KR20130071664A - Flavonoid comprising anti-virus activity - Google Patents
Flavonoid comprising anti-virus activity Download PDFInfo
- Publication number
- KR20130071664A KR20130071664A KR1020110139001A KR20110139001A KR20130071664A KR 20130071664 A KR20130071664 A KR 20130071664A KR 1020110139001 A KR1020110139001 A KR 1020110139001A KR 20110139001 A KR20110139001 A KR 20110139001A KR 20130071664 A KR20130071664 A KR 20130071664A
- Authority
- KR
- South Korea
- Prior art keywords
- virus
- quercetin
- influenza
- galactoside
- antiviral
- Prior art date
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- 229930003935 flavonoid Natural products 0.000 title claims abstract description 22
- 235000017173 flavonoids Nutrition 0.000 title claims abstract description 22
- 230000000694 effects Effects 0.000 title description 22
- 150000002215 flavonoids Chemical class 0.000 title description 2
- 230000002155 anti-virotic effect Effects 0.000 title 1
- 230000000840 anti-viral effect Effects 0.000 claims abstract description 51
- 239000000203 mixture Substances 0.000 claims abstract description 37
- -1 flavonoid compound Chemical class 0.000 claims abstract description 21
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Abstract
Description
본 발명은 항바이러스 억제 활성을 갖는 플라보노이드 화합물에 관한 것이다.
The present invention relates to flavonoid compounds having antiviral inhibitory activity.
독감은 주로 겨울철에 발생하는 호흡기질환 중에서 가장 많은 수를 차지하는 질병으로 주된 증상은 호흡기질환이지만, 그 영향은 온몸에 미친다. 급성 발열, 오한, 몸살, 식욕감퇴, 두통, 근육통, 요통의 증상을 나타내며 심한 가래나 기침, 콧물, 눈의 충혈 등의 증세를 보이기도 하며 설사를 수반하기도 한다. 인플루엔자 A 바이러스는 쥐에도 쉽게 감염되는데 인플루엔자바이러스에 감염된 쥐의 임상증상 중 가장 뚜렷한 증상은 급격히 체중이 감소하며 폐 기관지조직에 중성백혈구의 침윤이 일어나게 되고 폐사에 이른다. 항바이러스제의 구강투여는 인플루엔자바이러스에 감염된 쥐의 체중 감소를 억제하며 [Kash JC 등, 2011. MBio 2(5): e00172-11], 폐 기관지 조직에 중성백혈구의 침윤도 억제된다 [Sakai S 등 2000 J Viol 74(5): 2472-2476]. 이러한 현상은 인플루엔자바이러스를 감염시킨 뒤에 타미플루를 투여한 쥐에서도 확인된다 [Smee DF 등, 2009 Antimicrob Agent Chemother. 53(5):2120-8; Banitia S 등 2001 Antimicrob Agents Chemother 45(4):1162-1167]. The flu is the largest number of diseases of the respiratory disease that occurs mainly in winter. The main symptom is respiratory disease, but the effect is on the whole body. Acute fever, chills, body aches, loss of appetite, headache, muscle pain, low back pain. Severe phlegm, cough, runny nose, redness of the eyes, and diarrhea. Influenza A viruses are also easily infected in mice. The most obvious symptom of influenza virus-infected mice is their rapid weight loss, infiltration of neutrophils into the lung bronchial tissue, and death. Oral administration of antiviral agents inhibits weight loss in mice infected with influenza virus [Kash JC et al., 2011. MBio 2 (5): e00172-11], and also inhibits the infiltration of neutrophils into lung bronchial tissues [Sakai S et al. 2000 J Viol 74 (5): 2472-2476]. This phenomenon has also been identified in mice receiving Tamiflu following infection with influenza virus [Smee DF et al., 2009 Antimicrob Agent Chemother. 53 (5): 2120-8; Banitia S et al. 2001 Antimicrob Agents Chemother 45 (4): 1162-1167].
독감의 원인바이러스는 인플루엔자 바이러스로 (-) stranded RNA를 유전체로 하는 바이러스의 하나로 인플루엔자바이러스는 A, B, C 형으로 나뉘고 있으며, 이 중 A형과 B형이 사람에게 빈번하게 감염되는 형이다. 특히 A형 바이러스의 혈청형은 혈구응집소와 뉴라미니데이즈(Neuraminidase) 단백질의 아미노산 배열의 차이에 따라 결정된다. A형 인플루엔자 바이러스의 혈구응집소(H)는 16개의 다른 아형이 존재하며 뉴라미디데이즈 효소(N)는 9개의 다른 아형이 존재하는데 혈구응집소 단백질 아형과 뉴라미니데이즈 단백질 아형의 조합이 어떻게 이루어지는 가에 따라 새로운 변이형이 결정되며(예; H1N1), 또한 숙주의 면역체계에 적응도에 따라서도 새로운 변이형이 나올 수도 있다[Yuen KY & Wong SSY., 2005. Hong Kong Med. 11;189-199]. 따라서 인플루엔자바이러스의 새로운 변이종의 빈번한 발생은 백신의 효용성을 낮추고 있을 뿐만 아니라 백신은 조류독감 같은 인체에 감염능력을 가진 새로운 독감바이러스에 대처할 수 없다. 그래서 독감바이러스에 대처할 수 있는 다양한 치료제의 개발이 필요하다. 인플루엔자 바이러스의 증식을 억제하는 약제는 2 가지 형태가 있다. 하나는 아만타딘(amantadine)으로 1964년 Dupont 사에 의해 개발된 M이온 채널 억제제로서 1980년까지 인플루엔자 A형 바이러스 감염을 치료하는데 사용되었으며 구역질, 졸음, 만성적 불면증을 초래한다[LongJK., Mossad SB., Goldman MP. 2000. Cleve Clin J. med. 67:92-95]. 이후 아만타딘 보다 부작용이 적은 리만타딘(rimantadine)이 개발되었으나 리만타딘 역시 부작용 발생률이 높은 편이다[Jefferson 외 4인 2004. Cochrane Database Syst. Rev. (3): CD001169]. 두 번째 형태 약제는 뉴라미니데이즈 효소 저해제 기능을 가진 약제로 자나미비르(zanamivir, 상표명: Relenza)와 오셀타미비르 (osetamivir, 상표명: Tamiflu) 등이 인플루엔자 바이러스 치료제로 사용되고 있다[Dreitlein WB., Maratos J., Brocavich. 2001. Clin Ther. 23:327-355]. 자나미비르는 글락소웰컴사에서 리렌자(Relenza)라는 상표로 판매하고 있으며 흡입형으로 되어 있어 코로 약제 가루를 흡입하도록 되어 있으며, 오셀타미비르는 로쉬사에서 타미플루(Tamiflu)라는 명칭으로 판매하고 있고 있다. 리렌자는 호흡하는데 문제가 생길 수 있어 천식은 악화될 가능성이 있으며, 타미플루는 64,707명의 환자에서 14,900명이 부작용을 호소하고 있고 이중 3,854명은 부작용의 정도가 매우 심하였다[Donner B 등 2011. Pharmacoepithermiol Drug 20(5):532-543]. 또한, 릴렌자와 타미플루에 내성을 나타내는 많은 인플루엔자 A 바이러스 또는 인플루엔자 B 바이러스가 발견되고 있어 이러한 인플루엔자바이러스에 대처할 수 있는 새로운 바이러스의 개발이 요구되고 있다 [Carr S 등 2011. Pedatr Infect Dis J 30(4): 284-288].The influenza virus is an influenza virus, a virus that has a negative stranded RNA genome. Influenza viruses are divided into types A, B, and C. Among them, types A and B are frequently infected by humans. In particular, serotypes of type A viruses are determined by differences in the amino acid sequence of hemagglutinin and Neuraminidase proteins. The hemagglutinin (H) of influenza A virus has 16 different subtypes and the neuramididases enzyme (N) has 9 different subtypes.How does the combination of the hemagglutinin protein subtype and the neuraminidase protein subtype occur? New variants are determined (eg H1N1), and new ones may also be present depending on the adaptability of the host's immune system [Yuen KY & Wong SSY., 2005. Hong Kong Med. 11; 189-199. Thus, the frequent incidence of new mutants of influenza virus not only reduces the efficacy of the vaccine, but also prevents the vaccine from coping with new flu viruses that have the potential to infect humans such as avian influenza. Therefore, the development of various treatments to cope with the flu virus is necessary. There are two types of drugs that inhibit the growth of influenza viruses. One is amantadine, an M-ion channel inhibitor developed by Dupont in 1964 and used to treat influenza type A virus infections until 1980, resulting in nausea, drowsiness, and chronic insomnia [LongJK., Mossad SB., Goldman MP. 2000. Cleve Clin J. med. 67: 92-95. Since then, rimantadine has been developed with fewer side effects than amantadine, but rimantadine also has a high incidence of side effects [Jefferson et al. 4, 2004. Cochrane Database Syst. Rev. (3): CD001169]. The second form is a drug that acts as a neuraminidase enzyme inhibitor. Janamivir (zanamivir, Relenza) and oseltamivir (Tamiflu) are used to treat influenza virus [Dreitlein WB., Maratos J., Brocavich. 2001. Clin Ther. 23: 327-355. Janamivir is sold under the trademark Relenza by GlaxoWelcome, Inc. and is inhaled to inhale pharmaceutical powder into the nose. Oseltamivir is sold by Rosh under the name Tamiflu. Rerenza may cause breathing problems and asthma is likely to worsen. Tamiflu in 64,707 patients has 14,900 complaints of side effects, including 3,854 of whom severe side effects are severe [Donner B et al. 2011. Pharmacoepithermiol Drug 20 ( 5): 532-543]. In addition, many influenza A viruses or influenza B viruses that are resistant to relenza and Tamiflu have been found, and development of new viruses that can cope with such influenza viruses is required [Carr S et al. 2011. Pedatr Infect Dis J 30 (4). ): 284-288].
라이노바이러스는 (+) stranded RNA를 주형으로 하는 바이러스로서 호흡기질환을 유발하는 주원인 바이러스이며 천식질환의 원인에도 관여되어 있다 [Gavala ML 등 2011 Immunol Rev 242(1):69-90]. 라이노바이러스는 타미플루에 의해 억제되지 바이러스활성이 억제되지 않는 바이러스이다 [Boivin C 등 2002. J Clin Micobiol 40(2):330-334]. Lai Nova virus is (+) is a major cause of virus-induced respiratory disease as a stranded RNA virus as a template and is involved in the cause of asthmatic disease [Gavala ML etc. 2011 Immunol Rev 242 (1): 69-90]. Rhinoviruses are viruses that are inhibited by Tamiflu but do not inhibit viral activity (Boivin C et al. 2002. J Clin Micobiol 40 (2): 330-334).
리바비린은 리보스 당에 트리아졸 카복사미드가 결합되어 형태의 화합물로 피코르나비리데에 속하면서 구제역을 일으키는 FMD바이러스[Arias A 등 2008, J Virol 82(4): 12346-12355], 수족구병을 일으키는 엔테로바이러스[Fengqin L 등 2010 J Ethnopharmacol 127(2):221-228], 라이노바이러스에 항바이러스능을 나타내는 보고가 있으며[Choi HJ 등 2010 J med Food 13(2): 326-328), 헤파토바이러스의 하나인 C형 간염바이러스의 감염질환에 인터페론과 같이 치료제로 사용되는 의약이다[Jain MK & Zoellner C 2010 Expert Opin Pharmacother 11(4):673-683]. 그러나 리바비린은 심각한 빈혈증을 유발하여 심장질환을 악화시키는 것으로 알려져 있으며, 이외에도 피곤증, 두통 등 여러 부작용을 유발하는 단점이 있다[MacNicholas R & Norris S 2010 Aliment Pharmacol Ther 31(9):929-937]. Ribavirin is a compound in the form of a combination of triazole carboxamide to ribose sugar, which belongs to picornaviride and causes foot-and-mouth disease (Arias A et al. 2008, J Virol 82 (4): 12346-12355), foot and mouth disease Caused enterovirus [Fengqin L et al. 2010 J Ethnopharmacol 127 (2): 221-228], rhinoviruses have antiviral activity [Choi HJ et al. 2010 J med Food 13 (2): 326-328), Hepa It is a drug used as a therapeutic agent such as interferon in infectious diseases of hepatitis C virus, one of the toviruses (Jain MK & Zoellner C 2010 Expert Opin Pharmacother 11 (4): 673-683). However, ribavirin is known to aggravate heart disease by causing severe anemia and has other disadvantages such as fatigue and headache. [MacNicholas R & Norris S 2010 Aliment Pharmacol Ther 31 (9): 929-937] .
따라서, 독성과 부작용이 적고 호흡기질환 바이러스 모두에 효능이 뛰어난 항바이러스제의 개발이 요구되고 있다. Therefore, there is a need for the development of antiviral agents that are less toxic and have side effects and are excellent in both respiratory disease viruses.
플라보노이드의 항바이러스 활성에 대해서 여러 선행기술이 소개되고 있다.퀘르세틴에 당이 결합되어 있는 화합물의 항바이러스능에 대해서 여러 선행기술이 보고되었다. Several prior arts have been introduced on the antiviral activity of flavonoids. Several prior arts have been reported on the antiviral activity of compounds with sugars bound to quercetin.
퀘르세틴-3-글루코사이드는 헤르페스 심플렉스 1형 바이러스에 항바이러스능 활성을 갖고 있음이 보고되었으며 [Abou-Karam M 등 1992. J Nat Prod 55(10): 1525-1527] 인플루엔자바이러스에도 항바이러스능을 나타내고 있다[Kim Y 등 2010. Antiviral Res 88:227-235]. 퀘르세틴-3-람노코사이드는 일명 퀘세트린(quercitrin)이라고도 하는데 인플루엔자바이러스에 대한 활성도 보고되고 있다[ Choi 등 2009 Eur J Pharm Sci 37(304) 329-333; uchida N 등 2011 Molecules 16(3):2032-2052; Choi 등 2011. Phytother Res. 2011. doi10.1002/ ptr3529]. 퀘르세틴 7-람노사이드는 돼지 유행성 설사바이러스에 대한 항바이러스능을 갖고 있음이 알려졌다 [Song JH 등 2011. Virol J 8;480; Choi 등 2009 Antiviral Res 81(1):77-81]. Quercetin-3-glucoside has been reported to have antiviral activity against
퀘르세틴-3-갈락토사이드의 활성은 과산화수소수에 의한 세포괴사를 방지하거나[Li ZL 등 2011 J Ethnopharmcol] 신경독성을 유발하는 아리로이드베타 단백질의 활성을 저해하는 효능이 알려져 있다 [Zeng KW 2011 672(1-3):45-55]. Quercetin-3-galactoside activity is known to prevent cell death by hydrogen peroxide [Li ZL et al. 2011 J Ethnopharmcol] or to inhibit the activity of ariroidbeta protein that causes neurotoxicity. [Zeng KW 2011 672 (1-3): 45-55].
퀘르세틴-3-갈락토사이드의 항바이러스능 활성은 DNA 바이러스인 B형 간염바이러스에 대한 보고가 있으나[Wu LI 등 2007. 28(3):404-409], 역시 B형 간염바이러스에 대한 활성을 가진 아시클로비르[Wang WN 등 2005. Acta Pharmacol Sin 26(5):587-592] 는 DNA복제를 억제하는 화합물로서 RNA 바이러스인 인플루엔자바이러스에 대해 항바이러스활성을 나타내지 못하며 역시 B형 간염바이러스에 대한 활성을 가진 라미뷰딘(lamivudine)도 인플루엔자바이러스에 대한 활성을 보고된 바가 없다. 따라서 RNA 바이러스인 인플루엔자바이러스나 라이노바이러스에 대한 항바이러스활성을 유추할 수 없다. The antiviral activity of quercetin-3-galactoside has been reported for hepatitis B virus, a DNA virus [Wu LI et al. 2007. 28 (3): 404-409]. The acyclovir (Wang WN et al. 2005. Acta Pharmacol Sin 26 (5): 587-592) is a compound that inhibits DNA replication and does not show antiviral activity against influenza virus, an RNA virus, and also against hepatitis B virus. Lamivudine with activity has not been reported for influenza virus. Therefore, antiviral activity against RNA virus such as influenza virus or rhinovirus cannot be inferred.
퀘르세틴-3-글루코사이드와 퀘르세틴-3-람노코사이드, 퀘르세틴-3-갈락토사이드는 구조적으로 매우 유사한 형태를 하고 있으나 글루코사이드, 람노사이드, 갈락토사이드는 서로 다른 특성을 나타낸다. 박테리오파지 배양액에 람노스와 갈락토스를 투여하면 람노스를 투여한 배지에서는 0.5 mg/ml 의 농도에서 박테리오파지의 플라크가 99-100% 억제되었으나 갈락토스를 투여한 배지에서는 41% 이하의 억제률을 보였다. 유산균 세포막 단백질에의 결합도 람노스는 207 /mg 이나 글루코스는 람노스의 1/4 정도인 56 /mg 이고 갈락토스는 글루코스의 50%인 27 /mg 밖에 되지 않았다. 따라서 당의 종류에 따라 바이러스의 증식이 달라질 수 있음을 보고하고 있다[Vayasevi R 등 1990. Appl Environment Micirobiol 1882-1889]. Quercetin-3-glucoside, quercetin-3-lamnocoside, and quercetin-3-galactoside are structurally very similar, but glucoside, rhamnoside and galactoside have different characteristics. The administration of rhamnose and galactose to the bacteriophage cultures inhibited 99-100% of the bacteriophage plaques at a concentration of 0.5 mg / ml in the medium administered with rhamnose, but less than 41% in the medium administered with the galactose. The degree of binding to lactic acid cell membrane protein was only 207 / mg of lacnose, but 56 / mg of glucose was about 1/4 of rhamnose and 27 / mg of galactose was 50% of glucose. Therefore, it has been reported that the proliferation of the virus may vary depending on the type of sugar (Vayasevi R et al. 1990. Appl Environment Micirobiol 1882-1889).
이상의 선행기술에서 퀘르세틴-3-글루코사이드와 퀘르세틴-3-람노사이드, 퀘르세틴-3-글루코사이드는 항바이러스능을 각각 나타내고 있으나 퀘르세틴에 어떠한 당이 결합하는가에 따라 서로 다른 결과를 보여주고 있다. In the above prior arts, quercetin-3-glucoside, quercetin-3-rhamnoside, and quercetin-3-glucoside have antiviral activity, but they show different results depending on which sugar binds to quercetin.
퀘르세틴-3-갈락토사이드는 퀘르세틴-3-람노코사이드와 퀘르세틴-3-글루코사이드에 비해 탁월한 항인플루엔자바이러스을 나타냄으로써 단순하게 당 위치의 차이나 당 구조에서의 OH 변환으로 인한 당 차이에서 오는 항바이러스능에 대해서는 아직까지 밝혀지지 않은 상태에 있다.
Quercetin-3-galactosides exhibit superior anti-influenza viruses compared to quercetin-3-lamnocosides and quercetin-3-glucosides, resulting in a simple anti-viral activity resulting from sugar differences due to differences in sugar sites or OH conversion in the sugar structure. It is still unknown.
이에, 본 발명자들은 인체에 부작용을 최소화시키는 하기 화학식 1의 화합물이 인플루엔자 A형 및 B형 바이러스와 라이노바이러스의 활성을 탁월하게 억제할 수 있는 화합물임을 확인함으로써 본 발명을 완성하게 되었다.Thus, the present inventors have completed the present invention by confirming that the compound of
따라서, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항인플루엔자 바이러스 조성물을 제공하는데 그 목적이 있다.Accordingly, an object of the present invention is to provide an anti-influenza virus composition containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
상기 화학식 1에서, R1 내지 R5는 각각 독립적으로 -OH 또는 수소이다.
In
또한 본 발명은 하기 화학식 2로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항인플루엔자 바이러스 조성물을 제공하는데 그 목적이 있다.In addition, an object of the present invention is to provide an anti-influenza virus composition containing a compound represented by the following formula (2) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 2][Formula 2]
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 유효성분으로 함유하는 항인플루엔자 바이러스 조성물을 제공하는데 그 목적이 있다.An object of the present invention is to provide an anti-influenza virus composition containing a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[화학식 1][Formula 1]
상기 화학식 1에서, R1 내지 R5는 각각 독립적으로 -OH 또는 수소이다.
In
본원 발명의 특징 및 이점을 요약하면 다음과 같다.The features and advantages of the present invention are summarized as follows.
(i) 본 발명의 플라보노이드 화합물 또는 이의 약학적으로 허용가능한 염은 바이러스 감염으로 인한 질환 등을 치료하거나 예방하는데 유용하게 이용될 수 있다. (i) The flavonoid compounds of the present invention or pharmaceutically acceptable salts thereof may be usefully used to treat or prevent diseases caused by viral infections.
(ii) 특히, 본 발명의 플라보노이드 화합물은 타미플루에 내성을 나타내는 인플루엔자 B형 바이러스에도 뛰어난 억제능을 보여준다.(ii) In particular, the flavonoid compounds of the present invention show excellent inhibitory ability against influenza B virus which is resistant to Tamiflu.
(iii) 또한, 본 발명의 화합물은 감염 초기 증상이 매우 유사하지만 타미플루가 항바이러스능을 나타내지 않는 라이노바이러스에도 항바이러스능이 뛰어나서 바이러스성 호흡기질환을 치료하는 데 효과적이다.
(iii) The compounds of the present invention are also effective in treating viral respiratory diseases due to their excellent antiviral activity against rhinoviruses, which have very similar initial symptoms of infection but do not show antiviral activity.
도 1은 본 발명의 일실시예에 따른, 퀘르세틴 3-갈락토사이드의 인플루엔자 A 바이러스 감염동물모델에서 항바이러스능 효과를 타미플루와 비교한 그림이다.
도 2는 본 발명의 일실시예에 따른, 퀘르세틴 3-갈락토사이드의 인플루엔자 B 바이러스 에 대한 항바이러스 활성 그래프이다.1 is a diagram comparing the antiviral effect of Tamiflu in an influenza A virus infected animal model of quercetin 3-galactoside according to an embodiment of the present invention.
FIG. 2 is a graph of antiviral activity against influenza B virus of quercetin 3-galactoside, according to one embodiment of the invention. FIG.
본 발명의 일 양태에 따르면, 본 발명은 하기 화학식 1로 표시되는 플라보노이드 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하며 RNA를 주형으로 하는 바이러스에 대한 항바이러스용 조성물을 제공한다.According to one aspect of the present invention, the present invention provides a flavonoid compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and provides an antiviral composition against a virus having RNA as a template.
[화학식 1][Formula 1]
상기 화학식 1에서, R1 내지 R5는 각각 독립적으로 -OH 또는 수소이다.In
본 발명의 바람직한 구현예에 따르면, 상기 화학식 1로 표시되는 플라보노이드 화합물은 하기 화학식 2로 표시되는 퀘르세틴 3-갈락토사이드이다.According to a preferred embodiment of the present invention, the flavonoid compound represented by the formula (1) is quercetin 3-galactoside represented by the formula (2).
[화학식 2][Formula 2]
본 발명의 바람직한 구현예에 따르면, 상기 항바이러스용 조성물은 인플루엔자 A 바이러스, 인플루엔자 B 바이러스 또는 라이노바이러스인 호흡기질환 바이러스에 항바이러스효과를 보이는 것을 특징으로 하는 RNA를 주형으로 하는 바이러스 치료를 위한 항바이러스용 조성물이다.
According to a preferred embodiment of the present invention, the antiviral composition is antiviral for the treatment of viral viruses with RNA, characterized in that the anti-viral effect to the respiratory disease virus, influenza A virus, influenza B virus or rhinovirus It is a composition for.
본 발명의 다른 양태에 따르면, 화학식 1 또는 화학식 2의 플라보노이드 화합물을 포함하는 항바이러스용 식품조성물을 제공한다. According to another aspect of the present invention, there is provided an antiviral food composition comprising a flavonoid compound of
본 발명의 바람직한 구현예에 따르면, 상기 식품조성물의 식품은 드링크제로 만든다.
According to a preferred embodiment of the present invention, the food of the food composition is made of a drink.
이와 같은 본 발명을 더욱 상세하게 설명하면 다음과 같다.Hereinafter, the present invention will be described in detail.
본 발명은 플라보노이드 화합물의 인플루엔자 A 바이러스 및 인플루엔자 B 바이러스, 라이노바이러스에 대한 항바이러스능을 나타내는 조성물에 관한 것이다.
The present invention relates to a composition exhibiting the antiviral ability of the flavonoid compound against influenza A virus and influenza B virus, rhinovirus.
한편, 본 발명의 조성물의 유효성분으로 상기 화학식 1의 화합물 대신 이의 약학적으로 허용 가능한 염의 형태로 사용할 수 있으며, 상기 염으로는 약학적으로 허용 가능한 유리산(free acid)에 의해 형성된 산 부가염이 유용하다. 상기 화학식 1의 화합물은 당해 기술 분야에서 통상적인 방법에 따라 약제학적으로 형용되는 산 부가염을 형성할 수 있다. 유리산으로는 유리산과 무기산을 사용할 수 있으며, 무기산으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고 유기산으로는 구연산(citric acid), 초산, 젖산, 주석산(tartaric acid), 말레인산, 푸마르산(fumaric acid), 포름산, 프로피온산(propionic acid), 옥살산, 트리플루오로아세트산, 벤조산, 글루콘산, 메탄술폰산, 글리콜산, 숙신산, 4-톨루엔술폰산, 갈룩투론산, 엠본산, 글루탐산 또는 아스파르트산 등을 사용할 수 있다. On the other hand, as an active ingredient of the composition of the present invention can be used in the form of a pharmaceutically acceptable salt thereof instead of the compound of
마지막으로, 본 발명은 화학식 1 및 2로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 함유하는 항인플루엔자 바이러스 조성물을 포함한다.Finally, the present invention includes an anti-influenza virus composition containing a compound represented by the formula (1) and (2) or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 약제 조성물은 화학식 1로 표시되는 화합물 또는 약학적으로 허용 가능한 이의 염을 유효성분으로 함유하면서 인플루엔자 바이러스의 증식을 저해함으로써 인플루엔자 바이러스 감염으로 인한 고열, 설사, 탈수 등의 증상을 치료하거나 예방하는데 유용하게 이용될 수 있다. The pharmaceutical composition is useful for treating or preventing symptoms such as high fever, diarrhea and dehydration caused by influenza virus infection by inhibiting the growth of influenza virus while containing the compound represented by
본 발명의 조성물이 약제학적 조성물로 제조되는 경우, 본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.When the composition of the present invention is manufactured from a pharmaceutical composition, the pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers included in the pharmaceutical compositions of the present invention are those commonly used in the preparation, such as lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, Calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like It doesn't happen. In addition to the above components, the pharmaceutical composition of the present invention may further include a lubricant, a humectant, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제 조성물은 임상 투여 시에 경구 또는 비경구로 투여, 예를 들어 정맥 내, 피하, 복강 내 또는 국소 적용할 수 있으며, 일반적인 의약품 및 건강식품의 형태로 사용될 수 있다. The pharmaceutical composition of the present invention may be administered orally or parenterally, for example, intravenously, subcutaneously, intraperitoneally or topically, during clinical administration, and may be used in the form of general medicines and health foods.
본 발명의 약제 조성물은 경구 투여용 제형, 예를 들면 정제, 트로키제(troches), 로렌지(lozenge), 수용성 또는 유성현탁액, 조제분말 또는 과립, 에멀젼, 하드 또는 소프트 캡슐, 시럽 또는 엘릭실제(elixirs)로 제제화된다. Pharmaceutical compositions of the invention may be formulated for oral administration such as tablets, troches, lozenges, aqueous or oily suspensions, prepared powders or granules, emulsions, hard or soft capsules, syrups or elixirs ( formulated into elixirs).
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 본 발명의 약제학적 조성물에 포함된 화학식 1 및 2의 플라보노이드 화합물 및 분획물의 투여량은 성인 기준으로 0.001-100 ㎎/kg, 바람직하게는 0.1-100 ㎎/kg, 보다 바람직하게는 5-50 mg/kg 범위 내이다. 의사 또는 약사의 판단에 따라 일정 시간 간격으로 1 일 수회, 바람직하기로는 하루 2 회 내지 3 회 분할 투여될 수 있다.The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The dosage of the flavonoid compounds of
또한, 본 발명의 약제 조성물은 비경구로 투여할 수 있으며, 비경구 투여는 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사 주입방식에 의한다. 비경구 투여용 제형으로 제제화하기 위해서는 상기 화학식 1의 화합물을 안정제 또는 완충제와 함께 물에서 혼합하여 용액 또는 현탁액으로 제조하고 이를 앰플 또는 바이알의 단위 투여형으로 제제한다. In addition, the pharmaceutical composition of the present invention may be administered parenterally, and parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection injection. To formulate into a parenteral formulation, the compound of
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액, 시럽제 또는 유화액 형태이거나 엑스제, 산제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical compositions of the present invention may be prepared in unit dose form by formulating with a pharmaceutically acceptable carrier and / or excipient according to methods which can be easily carried out by those skilled in the art. Or may be prepared by incorporation into a multi-dose container. The formulation may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of extracts, powders, powders, granules, tablets or capsules, and may further comprise dispersants or stabilizers.
본 발명의 조성물이 화장료 조성물로 제조되는 경우, 본 발명의 조성물은 상술한 화학식 1 및 2의 플라보노이드 화합물 추출물 또는 분획물뿐만 아니라, 화장료 조성물에 통상적으로 이용되는 성분들을 포함하며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함한다. 또한, 본 발명의 조성물은 상술한 화학식 1 및 2의 플라보노이드 화합물 추출물 또는 분획물 이외에, 그 작용 (화학식 1 및 2의 플라보노이드 화합물 추출물에 의한 항바이러스 작용)을 손상시키지 않는 한도에서 종래부터 사용되어오던 항바이러스제를 함께 혼합하여 사용할 수 있다.
When the composition of the present invention is made of a cosmetic composition, the composition of the present invention includes not only the flavonoid compound extracts or fractions of the above formulas (1) and (2), but also components commonly used in cosmetic compositions, such as antioxidants, stabilizers , Conventional adjuvants such as solubilizers, vitamins, pigments and flavorings, and carriers. In addition, the composition of the present invention, in addition to the flavonoid compound extracts or fractions of the above-mentioned formulas (1) and (2), do not impair its action (antiviral action by the flavonoid compound extracts of
본 발명의 조성물이 식품 조성물로 제조되는 경우, 유효성분으로서 화학식 1 및 2의 플라보노이드 화합물 추출물 또는 분획물뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. 상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.When the composition of the present invention is prepared as a food composition, as an active ingredient, as well as extracts or fractions of the flavonoid compounds of the formulas (1) and (2), components commonly added during food production, for example, proteins, carbohydrates, fats Contains nutrients, seasonings and flavorings. Examples of the above-mentioned carbohydrates are monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, oligosaccharides and the like; And polysaccharides such as dextrin, cyclodextrin and the like, and sugar alcohols such as xylitol, sorbitol and erythritol. Natural flavorings such as tau martin and stevia extract (e.g., rebaudioside A and glycyrrhizin) and synthetic flavorings (saccharine, aspartame, etc.) can be used as flavorings.
예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 화학식 1 및 2의 플라보노이드 화합물 추출물 또는 분획물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다. For example, when the food composition of the present invention is prepared with a drink, in addition to the flavonoid compound extracts or fractions of the formulas (1) and (2) of the present invention, citric acid, liquid fructose, sugar, glucose, acetic acid, malic acid, fruit juice, tofu extract, jujube extract, licorice Extracts and the like may be further included.
또한, 건강식품이란, 상기 화학식 1로 표시되는 화합물 또는 이의 약학적으로 허용가능한 염을 음료, 차류, 향신료, 껌, 과자류 등의 식품소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있다.
In addition, the health food is a food prepared by adding the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof to food materials such as beverages, teas, spices, chewing gum, confectionary, or the like, encapsulated, powdered, suspension, etc. As such, ingesting it means that it brings a specific effect on health, but unlike general medicines, there is no side effect that can occur when taking long-term use of the drug as a food raw material.
이하, 본 발명은 다음 실시예에 의거하여 구체적으로 설명하겠는 바, 본 발명이 이에 한정되는 것은 아니다.
Hereinafter, the present invention will be described in detail with reference to the following examples, but the present invention is not limited thereto.
참조예Reference Example 1: One: 시험대조의약과Examination contrast medication 바이러스 virus
시험 화합물인 타미플루와 리바바린은 각각 로쉬(Roche)사와 시그마(Sigma)사에서 구입하여 사용하였다. Tamiflu and ribovarin, test compounds, were purchased from Roche and Sigma, respectively.
본 발명에 사용된 바이러스는 인플루엔자 A 바이러스(A/PR/8/34), 인플루엔자 B 바이러스(B/Lee/40), 와 라이노바이러스 3형(HRV-3)를 사용하였다. 각각의 바이러스는 ATCC로부터 구입하여, 바이러스 활성을 배양 측정한 후, -70℃에 보관하여 사용하였다.
Viruses used in the present invention were influenza A virus (A / PR / 8/34), influenza B virus (B / Lee / 40), and rhinovirus type 3 (HRV-3). Each virus was purchased from ATCC, measured for viral activity, and stored at -70 ° C for use.
실시예Example 1: One: 퀘르세틴Quercetin -3--3- 갈락토사이드의Galactoside 사람 인플루엔자 바이러스에 대한 증식 저해 효과 측정 Determination of Growth Inhibitory Effects on Human Influenza Viruses
퀘르세틴-3-갈락토사이드의 사람 인플루엔자 바이러스에 대한 증식 저해 효과를 측정하기 위하여, 본 발명자들은 개 신장세포 유래 세포주인 MDCK 세포를 이용하여 다음과 같은 생체 외 실험을 수행하였다.In order to determine the effects of quercetin-3-galactoside on the proliferation inhibitory effect on human influenza virus, the present inventors performed the following in vitro experiment using MDCK cells, which are cell lines derived from dog kidney cells.
퀘르세틴-3-갈락토사이드의 바이러스 증식 억제능 측정방법은 권두한 등(대한민국 특허등록 제682069호)이 특허 출원한 방법에 의거하여 인플루엔자 바이러스 A 형 바이러스 (A/WS/33)에 대한 바이러스 활성 저해 효과를 측정하였다. MDCK 세포를 96-웰 마이크로플레이트(96-well microplate)의 각 웰에서 바닥이 세포로 완전히 덮힐 때까지 배양하였다. 기존 배양액을 제거하고 인산 완충액으로 각 웰을 2회 세척한 후 TCID50의 농도로 조장된 인플루엔자 바이러스 용액들을 각 웰에 넣고 퀘르세틴-3-갈락토사이드와 기존 항인플루엔자 바이러스제인 타미플루(Tamiflu)를 구입하여 각각 디메틸설폭사이드(dimethylsulfoxide)에 용해시킨 뒤에 각각의 용액을 0.01 ~ 100 ㎍/㎖의 농도로 각 웰에 투여하고 48 시간 동안 배양하였으며 현미경으로 MDCK 세포의 모양을 관찰하여 항바이러스능 여부를 1차 판정하였다. 각 웰에 70 % 아세톤을 100 씩 첨가한 후 1 시간 동안 -20 ℃에 방치하고 건조기에서 건조시킨 후, 1%(v/v) 아세트산에 녹인 0.4%(w/v) SRB(sulforhodamine B) 용액 100 를 첨가해 30분 동안 염색시킨 다음 세포와 결합하지 않은 SRB 염색액을 1% (v/v) 아세트산으로 4회 세척한 다음 다시 건조시켰다. 각 웰 바닥에 세포와 결합되어 있는 염색제를 10 mM 트리스 용액(pH 10.5) 100 를 각 웰에 가하여 염색제를 녹인 후 562 nm에서 흡광도를 측정하여 바이러스 저해 효과를 비교하였다. 이때, DMSO만 처리한 세포와 DMSO 및 인플루엔자 바이러스 감염용액을 같이 투여한 세포를 대조군으로 사용하여 비교한 본 발명의 화합물이 나타내는 인플루엔자 바이러스의 증식 저해 효과를 결정하여 다음 표 1에 나타내었다.
The method for measuring virus growth inhibition of quercetin-3-galactoside is based on the method of patent application by Kwon Doo Han et al. (Korean Patent Registration No. 682069), and the effect of inhibiting virus activity against influenza virus type A virus (A / WS / 33). Was measured. MDCK cells were incubated in each well of a 96-well microplate until the bottom was completely covered with cells. Remove the existing cultures, wash each well twice with phosphate buffer, put influenza virus solutions prepared at a concentration of TCID 50 into each well, and purchase quercetin-3-galactoside and Tamiflu, an existing anti-influenza virus agent. After dissolving each in dimethylsulfoxide (dimethylsulfoxide) each solution was administered in each well at a concentration of 0.01 ~ 100 ㎍ / ㎖ and incubated for 48 hours and observed the shape of MDCK cells under a microscope to determine the
실시예Example 2: 2: 퀘르세틴Quercetin -3--3- 갈락토사이드의Galactoside 동물에서의 인플루엔자 A 바이러스에 대한 증식 저해 효과 측정 Determination of Growth Inhibitory Effect on Influenza A Virus in Animals
퀘르세틴-3-갈락토사이드의 동물에서의 인플루엔자 A 바이러스에 대한 증식 저해 효과를 측정하기 위하여, 본 발명자들은 개 신장세포 유래 세포주인 MDCK 세포를 이용하여 인플루엔자바이러스를 쥐에 감염시키고 퀘르세틴-3-갈락토사이드의 항바이러스능 확인 실험을 수행하였다.In order to measure the inhibitory effect of quercetin-3-galactoside on influenza A virus in animals, the present inventors used MDCK cells, which are dog kidney cell-derived cell lines, to infect mice with influenza virus and quercetin-3-gal. The antiviral activity test of lactoside was performed.
쥐 (품종:Balb/C)를 비감염군, 비약제 감염군, 퀘르세틴-3-갈락토사이드 투여군, 퀘르세틴-3-글루코사이드 투여군, 타미플루 투여군으로 나누어 각 군 별로 6 마리를 시험하였다. 인플루엔자 A 바이러스(A/PR/8/34)를 쥐들에 감염시키고 퀘르세틴-3-갈락토사이드, 퀘르세틴-3-글루코사이드, 타미플루 30 g를 각각 매일 1 회 구강투여의 방법으로 7 일간 복용시켰다. 시험결과는 각 군의 일일체중변화와 7일후의 체중변화를 비교하였다.
Rats (breed: Balb / C) were divided into an uninfected group, a non-pharmaceutical infected group, a quercetin-3-galactoside-treated group, a quercetin-3-glucoside-treated group, and a Tamiflu-administered group, and 6 mice were tested in each group. Influenza A virus (A / PR / 8/34) was infected with mice and 30 g of quercetin-3-galactoside, quercetin-3-glucoside, and Tamiflu, respectively, were taken for 7 days by oral administration once daily. The test results were compared with the change in daily weight and weight change after 7 days in each group.
실시예Example 3: 3: 퀘르세틴Quercetin -3--3- 글루코사이드의Glucoside 인플루엔자 B형 바이러스에 대한 증식 저해 효과 측정 Inhibition of proliferation inhibition against influenza B virus
퀘르세틴-3-갈락토사이드의 인플루엔자 B 바이러스에 대한 증식저해 효과를 같은 항인플루엔자바이러스 의약인 타미플루와 아만타딘, 항헤르페스심플렉스바이러스 의약인 아시클로비르와 비교측정하기 위하여, 본 발명자들은 개 신장 세포주인 MDCK 세포를 이용하여 다음과 같은 생체 외 실험을 수행하였다.In order to compare the anti-proliferative effect of quercetin-3-galactoside against influenza B virus with the same anti-influenza virus drugs Tamiflu and Amantadine, and the anti-herpes simplex virus drug Acyclovir, the present inventors In vitro experiments were performed using MDCK cells.
퀘르세틴-3-갈락토사이드의 바이러스 증식 억제능 측정방법은 권두한 등(대한민국 특허등록 제0682069호)이 특허 출원한 방법에 의거하여 인플루엔자 B형 바이러스(B/Lee/40)에 대한 바이러스 활성 저해 효과를 측정하였다. 이하는 실시예 3과 동일하게 실시하였다.
The method for measuring virus growth inhibition of quercetin-3-galactoside was based on the method of patent application by Kwon Doo Han et al. (Korean Patent Registration No. 0682069) to inhibit the virus activity against influenza B virus (B / Lee / 40). Measured. The following was carried out in the same manner as in Example 3.
실시예Example 4: 라이노바이러스에 대한 4: for rhinoviruses 퀘르세틴Quercetin -3--3- 갈락토사이드의Galactoside 항바이러스능Antiviral activity
HeLa 세포(2x104개)를 96 웰 플레이트(well plates)의 각 웰에 넣고 24시간 동안 배양하였다. 24시간 후에 각 웰의 배양 상등액을 제거하고 TCID50으로 적정한 라이노바이러스 3형 바이러스 용액을 각 웰에 넣은 다음, 퀘르세틴 3-갈락토사이드 및 리바비린의 농도가 각 0.1 /ml, 1 /ml, 10 /ml 및 100 /ml이 되도록 각 웰을 처리하였다. 퀘르세틴 3-갈락토사이드 및 리바비린의 바이러스 증식 억제능 측정은 한국등록특허 제10-0682069호에 제시된 방법에 따라 수행하였다.
HeLa cells ( 4 × 2 × 10) were placed in each well of 96 well plates and incubated for 24 hours. After 24 hours, the culture supernatant of each well was removed and the
실시예Example 5: 독성시험 5: toxicity test
본 발명의 퀘르세틴-3-갈락토사이드에 대하여 독성실험을 다음과 같이 수행하였다. Toxicity experiments were performed on quercetin-3-galactoside of the present invention as follows.
퀘르세틴-3-갈락토사이드를 물에 용해한 후 이를 마우스(군당 10마리)에 각각 10 g/㎏을 투여한 다음 7일간 관찰하였으나 사망하는 쥐는 없었다.
Quercetin-3-galactoside was dissolved in water, and then 10 g / kg each was administered to mice (10 per group) and observed for 7 days, but no mice died.
시험예Test Example 1: 인플루엔자 A형 바이러스에 대한 기존 의약과 1: Conventional Medicines for Influenza A Viruses 퀘르세틴Quercetin -3--3- 갈락토사이드Galactoside , , 퀘르세틴Quercetin -3--3- 글루코사이드Glucoside , , 퀘르세틴Quercetin -3--3- 람노사이드의Rhamnoside 항바이러스능Antiviral activity 비교 compare
하기 표 1에서 보는 바와 같이, 인플루엔자 A 바이러스에 대한 타미플루의 IC50 값은 7.88 ± 1.15 /ml인데 비하여 퀘르세틴 3-갈락토사이드의 IC50 값은 2.77± 2.50 /ml으로 바이러스에 대한 50% 억제농도가 타미플루가 나타낸 농도의 1/2보다 낮은 IC50 값을 나타내었다. 또한 퀘르세틴 3-글루코사이드, 퀘르세틴 3-람노사이드와도 비교할 때도 퀘르세틴 3-갈락토사이드의 IC50 값이 39.7%, 50.6% 박에 되지 않아 항바이러스능이 퀘르세틴 3-글루코사이드, 퀘르세틴 3-람노사이드에 비해 탁월함을 알 수 있으며, 의약으로서의 효용성을 나타내는 값인 SI(세포독성/항바이러스능)은 퀘르세틴 3-갈락토사이드는 180.5 인데 비하여 퀘르세틴 3-글루코사이드, 퀘르세틴 3-람노사이드는 71.74, 91.41로 퀘르세틴 3-글루코사이드, 퀘르세틴 3-람노사이드에 비해 2 배이상의 의약 효용성을 나타내었으며, 타미플루가 40.61 인 수치에 비하여는 퀘르세틴 3-갈락토사이드는 4 배 이상의 의약효용성을 나타내었다 (표 1). 하기 표 1은 인플루엔자 A형 바이러스에 대한 기존 의약과 퀘르세틴-3-갈락토사이드, 퀘르세틴-3-글루코사이드, 퀘르세틴-3-람노사이드의 항바이러스능 비교한 테이블이다.
As shown in Table 1 below, the IC 50 value of Tamiflu against influenza A virus is 7.88 ± 1.15 / ml, whereas the IC 50 value of quercetin 3-galactoside is 2.77 ± 2.50 / ml, 50% inhibitory concentration against the virus. Showed an IC 50 value lower than half of the concentration indicated by Tamiflu. Also, when compared to quercetin 3-glucoside and quercetin 3-rhamnoside, the IC50 value of quercetin 3-galactoside was not less than 39.7% and 50.6% per night, so the antiviral activity was superior to quercetin 3-glucoside and quercetin 3-rhamnoside. In the case of SI (cytotoxicity / antiviral activity), which is a value that indicates the efficacy as a medicament, quercetin 3-glucoside and quercetin 3-glucoside were 18.71, 74.91 and 91.41, respectively, compared to quercetin 3-galactoside. , Quercetin 3-rhamnoside showed more than two times the efficacy of the drug, compared to the value of Tamiflu 40.61, quercetin 3-galactoside showed more than four times the drug efficacy (Table 1). Table 1 below is a table comparing the antiviral activity of the conventional medicine and quercetin-3-galactoside, quercetin-3-glucoside, quercetin-3-rhamnoside against influenza type A virus.
(CC50/IC50)SI
(CC50 / IC50)
*바이러스: 사람 인플루엔자 A 바이러스(A/PR/8/34, H1N1)
Virus: Human Influenza A Virus (A / PR / 8/34, H1N1)
시험예Test Example 2: 2: 퀘르세틴Quercetin -3--3- 갈락토사이드의Galactoside 동물에서의 인플루엔자 A 바이러스에 대한 증식 저해 효과 측정 Determination of Growth Inhibitory Effect on Influenza A Virus in Animals
하기 표 2에서 보는 바와 같이, 비감염쥐의 체중은 실험시작 때 25.5±1.01g에서 28.15±1.01g 으로 2.65 g 이 증가하였다. 반면 인플루엔자바이러스를 감염시킨 쥐에서는 24.41±0.59g에서 17.11±1.16g 으로 7.3 g 이 감소하였다. 인플루엔자바이러스를 감염시킨 쥐에서 타미플루를 투여한 군은 3.91g 이 감소한 반면 퀘르세틴 3-갈락토사이드 투여군에서는 1.83 g 만이 감소하여 타미플루보다 탁월한 항바이러스능 약리효과를 나타내었다. 그러나 구조적으로 매우 유사한 퀘르세틴 3-람노사이드 투여군은 6.94 g 이 감소하여 퀘르세틴 3-갈락토사이드 뿐만 아니라 타미플루보다도 낮은 항바이러스능 약리효과를 나타내었다. 이러한 결과는 타미플루보다 낮은 약리효과를 나타내는 퀘르세틴 3-람노사이드 의 구조에서, 구조적으로 유사한 퀘르세틴 3-갈락토사이드가 타미플루보다 탁월한 항바이러스능 약리효과를 나타내는 효능을 유추할 수 없는 결과를 얻었다 (표 2, 도 2 참조). 하기 표 2는 인플루엔자 A 바이러스 감염쥐에서 퀘르세틴 3-갈락토사이드와 퀘르세틴 3-글루코사이드 투여군에서의 항바이러스능 비교한 테이블이다.
As shown in Table 2 below, the weight of the uninfected rats increased by 2.65 g from 25.5 ± 1.01g to 28.15 ± 1.01g at the start of the experiment. In contrast, mice infected with influenza virus had a decrease of 7.3 g from 24.41 ± 0.59g to 17.11 ± 1.16g. In the mice infected with influenza virus, the Tamiflu-administered group showed a 3.91 g reduction, while the quercetin 3-galactoside-administered group showed only 1.83 g of the antiviral activity, which was superior to Tamiflu. However, the structurally very similar quercetin 3-rhamnoside group showed a decrease of 6.94 g, which showed lower antiviral activity than Tamiflu as well as quercetin 3-galactoside. These results show that in the structure of quercetin 3-rhamnoside, which shows lower pharmacological effect than Tamiflu, the effect of structurally similar quercetin 3-galactoside showing better antiviral pharmacological effect than Tamiflu cannot be inferred. 2, see FIG. 2). Table 2 below is a table comparing the antiviral ability of the quercetin 3-galactoside and the quercetin 3-glucoside in the influenza A virus infected mice.
평균체중±표준오차Average weight of rats before test (g)
Average weight ± standard error
평균체중±표준오차Average weight of rats after 8 days (g)
Average weight ± standard error
(8일 후-시험전)Weight change ratio (%)
(8 days later-before test)
시험예Test Example 3: 인플루엔자 B 바이러스에 대한 기존 의약과 3: Conventional Medicines for Influenza B Viruses 퀘르세틴Quercetin -3--3- 갈락토사이드Galactoside , , 퀘르세틴Quercetin -3--3- 람노사이드의Rhamnoside 항바이러스능Antiviral activity 비교 compare
하기 표 3에서 보는 바와 같이, 항인플루엔자바이러스제인 타미플루는 인플루엔자 B 바이러스에 대하여 항바이러스능을 나타내지 못하였다. 인플루엔자 B 바이러스는 타미플루의 100 /ml 의 농도에서도 바이러스 활성이 거의 감소하지 않았다. 역시 항인플루엔자바이러스제인 아만타딘도 100 /ml 의 농도에서도 인플루엔자 B 바이러스의 CPE를 억제하지 못했으며, 항헤르페스심플렉스바이러스 의약인 아시클로비르도 100 /ml 의 농도에서도 인플루엔자 B 바이러스의 CPE를 억제하지 못했다. 이에 비하여 퀘르세틴 3-갈락토사이드의 IC50 값은 8.93± 3.19 /ml로서 퀘르세틴 3-람노사이드의 IC50 값(81.3±4.85/ml)에 비해 약 1/9의 값을 보여주여 퀘르세틴에 갈락토사이드와 람노사이드 두 당의 결합차이에 따라 항인플루엔자바이러스능 차이가 크게 나고 있음을 확인하였다 (표 3, 도 2). 하기 표 3은 인플루엔자 B형 바이러스에 대한 기존 의약(타미플루, 아만타딘)과 퀘르세틴-3-갈락토사이드, 퀘르세틴-3-람노사이드의 항바이러스능을 비교한 테이블이다.
As shown in Table 3 below, Tamiflu, an anti-influenza virus, did not show antiviral activity against influenza B virus. Influenza B virus showed little decrease in viral activity even at a concentration of 100 / ml of Tamiflu. Amantadine, an anti-influenza virus, also did not inhibit the CPE of influenza B virus at the concentration of 100 / ml, and acyclovir, the anti-herpes simplex virus drug, did not inhibit the CPE of the influenza B virus. . In comparison, the IC 50 value of quercetin 3-galactoside was 8.93 ± 3.19 / ml, which was about 1/9 compared to the IC 50 value of quercetin 3-rhamnoside (81.3 ± 4.85 / ml). It was confirmed that the anti-influenza virus activity difference is large according to the binding difference between the two sugars of the side and rhamnoside (Table 3, Figure 2). Table 3 below is a table comparing the antiviral ability of the conventional medicine (Tamiflu, Amantadine) and quercetin-3-galactoside, quercetin-3-rhamnoside against influenza B virus.
(CC50/IC50)SI
(CC50 / IC50)
*바이러스: 인플루엔자 B형 바이러스(B/Lee/40)
Virus: Influenza B Virus (B / Lee / 40)
시험예Test Example 4: 라이노바이러스에 대한 4: for rhinoviruses 퀘르세틴Quercetin -3--3- 갈락토사이드의Galactoside 항바이러스능Antiviral activity
하기 표 4에서 보는 바와 같이, 퀘르세틴 3-갈락토사이드는 인플루엔자 바이러스 뿐만 아니라 라이노바이러스 8종에 대해서도 모두 탁월한 항바이러스능을 나타내었다. 라이노바이러스 14형은 리바비린에 대해 내성을 나타냈으며, 라이노바이러스 3형에 대해 리바비린의 IC50 값은 4.77±1.01/ml인데 비하여 퀘르세틴 3-갈락토사이드의 IC50 값은 0.396±0.59/ml 으로 리바비린에 비해 1/10의 농도에서 같은 효과를 나타내고 있다. SI 값으로 비교하면 리바비린은 117.27의 수치를 보인데 비해 퀘르세틴에 3-갈락토사이드에서는 세포독성이 1000/ml에서도 나타나지 않아 SI 값은 2525 이상으로 리바비린에 비해 퀘르세틴 3-갈락토사이드는 20배의 수치를 보여 보다 탁월한 약리효과를 나타낼 수 있음을 보여주었다. 하기 표 4는 라이노바이러스에 대한 리바비린과 퀘르세틴-3-갈락토사이드의 항바이러스능 비교한 테이블이다.
As shown in Table 4 below, quercetin 3-galactoside showed excellent antiviral activity against all 8 influenza viruses as well as rhinoviruses. Rhinovirus type 14 was resistant to ribavirin and ribavirin had an IC 50 value of 4.77 ± 1.01 / ml, whereas quercetin 3-galactoside had an IC 50 of 0.396 ± 0.59 / ml. The same effect is obtained at the concentration of 1/10 compared with the. Compared with the SI value, ribavirin shows a value of 117.27, but quercetin does not show cytotoxicity in 3-galactoside at 1000 / ml, so the SI value is 2525 or more, and quercetin 3-galactoside is 20 times higher than ribavirin. The figures showed that the pharmacological effect could be more excellent. Table 4 below is a table comparing the antiviral ability of ribavirin and quercetin-3-galactoside against rhinoviruses.
제조예Manufacturing example 1 : 분말제의 제조 1: Manufacture of powder
유효성분(퀘르세틴-3-갈락토사이드) 10 g10 g of active ingredients (quercetin-3-galactoside)
옥수수 전분 50 gCorn starch 50 g
카르복시 셀룰로오스 40 g40 g of carboxycellulose
총 량 100 gTotal amount 100 g
상기에서 나열된 성분들을 잘게 부숴 혼합하여 분말을 제조하였다. 5 번 경질 캅셀에 분말 100 ㎎을 넣어 캅셀제를 제조하였다.
A powder was prepared by crushing and mixing the ingredients listed above. 100 mg of powder was added to the 5 times hard capsule to prepare a capsule.
제조예Manufacturing example 2: 정제의 제조 2: Preparation of tablets
유효성분(퀘르세틴-3-갈락토사이드) 10 g10 g of active ingredients (quercetin-3-galactoside)
락토스 70 gLactose 70 g
결정성 셀룰로오스 15 gCrystalline cellulose 15 g
스테아린산 마그네슘 5 g5 g of magnesium stearate
총 량 100 gTotal amount 100 g
상기에서 나열된 성분들을 잘게 부숴 혼합한 후 직타법(direct tableting method)에 의해 정제를 제조하였다. 각 정제의 총량은 100 ㎎이고, 그 중 유효성분의 함량은 10 ㎎이다.
The components listed above were finely crushed and mixed to prepare tablets by direct tableting method. The total amount of each tablet was 100 mg, and the content of the active ingredient was 10 mg.
제조예Manufacturing example 3 : 주사제의 제조 3: Preparation of Injection
유효성분(퀘르세틴-3-갈락토사이드) 10 ㎎Active ingredient (Quercetin-3-galactoside) 10 mg
염화나트륨 600 ㎎Sodium chloride 600 mg
아스코르빈산 100 ㎎
주사용 물 적량Water for injection
총량 100 ㎖
상기와 같은 조성으로 주사제를 제조하였다. 이 용액을 앰플에 넣고 120 ℃ 에서 30분 동안 가열 멸균하였다.
Injections were prepared in the same composition as above. This solution was placed in an ampoule and heat sterilized at 120 ° C. for 30 minutes.
제제예Formulation example 4 : 음료 제조 4: beverage manufacture
유효성분(퀘르세틴-3-갈락토사이드) 500 ㎎을 적당량의 물에 용해시킨 후에 보조성분으로서 비타민 C, 교미제로서 구연산, 구연산나트륨, 올리고당을 적당량 가하고, 보존제로서 적당량의 나트륨벤조에이트를 가한 후에 물을 가하여 전량을 100 ㎖로 만들어 음료용 조성물을 제조하였다. 이때 타우린이나 마이오 이노시톨, 엽산, 판토텐산 등을 단독으로 혹은 함께 첨가할 수 있다.
After dissolving 500 mg of the active ingredient (Quercetin-3-galactoside) in an appropriate amount of water, vitamin C as an auxiliary ingredient, citric acid, sodium citrate, oligosaccharides as an auxiliary agent, and an appropriate amount of sodium benzoate are added as a preservative. Water was added to make the whole amount to 100 ml to prepare a beverage composition. At this time, taurine, myo-inositol, folic acid, pantothenic acid, etc. may be added alone or together.
Claims (5)
[화학식 1]
상기 화학식 1에서, R1 내지 R5는 각각 독립적으로 -OH 또는 수소이다.
An antiviral composition for a virus comprising a flavonoid compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient and an RNA template:
[Formula 1]
In Formula 1, R 1 to R 5 are each independently -OH or hydrogen.
[화학식 2]
The antiviral composition according to claim 1, wherein the flavonoid compound represented by Chemical Formula 1 is quercetin 3-galactoside represented by Chemical Formula 2.
(2)
The antiviral composition according to claim 1, wherein the antiviral composition has an antiviral effect on an influenza A virus, an influenza B virus, or a rhinovirus.
An antiviral food composition comprising a flavonoid compound of Formula 1 or Formula 2.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832755A (en) * | 2016-05-24 | 2016-08-10 | 吉林大学 | Application of combination of hyperoside and oseltamivir to drug for prevention and treatment of H7N9 influenza |
| WO2021206498A1 (en) * | 2020-04-09 | 2021-10-14 | 권두한 | Flavonoid glycoside having anti-coronavirus activity |
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| US6350784B1 (en) * | 1996-02-12 | 2002-02-26 | Meryl J. Squires | Antimicrobial prevention and treatment of human immunedeficiency virus and other infectious diseases |
| KR101186264B1 (en) * | 2009-06-12 | 2012-09-27 | 한국생명공학연구원 | A composition for diseases mediated by IL-6 or rhinovirus infectious diseases comprising an extract of Hippophae rhamnoides or a compound isolated therefrom |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105832755A (en) * | 2016-05-24 | 2016-08-10 | 吉林大学 | Application of combination of hyperoside and oseltamivir to drug for prevention and treatment of H7N9 influenza |
| CN105832755B (en) * | 2016-05-24 | 2018-11-06 | 吉林大学 | Hyperoside and Oseltamivir combine the application in preventing H7N9 type flu pharmaceuticals |
| WO2021206498A1 (en) * | 2020-04-09 | 2021-10-14 | 권두한 | Flavonoid glycoside having anti-coronavirus activity |
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