로 허용되는 염뿐만 아니라, 통상의 방법에 의해 제조될 수 있는 모든 염, 수화물 및 용매화물을 모두 포함한다.In addition, Biocanin A of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.
본 발명에 따른 부가염은 통상의 방법으로 제조할 수 있으며, 예를 들, 비오카닌 A를 수혼화성 유기용매, 예를 들면 아세톤, 메탄올, 에탄올, 또는 아세토니트릴 등에 녹이고 과량의 유기산을 가하거나 무기산의 산 수용액을 가한 후 침전시키거나 결정화시켜서 제조할 수 있다. 이어서 이 혼합물에서 용매나 과량의 산을 증발시킨 후 건조시켜서 부가염을 얻거나 또는 석출된 염을 흡인 여과시켜 제조할 수 있다.The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving Biocanin A in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile or the like, adding an excessive amount of organic acid Adding an aqueous acid solution of an inorganic acid, and precipitating or crystallizing it. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.
본 발명의 조성물을 의약품으로 사용하는 경우, 비오카닌 A 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 약학적 조성물은 임상투여 시에 다양한 하기의 경구 또는 비경구 투여 형태로 제제화되어 투여될 수 있으나, 이에 한정되는 것은 아니다.When the composition of the present invention is used as a medicine, the pharmaceutical composition comprising biocanin A or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated into various oral or parenteral dosage forms at the time of clinical administration, But is not limited thereto.
경구 투여용 제형으로는 예를 들면 정제, 환제, 경/연질 캅셀제, 액제, 현탁제, 유화제, 시럽제, 과립제, 엘릭시르제 등이 있는데, 이들 제형은 유효성분 이외에 희석제(예: 락토즈, 덱스트로즈, 수크로즈, 만니톨, 솔비톨, 셀룰로즈 및/ 또는 글리신), 활택제(예: 실리카, 탈크, 스테아르산 및 그의 마그네슘 또는 칼슘염 및/또는 폴리에틸렌 글리콜)를 포함하고 있다. 정제는 또한 마그네슘 알루미늄 실리케이트, 전분 페이스트, 젤라틴, 메틸셀룰로즈, 나트륨 카복시메틸셀룰로즈 및/또는 폴리비닐피롤리딘과 같은 결합제를 포함할 수 있으며, 경우에 따라 전분, 한천, 알긴산 또는 그의 나트륨 염과 같은 붕해제 또는 비등 혼합물 및/또는 흡수제, 착색제, 향미제, 및 감미제를 포함할 수 있다.Examples of the formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules and elixirs. These formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, Silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols), in addition to the active ingredient (s). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.
본 발명의 비오카닌 A 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 약학적 조성물은 비경구 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사를 주입하는 방법에 의한다. 이때, 비경구 투여용 제형으로 제제화하기 위하여 비오카닌 A 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 약학적 조성물을 안정제 또는 완충제와 함께 물에 혼합하여 용액 또는 현탁액으로 제조하고, 이를 앰플 또는 바이알 단위 투여형으로 제조할 수 있다. 상기 조성물은 멸균되고/되거나 방부제, 안정화제, 수화제 또는 유화 촉진제, 삼투압 조절을 위한 염 및/또는 완충제 등의 보조제, 및 기타 치료적으로 유용한 물질을 포함할 수 있으며, 통상적인 방법인 혼합, 과립화 또는 코팅 방법에 따라 제제화할 수 있다.The pharmaceutical composition containing the biocanin A of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be administered parenterally, and parenteral administration can be carried out by subcutaneous injection, intravenous injection, intramuscular injection, It depends on the injection method. In this case, in order to formulate a formulation for parenteral administration, a pharmaceutical composition comprising biocanin A or a pharmaceutically acceptable salt thereof as an active ingredient is mixed with water or a stabilizer or a buffer to prepare a solution or suspension, Ampicillin or vial unit dosage forms. The compositions may comprise sterilized and / or contain adjuvants such as preservatives, stabilizers, wettable or emulsifying accelerators, salts for controlling osmotic pressure and / or buffers, and other therapeutically useful substances, Or may be formulated according to the coating method.
또한, 본 발명의 조성물의 인체에 대한 투여량은 환자의 나이, 몸무게, 성별, 투여형태, 건강상태 및 질환 정도에 따라 달라질 수 있으며, 몸무게가 60 ㎏인 성인 환자를 기준으로 할 때, 일반적으로 0.001 ~ 1,000 ㎎/일이며, 바람직하게는 0.01 ~ 500 ㎎/일이며, 의사 또는 약사의 판단에 따라 일정시간 간격으로 1일 1회 내지 수회로 분할 투여할 수도 있다.The dose of the composition of the present invention to the human body may be varied depending on the age, body weight, sex, dosage form, health condition, and disease severity of the patient. When the patient is 60 kg body weight, And may be 0.01 to 500 mg / day, preferably 0.01 to 500 mg / day, and may be administered once or several times a day at regular intervals according to the judgment of a doctor or pharmacist.
본 발명의 비오카닌 A 또는 이의 약학적으로 허용 가능한 염이 상기와 같은 퇴행성 뇌질환 예방 및 개선을 위해 이용되기 위해서는, 식품학 또는 약제학적 분야에서 공지된 다양한 방법에 의해 제조될 수 있으며 그 자체 또는 식품학적으로 허용되는 담체, 부형제, 희석제 등과 혼합하여 경구로 섭취할 수 있는 어떤 식품 형태로도 제조될 수 있다. 바람직하게는 음료, 환, 과립, 정제 또는 캅셀 형태이다.In order for the biocanin A of the present invention or a pharmaceutically acceptable salt thereof to be used for the prevention and improvement of degenerative brain diseases as described above, it may be prepared by various methods known in the field of pharmacy or pharmacy, Can be prepared in any food form that can be ingested orally by mixing with pharmaceutically acceptable carriers, excipients, diluents, and the like. Preferably in the form of beverage, ring, granule, tablet or capsule.
본 발명의 건강 기능 식품은, 식품 제조 시에 통상적으로 첨가되고 식품학적으로 허용되는 성분을 더 포함할 수 있다. 예컨대, 음료수로 제조되는 경우에는 본 발명의 비오카닌 A 또는 이의 약학적으로 허용 가능한 염 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙 등에서 하나 이상의 성분을 추가로 포함시킬 수 있다.The health functional food of the present invention may further comprise ingredients that are conventionally added at the time of food production and which are pharmaceutically acceptable. For example, in the case of beverage preparation, one or more components may be further included in citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, juice, etc., in addition to biocanin A of the present invention or pharmaceutically acceptable salts thereof.
본 발명에 따른 건강기능식품의 유효성분으로 포함될 수 있는 양은 퇴행성 뇌질환 예방 및 개선을 원하는 사람의 연령, 성별, 체중, 상태, 질병의 증상에 따라 적절히 선택될 수 있으며, 바람직하게는 성인기준 1일 0.01 g 내지 10.0 g 정도로 포함되는 것이 좋으며, 이러한 함량을 갖는 건강 기능 식품을 섭취함으로써 퇴행성 뇌질환 예방 및 개선 효과를 얻을 수 있다.The amount of the active ingredient of the health functional food according to the present invention may be appropriately selected depending on the age, sex, weight, condition and symptom of a person who desires to prevent or improve the degenerative brain disease, Day to 0.01 g to 10.0 g. By taking the health functional food having such a content, prevention and improvement of degenerative brain diseases can be obtained.
본 발명에 따른 비오카닌 A는 베타-아밀로이드 플라크의 생성 효소인 BACE1(beta-secretase 1)에 대한 저해 또는 억제를 통해 베타-아밀로이드 플라크의 생성을 효과적으로 억제할 수 있음을 확인하였고, 상기에 의하여 베타-아밀로이드 플라크에 의해 유도되는 퇴행성 뇌질환, 특히 알츠하이머성 치매를 효과적으로 예방 또는 치료할 수 있다. It has been confirmed that biocanin A according to the present invention can effectively inhibit the formation of beta-amyloid plaques through inhibition or inhibition of BACE1 (beta-secretase 1), which is an enzyme producing beta-amyloid plaques, Degenerative brain diseases induced by beta-amyloid plaques, especially Alzheimer ' s dementia, can be effectively prevented or treated.
도 1은 비오카닌 A의 화학적 구조를 나타낸 것이다.
도 2는 비오카닌 A을 처리하는 경우 BACE1(beta-secretase)의 저해 효과를 나타낸 것이다.
도 3은 비오카닌 A의 IC50값을 나타낸 것이다.
도 4는 기질 농도(substrate concentration)에 따른 비오카닌 A의 BACE1 저해 양상을 딕슨플롯(Dixon plot)으로 나타낸 것이다.
도 5는 비오카닌 A의 BACE1의 저해 양상을 라인웨버-벌크플롯(Lineweaver-Burk plot)으로 나타낸 것이다. Fig. 1 shows the chemical structure of biocanin A. Fig.
Fig. 2 shows the inhibitory effect of BACE1 (beta-secretase) upon treatment with biocanin A. Fig.
Figure 3 shows IC 50 values for biocanin A;
FIG. 4 shows the BACE1 inhibition pattern of biocanin A according to the substrate concentration in a Dixon plot.
Figure 5 shows the inhibition of BACEl of biocanin A by Lineweaver-Burk plot.
이하, 본 발명을 실시예 및 도면을 참조하여 상세히 설명하기로 한다. 그러나, 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail with reference to embodiments and drawings. However, these examples are for further illustrating the present invention, and the scope of the present invention is not limited to these examples.
실시예Example 1. 실험재료 1. Experimental material
비오카닌 A(Biochanin A, ≥97%)는 Sigma-aldrich 사로부터 구입되었고, 비오카닌 A가 BACE1(beta-secretase 1)을 저해하는지 확인하기 위한 실험에 필요한 키트(kit)는 Pan Vera 사에서 구입하였다. BACE1에 대한 특이성, 선택성 실험에 필요한 세린 프로테아제(serine proteases)와 TACE(alpha secretase)는 Sigma-aldrich 사에서 구입하였다.Biocinin A (≥97%) was purchased from Sigma-aldrich and the kit required for the experiment to determine if biocanin A inhibited BACE1 (beta-secretase 1) was purchased from Pan Vera Inc. . Serine proteases and TACE (alpha secretase) required for BACE1 specificity and selectivity experiments were purchased from Sigma-aldrich.
실시예Example 2. 2. BACE1(beta-secretase 1)의Of BACE1 (beta-secretase 1) 저해 효과 측정 및 저해 양상 파악 Measure inhibition effects and identify inhibition patterns
비오카닌 A의 알츠하이머성 치매에 대한 예방 및 치료 효과를 검증하기 위해 BACE1(beta-secretase 1) 저해 실험을 하였다. 기질(Rh-EVNLDAEFK-Quencher)은 BACE1 assay buffer을 이용하여 750 nM 로 분주하고, 저해제는 버퍼(buffer)에 10, 25 50, 100 μM 농도별로 희석한다. 그 후 BACE1을 1.0 U/mL로 희석하여 효소, 저해제 및 기질 순으로 384-black micro well plate에 넣고 25℃에서 60분간 반응시켰다. fluorescence microplate reader를 이용하여 excitation은 530 nm, emission은 590 nm에서 형광을 측정하였으며, 하기 수식에 의하여 저해율(inbibition)을 계산하였다. BACE1 (beta-secretase 1) inhibition experiments were conducted to verify the preventive and therapeutic effects of Biocanin A on Alzheimer's dementia. The substrate (Rh-EVNLDAEFK-Quencher) is diluted to 750 nM using BACE1 assay buffer and the inhibitor is diluted to 10, 25, 50 and 100 μM in buffer. BACE1 was diluted to 1.0 U / mL, and the enzyme, inhibitor and substrate were placed in a 384-black micro well plate and reacted at 25 ° C for 60 minutes. The fluorescence was measured at 530 nm for excitation and 590 nm for emission using a fluorescence microplate reader, and the inhibition rate was calculated by the following equation.
Inhibition (%) = [1 - (S - S 0 ) / (C - C 0 )] × 100Inhibition (%) = [1 - ( S - S 0 ) / ( C - C 0 )] 100
C : Fluorescence of control after 60min of incubation (enzyme, assay buffer and substrate) C : Fluorescence of control after 60 min of incubation (enzyme, assay buffer and substrate)
C 0 : Fluorescence of the control at time 0 C 0 : Fluorescence of the control at
S : Fluorescence of control after 60min of incubation (enzyme, sample solution and substrate) S : Fluorescence of control after 60 min of incubation (enzyme, sample solution and substrate)
S 0 : Fluorescence of the tested samples (S) at time 0 S 0 : Fluorescence of the tested samples ( S ) at
또한, 비오카닌 A의 BACE1 저해 패턴을 알아보고자 기질 농도를 달리하여 (250, 500, 750 nM) 각각의 저해능을 측정한 후, sigma plot ver. 12.3 프로그램을 이용하여, 딕슨플롯(Dixon plot)과 라인웨버-벌크플롯(Lineweaver-Burk plot)으로 나타내었다. In order to examine BACE1 inhibition pattern of biocanin A, the inhibition patterns of 250, 500, and 750 nM were measured at different substrate concentrations. Then, sigma plot ver. 12.3 program using a Dixon plot and a Lineweaver-Burk plot.
양성 대조군으로는 BACE1에 대한 억제 효과가 이미 알려진 레스베라트롤(resveratrol)을 사용하였고, 비오카닌 A는 농도별(10, 25, 50 및 100 μM)로 BACE1 에 대하여 21.20±0.44%, 33.50±0.91%, 54.03±130% 및 62.85±1.88%의 저해효과를 나타내었다(도 2). 비오카닌 A는 농도 의존적으로 BACE1를 저해하였으며, 유의적인 차이를 보였다 (p<0.001). 특히, 50μM 농도에서 레스베라트롤과 유사한 수준의 효과를 보였다. Resoratrol, a known inhibitor of BACE1, was used as a positive control. Biotanin A was found to be 21.20 ± 0.44%, 33.50 ± 0.91% for BACE1 at concentrations of 10, 25, 50 and 100 μM, , 54.03 ± 130% and 62.85 ± 1.88%, respectively (FIG. 2). Biocanin A inhibited BACE1 in a dose dependent manner and showed a significant difference ( p <0.001). Especially, at the concentration of 50 μM, the effect was similar to that of resveratrol.
비오카닌 A의 효소 저해 패턴을 딕슨플롯(Dixon plot)을 이용하여 연구한 결과, IC50 값은 6.2×10-5 M (도 3)으로 나타났고, Ki 는 4.9×10-5 M (도 4 및 도 5)을 나타났다. 따라서, Ki 가 χ절편 인 것으로 보아, 비오카닌 A는 BACE1 기질과 비경쟁적으로 BACE1을 저해하는 양상을 지닌 물질임을 알 수 있었다. The enzyme inhibition pattern of biocanin A was studied using a Dixon plot. As a result, IC 50 value was 6.2 × 10 -5 M (FIG. 3) and K i was 4.9 × 10 -5 M 4 and 5). Therefore, considering that K i is a χ intercept, biocanin A was found to be a substance that inhibits BACE1 in a non-competitive manner with BACE1 substrate.
실시예Example 3. 3. BACE1(beta-secretase 1)에BACE1 (beta-secretase 1) 대한 선택성·특이성 연구 Selectivity / specificity study
비오카닌 A가 BACE1만을 선택적으로 저해하는지 알아보기 위하여 트립신(trypsin), 키모트립신(chymotrypsin), 엘라스타아제(elastase)와 같은 세린단백질가수분해효소(serine proteases)에 대한 저해실험을 진행하였다. 트립신, 키모트립신 및 엘라스타아제의 저해 활성 측정은 0.05 M Tris-HCl (pH 8.2, 0.02 M CaCl2 buffer)를 사용하였고 기질은 각각 1.25 mM z-Arg-pNA, 1.25 mM z-L-Tyr-pNA, 3.6 mM N-Suc-(Ala)3-pNA를 사용하였다. 96-micro well plate를 사용하여 410 nm에서 OD(optical density) 값을 측정하였다. 또한, TACE(alpha secretase) 저해 정도를 측정하여 non-amylodogenic pathway에 대한 활성을 알아보고자 recombinant human TACE (0.1 ppm in 25 mM Tris buffer) 50 μL, sample 48 μL, Mca-PLAQAV-Dpa- RSSSR-NH2 (substrate)를 96-black micro well plate에 넣고 25℃에서 60분간 반응시킨 후, fluorescence ELISA를 이용하여 excitation은 320 nm, emission은 405 nm에서 형광강도를 측정하여 실시예 2의 BACE1과 동일한 방법으로 저해율을 계산하였다. Inhibition of serine proteases such as trypsin, chymotrypsin and elastase was investigated to see if biocanin A selectively inhibited BACE1 alone. Trypsin inhibitory activity Measurement of chymotrypsin and elastase dehydratase is 0.05 M Tris-HCl using (pH 8.2, 0.02 M CaCl 2 buffer) was the substrate is 1.25 mM z -Arg- p NA, 1.25 mM z -L-Tyr , respectively - p NA, 3.6 mM N- Suc- (Ala) 3 - p NA. The optical density (OD) was measured at 410 nm using a 96-well plate. In addition, 50 μL of recombinant human TACE (0.1 ppm in 25 mM Tris buffer), 48 μL of sample, and Mca-PLAQAV-DpA-RSSSR-NH were measured to determine the degree of TACE (alpha secretase) inhibition and activity against non-amylodogenic pathway 2 substrate was incubated at 25 ° C for 60 minutes and the fluorescence intensity was measured at 320 nm for excitation and 405 nm for emission using a fluorescence ELISA. The fluorescence intensity was measured using the same method as BACE1 in Example 2 To calculate the inhibition rate.
BACE1에 대한 효소특이성을 관찰하기 위하여 non-amyloidogenic pathway에 관여하는 TACE 및 세린 프로테아제(트립신, 키모트립신 및 엘라스타아제)에 대한 비오카닌 A의 억제 능력을 살펴보았다. 그 결과, 비오카닌 A는 TACE, 트립신, 키모트립신 및 엘라스타아제에 대한 저해효과는 보이지 않았다 (표 1).In order to observe the enzyme specificity for BACE1, we examined the inhibitory ability of biocanin A on TACE and serine proteases (trypsin, chymotrypsin and elastase) involved in the non-amyloidogenic pathway. As a result, biocanin A showed no inhibitory effect on TACE, trypsin, chymotrypsin and elastase (Table 1).
따라서, 비오카닌 A가 BACE1에 대한 선택적, 특이적인 억제제(specific inhibitor of BACE1)임을 확인할 수 있다.Therefore, it can be confirmed that biocanin A is a specific inhibitor of BACE1 against BACE1.
Claims (7)
[화학식 1]
A method of inhibiting BACE1 (beta-secretase 1) activity by treating biotanin A represented by the following formula 1 with BACE1 (beta-secretase 1) in Invitro.
[Chemical Formula 1]
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