KR101928553B1 - A Composition for Preventing or Treating Inflammasome Mediated Inflammatory Disease Containing Ginsenoside Compounds - Google Patents
A Composition for Preventing or Treating Inflammasome Mediated Inflammatory Disease Containing Ginsenoside Compounds Download PDFInfo
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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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
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- 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
- A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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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 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 유효성분으로 함유하는 인플라마좀 매개 염증성 질환의 예방, 개선 또는 치료용 조성물에 관한 것이다.The present invention relates to a composition for preventing, ameliorating or treating inflammatory mediated inflammatory diseases containing the ginsenoside compound represented by the general formula (1) or (2) as an active ingredient.
인플라마좀(inflammasomes)은 카스파제-1-활성화 복합 단백질 복합체로, 1) 감각 단백질(sensor protein)인 NLRP3(NOD-like receptor family, pyrin domain-containing 3), 2) 연결 단백질(adaptor protein)인 ASC(adaptor protein apoptosis-associated spec-like protein containing a caspase-recruitment domain) 및 3) 이펙터 단백질인 프로카스파제-1으로 구성된다. 상기한 인플라마좀 구성 성분들은 미생물의 감염이나 조직의 상해가 발생한 경우에 조립되는데, 시토졸에서 조립에 의해 활성화된 인플라마좀은 카스파제-1을 활성화시켜 인터루킨(IL)-1β 또는 인터루킨-18을 분비하여 숙주의 선천면역 방어기능을 수행한다(Schroder K, Tschopp J, Cell 140:821-832(2010); Franchi L, Munoz-Planillo R, Nunex, Nat Immunol 13:325-332(2012)).Inflammasomes are caspase-1-activated complex protein complexes, which are composed of 1) a sensor protein, NLRP3 (NLRP3), 2) an adapter protein, , And 3) an effector protein, pro-caspase-1, which is an ASC (apoptosis-associated spec-like protein containing a caspase-recruitment domain). The above inflammase components are assembled when microbial infection or tissue injury occurs. The inflammase activated by assembly in the cytosol activates caspase-1 to produce interleukin (IL) -1β or interleukin- 18, and performs the innate immune defense function of the host (Schroder K, Tschopp J, Cell 140: 821-832 (2010); Franchi L, Munoz-Planillo R, Nunex, Nat Immunol 13: 325-332 ).
상기한 메카니즘에 기초하여, NLRs(Nucleotide-binding Oligomerization Domain (NOD)-Like Receptors) 또는 ASC 및 인플라마좀 복합체의 형성 억제가 이들 단백질에 의해 매개되는 질환을 치료할 수 있는 잠재적인 방법으로 고려되었다(문헌[Ozaki et al., Journal of Inflammation Research 2015, 8:15-27]).Based on the above mechanism, inhibition of the formation of NLRs (Nucleotide-binding Oligomerization Domains (NOD) -Like Receptors) or ASCs and inflamase complexes has been considered as a potential way to treat diseases mediated by these proteins Ozaki et al., Journal of Inflammation Research 2015, 8: 15-27).
인삼에는 사포닌을 의미하는 다양한 종류의 진세노사이드가 함유되어 있다. 진세노사이드는 아글리콘(aglycone)의 구조에 따라 프로토파낙사이다이올계(Protopanaxadiol-type, PPD 타입) 진세노사이드, 프로토파낙사트라이올계(Protopanaxatriol-type, PPT 타입) 진세노사이드 및 올레아놀린산계(Oleanolic acid 타입) 진세노사이드의 세 가지로 분류될 수 있다. 이러한 세 그룹은 다시, 화합물 구조 중 아글리콘(aglycone) 고리의 3번 탄소, 6번 탄소 및 20번 탄소 위치에 글리코시드 결합 (glycosidic bond)에 의해 부착되는 당의 위치, 당의 수 및 당의 종류에 따라 분류된다. Ginseng contains various kinds of ginsenosides, which are saponins. The ginsenosides are classified as protopanaxadiol-type (PPD type) ginsenoside, protopanaxatriol-type (PPT type) ginsenoside, and oleanolin acid type based on the structure of aglycone (Oleanolic acid type) and ginsenosides. These three groups are again dependent on the position of the sugar attached by the glycosidic bond at the 3-carbon, 6-carbon and 20-carbon positions of the aglycone ring in the compound structure, the number of sugars and the type of sugar .
지페노사이드(gypenoside) LXXV는 PPD 타입, 진세노사이드(ginsenoside) Rf는 PPT 타입에 속하는 진세노사이드 화합물이다. 그러나, 상기 진세노사이드 화합물이 인플라마좀 활성을 억제하여 인플라마좀 매개 질환의 예방, 개선 또는 치료에 사용될 수 있는지는 전혀 알려진 바가 없다.Gypenoside LXXV is a PPD type, and ginsenoside Rf is a ginsenoside belonging to the PPT type. However, it is not known at all whether the ginsenoside compound can be used for the prevention, amelioration or treatment of inflammatory mediated diseases by inhibiting the activity of inflammose.
본 발명자들은 인삼에 함유된 다양한 진세노사이드 화합물들 중 화학식 1로 표시되는 PPD 계열의 진세노사이드 화합물 1종과 화학식 2로 표시되는 PPT 계열의 진세노사이드 화합물 1종이 현저히 우수한 인플라마좀 억제 효능이 있음을 확인하고 본 발명을 완성하였다.The inventors of the present invention found that among the various ginsenoside compounds contained in ginseng, one kind of PPD-based ginsenoside compound represented by Chemical Formula 1 and one kind of PPS-based ginsenoside compound represented by Chemical Formula 2 are remarkably excellent in the effect of inhibiting inflammation And completed the present invention.
따라서, 본 발명의 목적은 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 유효성분으로 함유하는, 인플라마좀 매개 염증성 질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다.Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating inflammatory disease mediated by inflammation, which comprises the ginsenoside compound represented by the general formula (1) or (2) as an active ingredient.
본 발명의 또 다른 목적은 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 유효성분으로 함유하는, 인플라마좀 매개 염증성 질환의 예방 또는 개선용 식품 조성물을 제공하는 것이다.It is still another object of the present invention to provide a food composition for preventing or ameliorating an inflammatory disease mediated by inflammation, comprising the ginsenoside compound represented by the general formula (1) or (2) as an active ingredient.
이를 구체적으로 설명하면 다음과 같다. 한편, 본 발명에서 개시된 각각의 설명 및 실시형태는 각각에 대한 다른 설명 및 실시형태에도 적용될 수 있다. 즉, 본 발명에 개시된 다양한 요소들의 모든 조합이 본 발명의 범주에 속한다. 또한, 하기 기술된 구체적인 서술에 의하여 본 발명의 범주가 제한된다고 볼 수 없다.This will be described in detail as follows. On the contrary, the description and the embodiments disclosed in the present invention can be applied to other descriptions and embodiments. That is, all combinations of various elements disclosed in the present invention fall within the scope of the present invention. Further, the scope of the present invention is not limited by the detailed description described below.
인플라마좀 매개 염증성 질환의 예방 또는 치료용 약학 조성물Pharmaceutical compositions for the prevention or treatment of inflammatory diseases mediated by inflammation
본 발명은 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 유효성분으로 함유하는, 인플라마좀 매개 염증성 질환의 예방 또는 치료용 약학 조성물을 제공한다.The present invention provides a pharmaceutical composition for preventing or treating inflammatory disease mediated by inflammation, which comprises, as an active ingredient, a ginsenoside compound represented by Chemical Formula (1) or Chemical Formula (2).
본 발명에서 용어 “진세노사이드(ginsenoside)”는 천연 스테로이드 글리코사이드이자 트라이터펜 사포닌의 일종으로, 인삼 속에 속하는 식물 속에서 많이 발견되며 인삼 화합물에 대해 약리학적 연구를 한 전통의학에서 오랫동안 사용해 온 물질이다.The term " ginsenoside " in the present invention is a kind of natural steroid glycoside isoturator pen saponin. It is found in many plants belonging to the genus Ginseng and has been used for a long time in traditional medicine which has conducted pharmacological studies on ginseng compounds Material.
본 발명의 화학식 1로 표시되는 진세노사이드 화합물은 하기 구조를 갖는 Gypenoside LXXV이다.The ginsenoside compound represented by
<화학식 1>≪ Formula 1 >
본 발명의 화학식 2로 표시되는 진세노사이드 화합물은 하기 구조를 갖는 Ginsenoside Rf이다:The ginsenoside compound represented by formula (2) of the present invention is Ginsenoside Rf having the following structure:
<화학식 2>(2)
상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물은 식물에서 추출될 수 있고, 당업계에 공지된 방법에 따라 산을 이용한 가수분해, 열을 이용한 가수분해, 초음파를 이용한 가수분해, 효소를 이용한 가수분해 또는 합성하여 사용할 수도 있으며, 상업적으로 시판되는 것을 사용할 수도 있다. 예컨대, 상기 화합물은 인삼 추출물에서 수득할 수 있다. 이때 사용되는 인산의 종류는 특별히 제한되지 않고, 수삼, 홍삼, 백삼, 태극삼, 미삼 등을 사용할 수 있다. 또한, 줄기, 뿌리, 잎, 꽃, 열매 등 인삼의 모든 부분으로부터의 추출물이 사용가능하고 어느 특정 부분의 추출물로 한정되지 않는다. 또한, 인삼 추출물로부터 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 추출하는 방법은 공지의 방법을 사용할 수 있다.The ginsenoside compound represented by Chemical Formula 1 or Chemical Formula 2 can be extracted from a plant and hydrolyzed using acid, hydrolysis using heat, hydrolysis using ultrasonic, Hydrolysis or synthesis may be used, or commercially available ones may be used. For example, the compound can be obtained from ginseng extract. The type of phosphoric acid to be used is not particularly limited, and ginseng, red ginseng, white ginseng, taegeuk ginseng, ginseng, etc. may be used. In addition, extracts from all parts of ginseng such as stem, root, leaf, flower, and fruit can be used and are not limited to any particular part of the extract. In addition, a known method may be used for extracting the ginsenoside compound represented by Chemical Formula 1 or Chemical Formula 2 from the ginseng extract.
본 발명의 약학 조성물은 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 조성물 총 중량에 대하여 0.001 내지 50 중량%의 양으로 함유할 수 있다.The pharmaceutical composition of the present invention may contain the ginsenoside compound represented by Formula 1 or Formula 2 in an amount of 0.001 to 50% by weight based on the total weight of the composition.
본 발명에서, 약학적으로 허용되는 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 칼륨, 나트륨 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산, 주석산 및 황산 등으로 제조된 무기산염, 아세트산, 트리플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 구연산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산 등으로 제조된 유기산염, 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산 등으로 제조된 설폰산염, 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염 및 트리메틸아민, 트라이에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다. 본 발명에 있어서 바람직한 염은 염산, 트라이플루오로아세트산, 시트르산, 브롬산, 말레산, 인산, 황산, 타르타르산을 포함한다.In the present invention, the pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry. Examples of the salt include inorganic ion salts such as calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, glutaric acid, Organic acid salts such as hydrochloric acid, hydrobromic acid, citric acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillyric acid and hydroiodic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and naphthalenesulfonic acid; amino acid salts prepared by glycine, arginine, lysine, and the like; and amino acid salts such as trimethylamine, triethylamine, Pyridine, picoline, and the like. However, the types of salts as defined in the present invention are not limited by the listed salts. Preferred salts in the present invention include hydrochloric acid, trifluoroacetic acid, citric acid, bromic acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.
본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 약학조성물은 인플라마좀의 활성화에 따른 IL-1β 생성을 효과적으로 억제함으로써 인플라마좀 매개 염증성 질환의 예방 또는 치료 효과가 탁월하다. 구체적으로, 본 발명의 실험예에서는 마우스 및 사람의 대식 세포를 대상으로 Nigericin 또는 ATP에 의해 유도된 인플라마좀의 활성과 그에 따른 IL-1β 생성이 본 발명의 약학 조성물에 의해 효과적으로 억제됨을 확인하였다(도 1 내지 도 8).The pharmaceutical composition containing the compound represented by the formula (1) or (2) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient effectively inhibits the production of IL-1β upon activation of the inflammase, Is excellent in the prevention or treatment effect. Specifically, in the experimental example of the present invention, it was confirmed that the activity of inflammase induced by Nigericin or ATP and the production of IL-1β in mice and human macrophages were effectively inhibited by the pharmaceutical composition of the present invention (Figs. 1 to 8).
본 발명에서 용어 “인플라마좀(inflammasome)”은 골수성세포(myeoloid cell)의 세포질에 존재하며 선천적 면역 수용체(NOD-like receptor), ASC 단백질 및 caspase-1으로 이루어진 단백질 복합체로써 세포의 감염이나 스트레스 등 선천성 면역 방어체계와 관련된 염증성 사이토카인의 전구체인 pro-IL-1β를 성숙한 IL-1β으로 전화시키는 데에 관여한다. NLRP1, NLRP3, NLRC4, AIM4 등으로 구성된 인플라마좀이 있으며 이중 NLRP3 인플라마좀은 다양한 자가면역질환의 발병과 연관되어있음이 보고되었다.The term " inflammasome " in the present invention exists in the cytoplasm of myeoloid cells and is a protein complex composed of innate immune receptors (NOD-like receptor), ASC protein and caspase-1, 1-beta, which is a precursor of inflammatory cytokines associated with the innate immune defense system, such as IL-1β, into mature IL-1β. NLRP1, NLRP3, NLRC4, and AIM4. Among these, NLRP3 inflammases have been reported to be associated with the onset of various autoimmune diseases.
또한, 증가된 IL-1β는 인간의 선천적 또는 후천적 질병과 관계있으며, IL-1β의 길항제나 수용체가 일부 질병의 성공적인 치료에 도움이 된다는 사실이 밝혀졌다. 따라서, 부적절한 인플라마좀의 작용과 선천적 및 후천적 염증성 질환의 관련성이 면역반응 조절기작에서 중요하게 부각되고 있다. 본 발명의 조성물은 이러한 인플라마좀의 활성을 억제함으로써, 염증성 사이토카인 IL-1β의 분비 양을 효과적으로 조절할 수 있어 염증성 질환의 예방 및 치료에 탁월한 효과를 갖는다.In addition, increased IL-1β has been implicated in human congenital or acquired diseases, and it has been found that antagonists or receptors of IL-1β help in the successful treatment of some diseases. Therefore, the relationship between inappropriate in fl ammers action and congenital and acquired inflammatory diseases has been highlighted in the regulation of immune response. The composition of the present invention can effectively control the secretion amount of inflammatory cytokine IL-1 beta by inhibiting the activity of such inflammas, and thus has an excellent effect for the prevention and treatment of inflammatory diseases.
본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 약학조성물은 인플라마좀 매개 염증성 질환의 예방 또는 치료에 유용하게 사용될 수 있다.The pharmaceutical composition containing the compound represented by the formula (1) or (2) of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be usefully used for the prophylaxis or treatment of an inflammatory mediated inflammatory disease.
본 발명에서 용어 “인플라마좀 매개 염증성 질환”은 인플라마좀 (예컨대, NLRP3 인플라마좀)의 활성을 억제함으로써 예방, 개선 또는 치료 효과를 기대할 수 있는 상태 또는 질환으로, 인플라마좀 매개 염증성 질환의 구체적 종류는 당업계에 널리 공지되어 있다.As used herein, the term " inflammatory mediated inflammatory disease " refers to a condition or disease that can be expected to have an effect of preventing, ameliorating or treating by inhibiting the activity of inflammase (e.g., NLRP3 inflammase) Are well known in the art.
예컨대, 문헌[Shao, Bo-Zong, et al. Frontiers in pharmacology 6 (2015): 262.]은 NLRP3 인플라마좀이 대사성 질환, 다발성 경화증(multiple sclerosis), 염증성 장질환, 크리오피린 관련 주기적 증후군(cryopyrin-associated periodic syndrome; CAPS), 기타 자가면역질환 및 자가염증성 질환 등의 개시 및 진행과 관련되어 있음을 개시한다. 상기 문헌은 MCC950(디아실술포닐우레아-함유 화합물), β-하이드록시부티레이트(BHB), type I 인터페론 및 IFN-β와 같은 NLRP3 인플라마좀 억제제가 IL-1β 분비 억제를 통해 관련 질환의 치료에 사용될 수 있음을 시사한다.See, for example, Shao, Bo-Zong, et al. Frontiers in pharmacology 6 (2015): 262.] have shown that NLRP3 inflammase is effective against metabolic diseases, multiple sclerosis, inflammatory bowel disease, cryopyrin-associated periodic syndrome (CAPS) And autologous inflammatory disease, and the like. This document discloses that NLRP3 inflammase inhibitors such as MCC950 (diacylsulfonylurea-containing compound), beta -hydroxybutyrate (BHB), type I interferon and IFN-beta inhibit IL- It can be used.
문헌[Coll, Rebecca C., et al. Nature medicine 21.3 (2015): 248.]은 NLRP 인플라마좀의 비정상적 활성화가 CAPS와 같은 유전 질환 및 다발성 경화증, 제2형 당뇨병 및 죽상동맥경화증(atherosclerosis) 같은 복합 질환과 연관되어 있음을 개시한다. NLRP3 억제제인 MCC950은 AIM2, NLRC4 또는 NLRP1 활성이 아닌 NLRP3의 활성을 특이적으로 억제하여 canonical 및 non-canonical NLRP3 활성을 차단하고, IL-1β 생성을 억제하여 다발성 경화증의 질환 모델인 자가면역성 뇌척수염(encephalomyelitis; EAE)의 증상을 완화하고, CAPS 마우스 모델의 사후 치사율을 회복시키며, 머켈-웰스(Muckel-Wells) 증후군을 앓는 개체의 ex vivo 샘플에 활성을 갖는 등 자가염증 및 자가면역성 질환을 포함하는 NLRP3-관련 질환의 치료제임을 시사한다.See Coll, Rebecca C., et al. Nature medicine 21.3 (2015): 248.) discloses that the abnormal activation of NLRP inflammase is associated with genetic disorders such as CAPS and multiple diseases such as multiple sclerosis,
문헌[Ozaki, Ema, Matthew Campbell, and Sarah L. Doyle. Journal of inflammation research 8 (2015): 15.]은 NLRP3 인플라마좀이 알츠하이머병, 죽상동맥경화증, 대사 증후군, 및 연령관련 황반변성(age-related macular degeneration; AMD) 등과 연관되어 있으며, 인플라마좀의 최종 산물인 성숙한 IL-1β의 억제(예컨대, IL-1β에 대한 항체)가 NLRP3 인플라마좀 관련 질환에 대한 치료적 전략임을 개시한다.See Ozaki, Ema, Matthew Campbell, and Sarah L. Doyle. The Journal of Inflammation Research 8 (2015): 15.] has shown that NLRP3 inflammase is associated with Alzheimer's disease, atherosclerosis, metabolic syndrome, and age-related macular degeneration (AMD) (I. E., An antibody to IL-1 [beta]), which is the final product of IL-1 [beta], is a therapeutic strategy for NLRP3 inflammase related diseases.
문헌[Yang, Gabsik, Hye Eun Lee, and Joo Young Lee. Scientific reports 6 (2016): 24399.]은 NLRP3 인플라마좀의 약리학적 억제가 고지방 식단으로부터 유도된 비알코올성 지방간 질환을 억제할 수 있음을 시사한다.Yang, Gabsik, Hye Eun Lee, and Joo Young Lee. Scientific reports 6 (2016): 24399.] suggest that pharmacological inhibition of NLRP3 inflammas may inhibit nonalcoholic fatty liver disease induced by high-fat diets.
문헌[Mao, Zhijuan, et al. Neurochemical research 42.4 (2017): 1104-1115.]은 NLRP3 인플라마좀이 파킨슨병의 발병과 연관되어 있고, NLRP3/caspase-1/IL-1β 다운스트림 경로의 억제가 파킨슨병의 발병을 완화할 수 있음을 개시한다.Mao, Zhijuan, et al. Neurochemical research 42.4 (2017): 1104-1115.) Is associated with the onset of NLRP3 inflammatory Parkinson's disease and inhibition of NLRP3 / caspase-1 / IL-1β downstream pathways may alleviate the onset of Parkinson's disease Lt; / RTI >
문헌[Lee, Hye Eun, et al. Scientific reports 6 (2016): 38622.]은 통풍성 관절염이 NLRP3 인플라마좀의 활성을 유도하는 요산 결정의 침착에 의해 발생하며, 통풍성 관절염을 포함하는 다양한 대사성 질환의 발병과 밀접하게 연관되어 있음을 개시한다.Lee, Hye Eun, et al. Scientific reports 6 (2016): 38622.] reported that gouty arthritis is caused by deposition of uric acid crystals that induce the activity of NLRP3 inflammase and is closely related to the onset of various metabolic diseases including gouty arthritis do.
상기 문헌들에서 확인할 수 있듯이, 인플라마좀의 활성을 억제하여 IL-1β 생성을 억제하는 인플라마좀 억제 활성을 갖는 물질이 다양한 질환을 치료할 수 있는 방법이라는 점이 당업계에 공지되어 있다.As can be seen in the above-mentioned documents, it is known in the art that a substance having an inhibitory activity of inflammase that inhibits the activity of inflammose and inhibits IL-1? Production is a method capable of treating various diseases.
본 발명에서 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 함유하는 약학적 조성물은 인플라마좀 활성을 억제한다. 본 발명의 일 실시양태에서, 상기 인플라마좀은 NLRP3(NOD-like receptor family, pyrin domain-containing 3)이다.In the present invention, the pharmaceutical composition containing the ginsenoside compound represented by the general formula (1) or (2) inhibits the activity of the inflammase. In one embodiment of the invention, the inflammase is a NOD-like receptor family (NLRP3).
본 발명에서 인플라마좀 매개 염증성 질환은 자가 염증성 질환, 신경 염증성 질환 및 대사성 질환으로 구성된 군으로부터 선택되는 1종 이상의 질환을 포함한다. 상기 자가 염증성 질환은 머클-웰스 증후군(Muckle-Wells syndrome; MWS), 성인성 지연성 자가면역 당뇨병(LADA), 가족성 한랭 자가면역성 증후군(FCAS), 크리오피린-관련 주기성 증후군(CAPS), 신생아-발병 다기관 염증성 증후군(NOMID), 만성 영아 신경 피부 관절(CINCA) 증후군, 가족성 지중해열(FMF), 전신 발병 소아 특발성 관절염(SJIA), 소아 류마티스 관절염, 성인 류마티스 관절염, 연령관련 황반변성, 아토피성 피부염 및 건선으로 구성된 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지 않으며 당업계에 공지된 기타의 자가 염증성 질환을 포함한다.In the present invention, an inflammatory mediated inflammatory disease includes at least one disease selected from the group consisting of autoinflammatory diseases, neuroinflammatory diseases and metabolic diseases. The autoinflammatory diseases are selected from the group consisting of Muckle-Wells syndrome (MWS), adult delayed autoimmune diabetes (LADA), familial cold autoimmune syndrome (FCAS), cryopyrin- related periodic syndrome (CAPS) (NOMID), CINCA syndrome, FMF, systemic onset idiopathic arthritis (SJIA), pediatric rheumatoid arthritis, adult rheumatoid arthritis, age-related macular degeneration, atopic dermatitis Rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, rheumatoid arthritis, dermatitis, and psoriasis.
상기 신경 염증성 질환은 알츠하이머병, 파킨슨병, 헌팅턴병, 루게릭병, 크로이츠펠트야콥병, 다발성 경화증, 근위축성 측삭 증후군, 미만성루이소체병, 백색질뇌염, 측두엽간질, 및 염증성 척추손상으로 구성된 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지 않으며 당업계에 공지된 기타의 신경 염증성 질환을 포함한다.Wherein said neuroinflammatory disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, Lou Gehrig's disease, Creutzfeldt Jakob disease, multiple sclerosis, amyotrophic lateral scrotosis, diffuse ryocellulosis, albino encephalitis, temporal lobe epilepsy, And may include, but is not limited to, other neuroinflammatory diseases known in the art.
상기 대사성 질환은 비만, 제2형 당뇨병, 고지혈증, 고콜레스테롤증, 죽상동맥경화증, 비알코올성지방간(NAFLD) 및 비알코올성지방간염(NASH)으로 구성된 군으로부터 선택되는 어느 하나 이상일 수 있으나, 이에 제한되지 않으며 당업계에 공지된 기타의 대사성 질환을 포함한다.The metabolic diseases may be selected from the group consisting of obesity,
본 발명의 약학 조성물은 투여를 위해서 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염 외에 추가로 약학적으로 허용되는 담체를 1 종 이상 더 포함할 수 있다. 약학적으로 허용 가능한 담체는 식염수, 멸균수, 링거액, 완충 식염수, 덱스트로즈 용액, 말토 덱스트린 용액, 글리세롤, 에탄올 및 이들 성분 중 1 성분 이상을 혼합하여 사용할 수 있으며, 필요에 따라 항산화제, 완충액, 정균제 등 다른 통상의 첨가제를 첨가할 수 있다. 또한 희석제, 분산제, 계면활성제, 결합제 및 윤활제를 부가적으로 첨가하여 수용액, 현탁액, 유탁액 등과 같은 주사용 제형, 환약, 캡슐, 과립 또는 정제로 제제화할 수 있다. 따라서, 본 발명의 조성물은 패치제, 액제, 환약, 캡슐, 과립, 정제, 좌제 등일 수 있다. 이들 제제는 당 분야에서 제제화에 사용되는 통상의 방법 또는 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA 에 개시되어 있는 방법으로 제조될 수 있으며 각 질환에 따라 또는 성분에 따라 다양한 제제로 제제화될 수 있다.The pharmaceutical composition of the present invention may further contain at least one pharmaceutically acceptable carrier in addition to the compound represented by
본 발명의 약학 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여(예를 들어, 정맥 내, 피하, 복강 내 또는 국소에 적용)할 수 있으며, 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양하다. 본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물의 일일 투여량은 약 1 내지 1000 ㎎/㎏ 이고, 바람직하게는 5 내지 100 ㎎/㎏이며, 하루 일회 내지 수회에 나누어 투여할 수 있다.The pharmaceutical composition of the present invention may be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically) depending on the intended method, and the dose may be appropriately determined depending on the body weight, age, sex, The range varies depending on the condition, diet, administration time, method of administration, excretion rate, and severity of the disease. The daily dose of the compound represented by the formula (1) or (2) of the present invention is about 1 to 1000 mg / kg, preferably 5 to 100 mg / kg, and can be administered once or several times a day.
본 발명의 약학 조성물은 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 각각 함유하거나, 또는 상기 화학식 1로 표시되는 진세노사이드 화합물과 화학식 2로 표시되는 진세노사이드 화합물을 모두 함유할 수 있다. 본 발명의 약학 조성물이 상기 화학식 1 및 화학식 2로 표시되는 화합물을 모두 함유할 경우, 화학식 1로 표시되는 화합물과 화학식 2로 표시되는 화합물을 1:10 내지 10:1의 중량비로 함유할 수 있다.The pharmaceutical composition of the present invention may contain the ginsenoside compound represented by the above formula (1) or (2), or may contain both the ginsenoside compound represented by the above formula (1) and the ginsenoside compound represented by the formula have. When the pharmaceutical composition of the present invention contains all of the compounds represented by
본 발명의 상기 약학적 조성물은 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 이의 약학적으로 허용되는 염 외에 동일 또는 유사한 약효를 나타내는 유효성분을 1 종 이상 더 포함할 수 있다. The pharmaceutical composition of the present invention may further contain at least one active ingredient which exhibits the same or similar pharmacological effect in addition to the ginsenoside compound represented by the above formula (1) or (2) or a pharmaceutically acceptable salt thereof.
본 발명은 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 이의 약학적으로 허용되는 염의 치료학적으로 유효한 양의 투여를 포함하는 인플라마좀 매개 염증성 질환을 예방 또는 치료하는 방법을 제공한다. The present invention provides a method of preventing or treating an inflammatory mediated inflammatory disease comprising administration of a therapeutically effective amount of a ginsenoside compound represented by
본 발명에서 사용되는 “치료학적으로 유효한 양”이라는 용어는 인플라마좀 매개 염증성 질환의 예방 또는 치료에 유효한 상기 화학식 1 또는 화학식 2로 표시되는 화합물의 양을 나타낸다.As used herein, the term " therapeutically effective amount " refers to the amount of the compound of formula (I) or (II) effective for the prevention or treatment of inflammatory mediated inflammatory diseases.
또한, 본 발명은 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염을 인간을 포함하는 포유류에 투여하여 인플라마좀을 억제하는 방법을 제공한다.In addition, the present invention provides a method for inhibiting inflammase by administering a compound represented by the above formula (1) or (2) or a pharmaceutically acceptable salt thereof to a mammal including a human.
본 발명의 인플라마좀 매개 염증성 질환의 예방 또는 치료 방법은 상기 화학식 1 또는 화학식 2로 표시되는 화합물을 투여함으로써, 징후의 발현 전에 질병 그 자체를 다룰 뿐만 아니라, 이의 징후를 저해하거나 피하는 것을 또한 포함한다. 질환의 관리에 있어서, 특정 활성 성분의 예방적 또는 치료학적 용량은 질병 또는 상태의 본성(nature)과 심각도, 그리고 활성 성분이 투여되는 경로에 따라 다양할 것이다. 용량 및 용량의 빈도는 개별 환자의 연령, 체중 및 반응에 따라 다양할 것이다. 적합한 용량 용법은 이러한 인자를 당연히 고려하는 이 분야의 통상의 지식을 가진 자에 의해 쉽게 선택될 수 있다. 또한, 본 발명의 인플라마좀 매개 염증성 질환의 예방 또는 치료 방법은 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물과 함께 질환 치료에 도움이 되는 추가적인 활성 제제의 치료학적으로 유효한 양의 투여를 더 포함할 수 있으며, 추가적인 활성제제는 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물과 함께 시너지 효과 또는 보조적 효과를 나타낼 수 있다.The method for the prophylaxis or treatment of an inflammatory mediator of inflammatory disease according to the present invention not only treats the disease itself before the manifestation of the symptoms but also inhibits or avoids the symptoms thereof by administering the compound represented by the
본 발명은 또한 인플라마좀 매개 염증성 질환의 치료용 약제의 제조를 위한 상기 화학식 1 또는 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용되는 염의 용도를 제공한다. 약제의 제조를 위한 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물은 허용되는 보조제, 희석제, 담체 등을 혼합할 수 있으며, 기타 활성제제와 함께 복합 제제로 제조되어 활성 성분들의 상승 작용을 가질 수 있다. The present invention also provides the use of a compound represented by the above formula (1) or (2) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of inflammatory mediated inflammatory diseases. The ginsenoside compound represented by the above formula (1) or (2) for the preparation of a medicament may be mixed with an acceptable adjuvant, diluent, carrier or the like, and may be prepared as a combined preparation together with other active agents, .
본 발명의 용도, 조성물, 치료 방법에서 언급된 사항은 서로 모순되지 않는 한 동일하게 적용된다.The matters mentioned in the use, composition and treatment method of the present invention are applied equally unless they are mutually contradictory.
인플라마좀 매개 염증성 질환의 예방 또는 개선용 식품 조성물Food compositions for the prevention or amelioration of inflammatory disease mediated inflammatory diseases
본 발명은 또한, 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물 또는 그의 염을 함유하는, 인플라마좀 매개 염증성 질환의 예방 또는 개선용 식품 조성물을 제공한다.The present invention also provides a food composition for preventing or ameliorating an inflammatory mediated inflammatory disease, which comprises a ginsenoside compound represented by the general formula (1) or (2) or a salt thereof.
상기 화학식 1 또는 화학식 2는 위에서 정의한 바와 같다.(1) or (2) are as defined above.
본 발명의 일 실시양태에서, 식품 조성물은 건강기능식품 또는 건강보조식품일 수 있다.In one embodiment of the invention, the food composition may be a health functional food or a health supplement.
본 발명에서 사용되는 용어, "건강식품 (health food)"은 일반 식품에 비해 적극적인 건강 유지나 증진 효과를 가지는 식품을 의미하고, "건강보조식품 (health supplement food)"은 건강 보조 목적의 식품을 의미한다. 경우에 따라, 기능성 식품, 건강식품, 건강보조식품의 용어는 호용된다. 상 기 식품은 유용한 효과를 얻기 위하여 정제, 캅셀, 분말, 과립, 액상, 환 등의 다양한 형태로 제조될 수 있다.The term " health food " used in the present invention refers to a food having an active health promotion effect or enhancement effect compared to a general food, and " health supplement food " do. In some cases, the terms functional foods, health foods, and health supplements are commonly used. The food can be prepared in various forms such as tablets, capsules, powders, granules, liquids, rings and the like in order to obtain useful effects.
본 발명에서 사용되는 용어, "기능식품 (functional food)"은 특정보건용 식품 (food for special health use, FoSHU)와 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다.The term " functional food " used in the present invention refers to a food for special health use (FoSHU) It means foods with high effectiveness.
본 발명의 건강기능식품의 구체적인 예로, 상기 화학식 1 또는 화학식 2로 표시되는 진세노사이드 화합물을 이용하여 농산물의 특성을 살려 변형시키는 동시에 저장성을 좋게 한 가공식품을 제조할 수 있다.As a specific example of the health functional food of the present invention, it is possible to produce a processed food having good storage properties while utilizing the characteristics of agricultural products using the ginsenoside compound represented by the above formula (1) or (2).
본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물 또는 그의 약학적으로 허용되는 염을 유효성분으로 함유하는 조성물은 인플라마좀의 활성화에 따른 IL-1β 생성을 효과적으로 억제함으로써 인플라마좀 매개 염증성 질환의 예방 또는 치료 효과가 탁월하다. 따라서, 본 발명의 조성물은 다양한 NLRP3 인플라마좀 매개 염증성 질환의 예방, 개선 또는 치료제로 유용하게 사용될 수 있다.The composition containing the compound represented by the formula (1) or (2) or the pharmaceutically acceptable salt thereof of the present invention as an active ingredient effectively inhibits the production of IL-1β by the activation of inflammase, Prevention or treatment effect is excellent. Therefore, the composition of the present invention can be usefully used as a preventive, ameliorating, or therapeutic agent for a variety of NLRP3 inflammatory mediated inflammatory diseases.
도 1은 본 발명의 화합물이 인플라마좀 활성화에 미치는 영향을 나타낸다.
도 2는 본 발명의 화합물의 세포 독성 측정 결과를 나타낸다.
도 3은 본 발명의 화합물의 농도별 nigericin유도 IL-1β 생성 억제 효과를 나타낸다.
도 4는 본 발명의 화합물의 농도별 ATP-유도 IL-1β 생성 억제 효과를 나타낸다.
도 5는 인간 대식세포주에서 본 발명의 화합물에 의한 nigericin유도 IL-1β 생성 억제 효과를 나타낸다.
도 6은 본 발명의 화합물에 의한 nigericin유도 IL-1β 생성 억제 IC50
도 7은 인간 대식세포주에서 본 발명의 화합물에 의한 ATP유도 IL-1β 생성 억제 효과를 나타낸다.
도 8은 본 발명의 화합물에 의한 ATP유도 IL-1β 생성 억제 IC50를 나타낸다.Figure 1 shows the effect of the compounds of the present invention on the activation of inflammation.
2 shows the cytotoxicity measurement results of the compounds of the present invention.
Fig. 3 shows the nigericin-induced inhibition of IL-1β production by concentration of the compound of the present invention.
Fig. 4 shows the ATP-induced IL-1? Production inhibitory effect of the compound of the present invention by concentration.
Fig. 5 shows the inhibitory effect of the compound of the present invention on nigericin-induced IL-1? Production in human macrophage cell lines.
Figure 6 shows the inhibition of nigericin-induced < RTI ID = 0.0 > IL-1 &
Fig. 7 shows the effect of inhibiting ATP-induced IL-1? Production by the compounds of the present invention in human macrophage cell lines.
Figure 8 shows the ATP induced IL-1β IC 50 generates inhibition by compounds of the invention.
이하, 본 발명을 하기 실시예를 통하여 보다 상세하게 설명한다. 그러나 실시예는 본 발명을 설명하기 위해 예시적으로 제공되었을 뿐, 본 발명의 범위가 실시예의 기재에 한정되지 않는다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the embodiments have been provided by way of example only for explaining the present invention, and the scope of the present invention is not limited to the description of the embodiments.
<실시예> 실험 재료 및 방법EXAMPLES Materials and Methods
1. 진세노사이드 화합물의 준비1. Preparation of ginsenoside compounds
실험에 사용한 화학식 1 또는 화학식 2로 표시되는 화합물은 에이스엠자임으로부터 순도 98% 이상의 표준물질을 구입하여 사용하였다.The compound represented by the formula (1) or (2) used in the experiment was purchased from Ace Emzyme with a standard material having a purity of 98% or more.
2. 세포 배양2. Cell culture
문헌[Joung SM, Park ZY, Rani S, Takeuchi O, Akira S, Lee JY. Akt contributes to activation of the TRIF-dependent signaling pathways of TLRs by interacting with TANK-binding kinase 1. J Immunol, 186(1): 499-507.] 등에 공지된 방법에 따라, C57BL/6 생쥐로부터 골수 및 골수 유래 초대 마이크로파지(bone marrow-derived primary macrophages; BMDMs)를 분리하였다. THP-1세포는 ATCC(Manassas, US)로부터 구입하였다. [Joung SM, Park ZY, Rani S, Takeuchi O, Akira S, Lee JY. Bone marrow and bone marrow were isolated from C57BL / 6 mice according to the method known by J Immunol, 186 (1): 499-507, etc., by TRIF-dependent signaling pathways of TLRs by interacting with TANK- And bone marrow-derived primary macrophages (BMDMs). THP-1 cells were purchased from ATCC (Manassas, US).
3. 시약3. Reagents
대장균으로부터 정제된 LPS는 List Biological Laboratory Inc (Hornby, Canada)로부터 얻어 무독소 용액에 용해시켜 사용하였다. 실험에 사용된 33종의 진세노사이드는 98%이상의 고순도 물질을 사용하였다.LPS purified from E. coli was obtained from List Biological Laboratory Inc (Hornby, Canada) and dissolved in the toxin solution. For the 33 species of ginsenosides used in the experiment, 98% or more of high purity substance was used.
ATP 및 Nigericin은 Invivogen (San Diego, USA)에서 구입하였으며, 인터루킨(interleukin; IL)-1β는 R&D Systems (Minneapolis, MN, USA)에서 구입하였다.ATP and Nigericin were purchased from Invivogen (San Diego, USA) and interleukin (IL) -1β was purchased from R & D Systems (Minneapolis, MN, USA).
4. 실험방법4. Experimental Method
ELISA 실험을 위해, 공지 문헌[Levels of IL-1β in cell culture supernatants were determined with an ELISA kit (IL-1β: R&D Systems) according to the manufacturer’s instructions]에 기재된 방법을 사용하였다. 세포 배양 상청액 중 IL-1β 수준을 ELISA 키트 (IL-1β : R & D Systems)를 사용하여 제조자의 지시에 따라 결정 하였다.For the ELISA experiments, the method described in accordance with a known document [Levels of IL-1β in cell culture supernatants were determined with an ELISA kit (IL-1β: R & D Systems)] was used. Levels of IL-1 [beta] in cell culture supernatants were determined using an ELISA kit (IL-1 [beta]: R & D Systems) according to the manufacturer's instructions.
<실험예 1> 세포 시스템에서 인플라마좀 제어 효능을 가진 인삼의 진세노사이드 물질 발굴Experimental Example 1: Detection of ginsenoside substance of ginseng having an effect of controlling inflammase in a cell system
인삼의 진세노사이드 물질이 인플라마좀 활성화에 미치는 영향을 분석하고자, 다양한 진세노사이드 화합물을 마우스 대식세포에 처리하고, 인플라마좀 활성화제인 nigericin을 처리하였다. Nigericin은 세포 K+ 이온의 방출을 유도하여 NLRP3 인플라마좀의 활성을 유도하며, NLRP3 인플라마좀의 활성화는 pro-caspase-1을 caspase-1으로 활성화시켜, pro-IL-1β를 성숙한(mature) IL-1β로 절단한다는 것이 공지되어 있다. 본 실험예에서는 세포 배양액 내 성숙한 IL-1β의 양을 ELISA로 측정함으로써 NLRP3 인플라마좀의 활성화 정도를 확인하였다.To investigate the effect of ginsenoside ginsenoside on the activation of inflammation, various ginsenoside compounds were treated with mouse macrophages and treated with nigericin, an in fl ammax activator. Nigericin induces NLRP3 inflammase activity by inducing the release of K + ions. Activation of NLRP3 inflammase activates pro-caspase-1 to caspase-1 and activates pro-IL-1β to mature ) IL-l [beta]. ≪ / RTI > In this experimental example, the degree of activation of NLRP3 inflammase was confirmed by measuring the amount of mature IL-1β in the cell culture by ELISA.
구체적으로, 다양한 인삼의 진세노사이드 물질(22종의 PPD 계열 화합물 및 9종의 PPT 계열 화합물)을 100 μg/ml 농도로 마우스 대식 세포에 처리하여, NLRP3 작용제인 nigericin에 의하여 유도되는 성숙한 IL-1β 생성에 미치는 영향을 조사하였다.Specifically, ginsenosides of various ginseng (22 kinds of PPDs and 9 kinds of PPTs) were treated with mouse macrophages at a concentration of 100 μg / ml, and the mature IL-12 induced by nigericin, an NLRP3 agonist, 1β production.
그 결과, nigericin 처리에 의해 유도된 IL-1β는 200 pg/ml인 반면, 본 발명 따른 화학식 1 및 화학식 2의 화합물은 IL-1β 생성을 50% 이상 억제하는 효과가 있음을 확인하였다 (도 1).As a result, it was confirmed that IL-1? Induced by nigericin treatment was 200 pg / ml while compounds of formula (1) and (2) according to the present invention had an effect of inhibiting IL-1? Production by more than 50% ).
상기 실험예를 통해, 본 발명의 조성물은 우수한 NLRP3 인플라마좀 억제 활성을 나타냄으로써 NLRP3 인플라마좀 관련 질환의 예방, 개선 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental example, it was confirmed that the composition of the present invention exhibits excellent NLRP3 inflammase inhibitory activity and can be used as a preventive, ameliorating or therapeutic agent for NLRP3 inflammase related diseases.
<실험예 2> 화학식 1 또는 화학식 2 화합물의 세포 독성 측정Experimental Example 2 Cytotoxicity measurement of the compound of formula (1) or (2)
실험예 1에서 확인한 본 발명의 화학식 1 또는 화학식 2로 표시되는 화합물의 IL-1β 생성억제 효과가 세포 사멸에 의한 IL-1β 생성 억제 효과인지 확인하기 위하여 대식 세포에 상기 화합물을 16시간 처리한 후 세포 생존율을 측정하였다.In order to confirm whether IL-1? Production inhibitory effect of the compounds of formula (1) or (2) of the present invention as determined in Experimental Example 1 was inhibiting IL-1? Production by cell death, macrophages were treated with the compound for 16 hours Cell viability was measured.
그 결과, 본 발명의 화학식 1 또는 화학식 2 화합물은 약물 처리농도 100 ㎍/ml에서 세포생존율에 별다른 영향을 미치지 않아 세포독성이 없는 것을 확인하였다 (도 2).As a result, the compound of formula (I) or (II) of the present invention had no significant effect on the cell survival rate at a drug treatment concentration of 100 占 퐂 / ml, indicating that the compound was not cytotoxic.
상기 실험예를 통해, 본 발명의 조성물은 부작용을 갖지 않는 우수한 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental examples, it was confirmed that the composition of the present invention can be used as a preventive, ameliorating, or therapeutic agent for excellent NLRP3 inflammation-related diseases without side effects.
<실험예 3> 화학식 1 또는 화학식 2 화합물의 nigericin-유도 인플라마좀 제어 효능을 농도별 확인<Experimental Example 3> The nigericin-induced inflammation control effect of the compound of formula (1) or (2)
Nigericin에 노출된 단핵 세포는 IL-1β 활성화가 유도되고 활성화된 IL-1β는 NLRP3 염증조절복합체(인플라마좀)의 생성을 유도하는 것이 보고되었다. 이에 따라, Nigericin에 의해 유도되는 NLRP3 인플라마좀에 대한 화학식 1 또는 화학식 2의 화합물의 효과를 규명하기 위해 도 3에 나타난 것과 같은 과정으로 골수 유래 대식세포인 BMDM에서 실험을 수행하였다.It has been reported that monocytes exposed to nigericin induce IL-1β activation and that activated IL-1β induces the production of the NLRP3 inflammatory regulatory complex (inflammase). Therefore, in order to investigate the effect of the compound of formula (1) or (2) on the NLRP3 inflammase induced by Nigericin, the experiment was carried out in the bone marrow-derived macrophage BMDM by the same process as shown in FIG.
먼저, LPS에 의한 TLR-4의 자극은 pro IL-1β및 NLRP3 전사를 유도하기 때문에, LPS의 가능성을 제외하기 위해 PBS로 세척하고 LPS가 사전에 처리된 BMDM 세포를 25, 50, 100 ㎍/ml 농도의 화학식 1 또는 화학식 2의 화합물이 포함된 조건에서 사전 배양한 후 Nigericin으로 자극하고 ELISA 분석을 수행하였다.First, TLR-4 stimulation by LPS induces pro-IL-1β and NLRP3 transcription. Therefore, to exclude the possibility of LPS, the cells were washed with PBS and LPS-pretreated BMDM cells were treated with 25, 50, 100 μg / ml of the compound of formula (1) or (2), followed by stimulation with Nigericin and ELISA analysis.
그 결과, Nigericin에 의해 활성화된 IL-1β는 화학식 1 또는 화학식 2의 화합물 처리군 (25 내지 100 μM)에서 분비가 억제된 것을 확인할 수 있었다 (도 3).As a result, it was confirmed that the secretion of IL-1? Activated by Nigericin was inhibited in the group treated with Compound (1) or (2) (25-100 μM) (FIG. 3).
상기 실험예를 통해, 본 발명의 조성물은 농도 의존적으로 우수한 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental examples, it was confirmed that the composition of the present invention can be used as a preventive, ameliorating, or therapeutic agent for NLRP3 inflammation-related diseases which are excellent in concentration-dependency.
<실험예 4> 화학식 1의 화합물의 ATP-유도 인플라마좀 제어 효능을 농도별 확인Experimental Example 4 ATP-Induced Inflammase Control Effect of Compound (1)
인플라마좀 제어 효능을 가진 활성성분을 도출하기 위하여 화학식 1 또는 화학식 2의 화합물이 NLRP3의 다른 작용제인 ATP-유도 인플라마좀 활성을 억제하는지 조사하였다. 구체적으로, 세 개의 농도 범위를 사용하여 농도 의존성을 확인하였다.In order to elicit an active ingredient with an inflammatory control effect, the inventors investigated whether the compounds of the formula (1) or (2) inhibit the other ATP-induced in fl ammase activity of NLRP3. Specifically, concentration dependence was confirmed using three concentration ranges.
ATP에 노출된 단핵 세포는 IL-1β 활성화가 유도되고 활성화된 IL-1β는 NLRP3 염증조절복합체(인플라마좀)의 생성을 유도하는 것이 보고되었다. 이에 따라, ATP에 의해 유도되는 NLRP3 인플라마좀에 대한 화학식 1의 화합물의 효과를 규명하기 위해, 도 4와 같은 과정으로 골수 유래 대식세포인 BMDM에서 실험을 수행하였다.It has been reported that monocytes exposed to ATP induce IL-1β activation and that activated IL-1β induces the production of NLRP3 inflammatory regulatory complex (inflammase). Thus, in order to investigate the effect of the compound of
먼저, LPS에 의한 TLR-4의 자극은 pro IL-1β및 NLRP3 전사를 유도하기 때문에, LPS의 가능성을 제외하기 위해 PBS로 세척하고 LPS가 사전에 처리된 BMDM 세포를 25, 50, 100 ㎍/ml 농도의 화학식 1 또는 화학식 2의 화합물이 포함된 조건에서 사전 배양한 후 ATP로 자극하고 ELISA 분석을 수행하였다.First, TLR-4 stimulation by LPS induces pro-IL-1β and NLRP3 transcription. Therefore, to exclude the possibility of LPS, the cells were washed with PBS and LPS-pretreated BMDM cells were treated with 25, 50, 100 μg / ml of the compound of formula (1) or (2), followed by stimulation with ATP and ELISA analysis.
그 결과, 도 4에 나타난 것처럼 ATP에 의해 활성화된 IL-1β는 화학식 1 또는 화학식 2의 화합물 처리군에서 분비가 억제된 것을 확인할 수 있었다.As a result, it was confirmed that the secretion of IL-1? Activated by ATP was inhibited in the group treated with the compound of
상기 실험예를 통해, 본 발명의 조성물은 농도 의존적으로 우수한 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental examples, it was confirmed that the composition of the present invention can be used as a preventive, ameliorating, or therapeutic agent for NLRP3 inflammation-related diseases which are excellent in concentration-dependency.
<실험예 5><Experimental Example 5> 화학식 1의 화합물의 인간 대식세포주인 THP-1 세포주에서 nigericin-유도 인플라마좀 제어 효능 확인Determination of nigericin-induced inflammase control efficacy in the THP-1 cell line, the human macrophage cell line of the compound of formula
마우스 대식세포에서 도출한 화학식 1의 화합물이 인간 대식세포주인 THP-1 세포주에서 nigericin-유도 인플라마좀 활성을 억제하는지를 조사하였음.We investigated whether the compound of
그 결과, 화학식 1의 화합물이 nigericin-유도 IL-1β 분비를 25 내지 100 μM 범위에서 농도 의존적으로 억제하는 것을 확인하였다 (도 5). Nigericin-유도 IL-1β를 억제하는 화학식 1의 화합물의 IC50 값은 31.92 ㎍/ml임을 확인하였다 (도 6).As a result, it was confirmed that the compound of
상기 실험예를 통해, 본 발명의 조성물은 농도 의존적으로 우수한 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental examples, it was confirmed that the composition of the present invention can be used as a preventive, ameliorating, or therapeutic agent for NLRP3 inflammation-related diseases which are excellent in concentration-dependency.
<실험예 6> 화학식 1 또는 화학식 2의 화합물의 인간 대식세포주( THP-1)에서 ATP-유도 인플라마좀 제어 효능 확인EXPERIMENTAL EXAMPLE 6 Confirmation of ATP-Induced Inflammation Control Efficiency in Human Macrophage Cell Line (THP-1) of Compound of
본 발명의 화학식 1 또는 화학식 2 화합물이 인간 대식세포주인 THP-1 세포주에서 ATP-유도 인플라마좀 활성을 억제하는지를 조사하였다.It was investigated whether the compounds of the formula (1) or (2) of the present invention inhibit ATP-induced in fl ammase activity in THP-1 cell line which is a human macrophage cell line.
그 결과, 화학식 1의 화합물이 ATP-유도 IL-1β 분비를 효과적으로 억제하는 것을 확인하였다(도 7). ATP-유도 IL-1β를 억제하는 화학식 1의 화합물의 IC50 값은 15.38 ㎍/ml임을 확인하였다 (도 8).As a result, it was confirmed that the compound of
상기 실험예를 통해, 본 발명의 조성물은 농도 의존적으로 우수한 NLRP3 인플라마좀 관련 질환의 예방, 개선, 또는 치료제로 사용될 수 있음을 확인하였다.Through the above experimental examples, it was confirmed that the composition of the present invention can be used as a preventive, ameliorating, or therapeutic agent for NLRP3 inflammation-related diseases which are excellent in concentration-dependency.
상기 실험예 1 내지 실험예 6의 결과로부터 화학식 1 또는 화학식 2의 화합물은 in-vitro에서 ATP 및 Nigericin에 의해 유도되는 IL-1β의 분비를 억제하는 효과를 나타내었으며, 이는 화학식 1 또는 화학식 2의 화합물이 NLRP3 인플라마좀에 의해 유도되는 IL-1β의 활성 억제를 통하여 염증반응을 억제하는 기능이 있음을 확인할 수 있으며, NLRP3 인플라마좀의 활성으로 인한 질환을 억제하는 치료제의 개발을 할 수 있다고 제안할 수 있다.From the results of Experimental Examples 1 to 6, the compounds of
이상으로 본 발명의 특정한 부분을 상세히 기술하였는바, 관련 기술 분야의 통상의 지식을 가진 자에게 있어 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구범위와 그의 등가물에 의하여 정의될 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the invention will be defined by the appended claims and their equivalents.
Claims (14)
상기 자가 염증성 질환은 머클-웰스 증후군(Muckle-Wells syndrome; MWS), 가족성 한랭 자가면역성 증후군(FCAS), 크리오피린-관련 주기성 증후군(CAPS), 신생아-발병 다기관 염증성 증후군(NOMID), 만성 영아 신경 피부 관절(CINCA) 증후군, 가족성 지중해열(FMF), 전신 발병 소아 특발성 관절염(SJIA), 소아 류마티스 관절염, 성인 류마티스 관절염, 연령관련 황반변성, 아토피성 피부염 및 건선으로 구성된 군으로부터 선택되는 어느 하나 이상이고,
상기 대사성 질환은 비만, 고지혈증, 고콜레스테롤증, 죽상동맥경화증, 비알코올성지방간(NAFLD) 및 비알코올성지방간염(NASH)으로 구성된 군으로부터 선택되는 어느 하나 이상인 약학 조성물:
<화학식 1>
The autoinflammatory disease may be selected from the group consisting of Muckle-Wells syndrome (MWS), familial cold autoimmune syndrome (FCAS), krypyrin-related periodic syndrome (CAPS), neonatal-onset manifestation inflammatory syndrome (NOMID) Which is selected from the group consisting of CINCA syndrome, FMF, systemic onset idiopathic arthritis (SJIA), pediatric rheumatoid arthritis, adult rheumatoid arthritis, age-related macular degeneration, atopic dermatitis and psoriasis One or more,
Wherein the metabolic disease is any one or more selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic fatty liver disease (NASH)
≪ Formula 1 >
상기 자가 염증성 질환은 머클-웰스 증후군(Muckle-Wells syndrome; MWS), 가족성 한랭 자가면역성 증후군(FCAS), 크리오피린-관련 주기성 증후군(CAPS), 신생아-발병 다기관 염증성 증후군(NOMID), 만성 영아 신경 피부 관절(CINCA) 증후군, 가족성 지중해열(FMF), 전신 발병 소아 특발성 관절염(SJIA), 소아 류마티스 관절염, 성인 류마티스 관절염, 연령관련 황반변성, 아토피성 피부염 및 건선으로 구성된 군으로부터 선택되는 어느 하나 이상이고,
상기 대사성 질환은 비만, 고지혈증, 고콜레스테롤증, 죽상동맥경화증, 비알코올성지방간(NAFLD) 및 비알코올성지방간염(NASH)으로 구성된 군으로부터 선택되는 어느 하나 이상인 식품 조성물:
<화학식 1>
The autoinflammatory disease may be selected from the group consisting of Muckle-Wells syndrome (MWS), familial cold autoimmune syndrome (FCAS), krypyrin-related periodic syndrome (CAPS), neonatal-onset manifestation inflammatory syndrome (NOMID) Which is selected from the group consisting of CINCA syndrome, FMF, systemic onset idiopathic arthritis (SJIA), pediatric rheumatoid arthritis, adult rheumatoid arthritis, age-related macular degeneration, atopic dermatitis and psoriasis One or more,
Wherein the metabolic disease is any one or more selected from the group consisting of obesity, hyperlipidemia, hypercholesterolemia, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic fatty liver disease (NASH)
≪ Formula 1 >
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| KR102059659B1 (en) * | 2019-06-13 | 2019-12-26 | 주식회사 모든바이오 | A Composition for treating neurodegenerative disease comprising a Gypenoside compound as an active ingredient |
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| KR102059659B1 (en) * | 2019-06-13 | 2019-12-26 | 주식회사 모든바이오 | A Composition for treating neurodegenerative disease comprising a Gypenoside compound as an active ingredient |
| WO2020250182A3 (en) * | 2019-06-13 | 2021-05-06 | 주식회사 모든바이오 | Composition for treating neurodegenerative disease comprising gypenoside compound as active ingredient |
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