KR20120087928A - Anti-influenza virus agent - Google Patents
Anti-influenza virus agent Download PDFInfo
- Publication number
- KR20120087928A KR20120087928A KR1020127010366A KR20127010366A KR20120087928A KR 20120087928 A KR20120087928 A KR 20120087928A KR 1020127010366 A KR1020127010366 A KR 1020127010366A KR 20127010366 A KR20127010366 A KR 20127010366A KR 20120087928 A KR20120087928 A KR 20120087928A
- Authority
- KR
- South Korea
- Prior art keywords
- extract
- influenza virus
- extracting
- virus
- ethanol water
- Prior art date
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Abstract
일상적으로 안심하고 사용할 수 있는 안전성 높은 식물 추출물을 이용하여, 인플루엔자 바이러스 흡착 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 mRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 vRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 cRNA 합성 억제제, 바이러스막 융합 활성 시험에서의 용혈 억제제 및 인플루엔자 바이러스의 엔벨로프 파괴제의 제공. 모과를 50% 에탄올수를 사용하여, 추출하고, 그 추출액을 칼럼 분획하여 정제함으로써 얻은 추출물을 유효성분으로 하는 것을 특징으로 하는 항인플루엔자 바이러스제.Inhibitors of influenza virus adsorption, virus mRNA synthesis inhibitors in influenza virus infected cells, virus vRNA synthesis inhibitors in influenza virus infected cells, and viral cRNAs in influenza virus infected cells, using safe plant extracts that can be used with confidence in daily use Provision of Synthetic Inhibitors, Hemolytic Inhibitors in Viral Membrane Fusion Activity Tests, and Envelope Destructors of Influenza Viruses. An anti-influenza virus agent characterized by extracting the Chinese quince using 50% ethanol water and extracting the extract by column fractionation and purifying the extract.
Description
본 발명은 인플루엔자 바이러스의 감염 억제 작용을 갖는 식물 유래의 추출물을 유효 성분으로 하는 항인플루엔자 바이러스제, 인플루엔자 바이러스 흡착 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 mRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 vRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 cRNA 합성 억제제, 바이러스막 융합 활성 시험에서의 용혈 억제제 및 인플루엔자 바이러스의 엔벨로프 파괴제에 관한 것이다.The present invention provides an anti-influenza virus agent, an influenza virus adsorption inhibitor, an inhibitor of virus mRNA synthesis in influenza virus infected cells, and a virus vRNA synthesis inhibitor in influenza virus infected cells, comprising as an active ingredient extracts derived from plants having an infection inhibitory effect of influenza virus. , Inhibitors of viral cRNA synthesis in influenza virus infected cells, hemolytic inhibitors in viral membrane fusion activity tests, and envelope destroyers of influenza viruses.
매년 인플루엔자의 유행을 일으키는 인플루엔자 바이러스는 직경 1 만분의 1 밀리미터 정도의 엔벨로프막을 갖는 RNA 바이러스이다. 그 항원성의 차이에서 A, B, C 3 개의 형태로 분류되지만, 유행적인 확산을 보이는 것은 A 형, B 형이다. 이들 바이러스의 입자 표면에는, 적혈구 응집소 (HA) 와 뉴라미니다아제 (NA) 라는 2 종류의 당단백이 스파이크상으로 돌출되어 있고 내부에는 8 개로 분절된 유전자 RNA 가 존재한다. 바이러스의 표면에 있는 HA 와 NA 는 동일한 아형 (亞型) 내에서 변이를 빈번하게 일으켜, 매년과 같이 새로운 항원 변이주가 출현한다.The influenza virus that causes the pandemic of influenza every year is an RNA virus having an envelope membrane about 10,000 millimeters in diameter. The antigenic differences are classified into three types, A, B, and C, but the most prevalent spreads are A and B. On the particle surface of these viruses, two types of glycoproteins, erythrocyte agglutinates (HA) and neuraminidase (NA), protrude in the form of spikes and there are 8 segmented gene RNAs inside. HA and NA on the surface of the virus frequently cause mutations within the same subtype, resulting in new antigenic variants as each year.
기침으로 인한 비말 (飛沫) 에 의해 방출된 인플루엔자 바이러스는 사람의 코나 입으로 침입하고, 바이러스 표층의 스파이크상 당단백질 HA 에 의해 상기도 (上氣道) 의 점막 표피 세포에 흡착하여, 세포에 침입 후 증식을 개시한다. 최근의 연구에 의해, 바이러스의 감염 메커니즘이 밝혀지고 있다. 바이러스는 사람의 표적 세포의 표층에 존재하는 당 사슬로 이루어지는 리셉터에 결합하고, 엔도좀에 수용되어 바이러스막과 엔도좀막의 융합에 의해 세포 내에 침입하고, 탈각?이행을 거쳐, 바이러스 유전자의 발현과 복제가 일어나, 마지막으로 숙주 세포막으로부터의 출아에 의해 자손 바이러스 입자를 형성하여 증식한다.The influenza virus released by the cough droplets invades the human nose or mouth, adsorbs to the mucosal epidermal cells of the upper airway by the spiked glycoprotein HA of the viral surface layer, and then invades the cells. Initiate proliferation. Recent studies have revealed the infection mechanism of viruses. The virus binds to receptors consisting of sugar chains present on the surface of human target cells, is housed in endosomes, invades the cells by fusion of the viral membrane and the endosomal membrane, and through decontamination and execution, the expression of viral genes and Replication takes place and finally progeny virus particles are formed and propagated by budding from the host cell membrane.
인플루엔자 바이러스의 감염에 의해 며칠 내에 갑작스런 발열, 두통, 관절의 통증, 전신 권태감 등의 증상이 나타나며, 그것과 전후하여 기침이나 목의 통증, 콧물, 코막힘 등의 호흡기 증상이 출현한다. 이른바 감기와는 상이하고, 감염력이 강하여 단기간에 폭발적인 유행을 일으키는 것이 특징이다. 또한 인플루엔자 바이러스의 HA 단백질의 구조는 해마다 변이를 반복하여, 과거의 감염에 의해 만들어진 항체가 그다지 도움이 되지 않는 것도 감염을 확산시켜 버리는 요인이 되고 있다.Influenza virus infection causes symptoms such as sudden fever, headache, joint pain, and systemic malaise within a few days, and before and after it, respiratory symptoms such as cough, sore throat, runny nose, and stuffy nose appear. It is different from the so-called cold, and its infectivity is strong, and it is characterized by an explosive fashion in a short time. In addition, the structure of the HA protein of influenza virus is mutated every year, and the fact that antibodies produced by past infections do not help much has become a factor in spreading the infection.
인플루엔자 바이러스의 감염을 억제하기 위해서는, 표피 세포에 대한 흡착의 저해, 세포에 대한 침입의 저해, 유전자의 전사?복제의 억제, 단백질의 합성 저해, 세포로부터의 방출 억제 등이 고려되며, 각각이 항바이러스약의 타겟으로 되어 있다. 현재까지, 아만타진, 리만타진, 자나미빌 등의 항바이러스약이 개발되어 있지만, 과민증, 정신 신경 증상, 소화기계 증상, 자율 신경계 증상 등의 부작용이 보고되고 있으며, 그 응용에 관해서는 주의가 필요하다.In order to suppress the infection of influenza virus, inhibition of the adsorption to epidermal cells, inhibition of invasion to cells, inhibition of gene transcription and replication, inhibition of protein synthesis, inhibition of release from cells are considered. It is targeted for viral medicine. To date, antiviral drugs such as amantazin, rimantazin, and zanamiville have been developed, but side effects such as hypersensitivity, mental neurological symptoms, digestive system symptoms, and autonomic nervous system symptoms have been reported. need.
또한 인플루엔자 바이러스는 기도 점막 표피에서 감염, 증식하는 점이나, 그 해의 유행형을 정확하게는 예상할 수 없는 점에서, 백신의 접종에 의해 감염을 억제하는 것도 곤란하다고 생각되고 있다. 빈번한 구강 세척과 목의 건조를 피하는 것, 영양과 휴식을 충분히 취하는 것 등이 현재 가장 유효한 예방책으로 고려되고 있다. 감염 억제 효과가 높고, 또한 안전성에 문제가 없으며, 일상적으로 이용할 수 있는 항인플루엔자 바이러스제의 개발이 요망되고 있다.Influenza viruses are also thought to be difficult to suppress infection by inoculation of vaccines, since the influenza virus infects and proliferates in the airway mucosal epidermis, and the epidemic of the year cannot be accurately predicted. Frequent oral cleaning, avoiding dry throat, getting plenty of nutrition and rest are currently considered the most effective precautions. There is a demand for the development of anti-influenza virus agents that have high infection inhibitory effects, have no safety problems, and which can be used on a daily basis.
최근, 천연물 유래의 항인플루엔자 소재로서 차나 홍차의 폴리페놀 성분이 보고되어 있고 (비특허문헌 1 및 2), 사람을 이용한 시험에 의해 홍차의 구강 세척이 실제의 바이러스 감염을 억제하는 것이 밝혀지고 있다 (비특허문헌 3). 또 황금 유래의 플라보노이드 성분이 바이러스의 시알리다아제 저해 활성에 의해 인플루엔자 감염 억제 효과를 나타내는 것이 보고되고 있다(비특허문헌 4). 또한 한방 제제인 계지이월비일탕 (桂枝二越婢一湯) (특허문헌 1), 블랙 구스베리 (gooseberry) 추출물 (특허문헌 2), 감자 안토시아닌 색소 (특허문헌 3), 구아바 (guava) 잎 추출물 (특허문헌 4), 나포마 (羅布麻) 추출물 (특허문헌 5) 등의 항바이러스 효과가 보고되고 있다.In recent years, polyphenol components of tea and black tea have been reported as anti-influenza materials derived from natural products (Non-Patent
또한, 장미과 식물에서는, 그 꽃망울 또는 꽃잎의 추출물을 유효 성분으로 하는 항인플루엔자제가 개시되어 있고 (특허문헌 6), 모과의 추출물 (특허문헌 8), 모과의 칼럼 분획물 (비특허문헌 5) 의 항인플루엔자 바이러스 효과가 보고되고 있다. 그러나, 본원 발명 특허에 나타낸 모과의 칼럼 분획물의 인플루엔자 바이러스 흡착 억제 효과, 인플루엔자 바이러스 감염 세포에서의 바이러스 mRNA 합성 억제 효과, 인플루엔자 바이러스 감염 세포에서의 바이러스 vRNA 합성 억제 효과, 인플루엔자 바이러스 감염 세포에서의 바이러스 cRNA 합성 억제 효과, 바이러스막 융합 활성 시험에서의 용혈 억제 효과 및 인플루엔자 바이러스의 엔벨로프 파괴 효과에 관한 보고는 보이지 않고, 본원 발명에 의해 처음으로 밝혀진 것이다.Moreover, in the rosacea plant, the anti-influenza agent which uses the extract of the bud or the petal as an active ingredient is disclosed (patent document 6), the extract of the quince (patent document 8), and the column fraction of the quince (nonpatent literature 5). Influenza virus effects have been reported. However, the effect of inhibiting influenza virus adsorption of the column fractions of the quince in the present invention patent, the effect of inhibiting viral mRNA synthesis in influenza virus infected cells, the effect of inhibiting viral vRNA synthesis in influenza virus infected cells, the viral cRNA in influenza virus infected cells The report on the effect of inhibiting the synthesis, the effect of inhibiting hemolysis in the virus membrane fusion activity test, and the effect of envelope destruction of the influenza virus was not seen, and was first discovered by the present invention.
본 발명의 목적은 일상적으로 안심하고 사용할 수 있는 안전성이 높은 식물 추출물을 이용하여, 인플루엔자 바이러스 흡착 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 mRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 vRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 복제 억제제, 바이러스막 융합 활성 시험에서의 용혈 억제제 및 인플루엔자 바이러스의 엔벨로프 파괴제를 제공하는 것이다.An object of the present invention is to influenza virus adsorption inhibitors, virus mRNA synthesis inhibitors in influenza virus infected cells, virus vRNA synthesis inhibitors in influenza virus infected cells, influenza virus using high-safety plant extracts that can be used with confidence in daily life To provide viral replication inhibitors in infected cells, hemolytic inhibitors in viral membrane fusion activity tests and envelope disruptors of influenza viruses.
상기 과제를 해결하기 위해서, 본 발명자들은 부작용이 없고 안전성이 높은 모과에 착안하여, 인플루엔자 바이러스를 첨가한 MDCK 세포에서의 mRNA, vRNA, cRNA의 RT-PCR 법 해석, 닭 적혈구를 사용한 용혈 반응, 바이러스 입자의 전자 현미경 관찰에 대한, 모과 추출물의 효과를 발견하여, 본 발명품을 완성시켰다.In order to solve the above problems, the present inventors focus on quince without high side effects and high safety, and analyze the RT-PCR method of mRNA, vRNA, cRNA in MDCK cells added with influenza virus, hemolytic reaction using chicken erythrocytes, virus The effect of the quince extract on the electron microscopic observation of the particles was found to complete the present invention.
즉, 본 발명은 모과 (Chaenomeles sinensis, Pseudocydonia sinensis) 의 추출물을 유효 성분으로 하는 것을 특징으로 하는 인플루엔자 바이러스 흡착 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 mRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 vRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 cRNA 합성 억제제, 바이러스막 융합 활성 시험에서의 용혈 억제제 및 인플루엔자 바이러스의 엔벨로프 파괴제이다. 또한, 본 발명은 모과 추출물을 함유하는 항인플루엔자 바이러스 작용을 갖는 음식품이다.That is, the present invention is an influenza virus adsorption inhibitor, a virus mRNA synthesis inhibitor in influenza virus infected cells, a virus vRNA synthesis inhibitor in influenza virus infected cells, characterized in that the extract of the Chinese quince (Chaenomeles sinensis, Pseudocydonia sinensis) is an active ingredient. , Inhibitors of viral cRNA synthesis in influenza virus infected cells, hemolytic inhibitors in viral membrane fusion activity tests, and envelope destroyers of influenza viruses. In addition, the present invention is a food and drink having an anti-influenza virus action containing a Chinese quince extract.
본 발명은 안전성이 높은 모과의 추출물을 유효 성분으로 하여, 인플루엔자 바이러스에 대해서 강한 인플루엔자 바이러스 흡착 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 mRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 vRNA 합성 억제제, 인플루엔자 바이러스 감염 세포에서의 바이러스 복제 억제제, 바이러스막 융합 활성 시험에서의 용혈 억제제 및 인플루엔자 바이러스의 엔벨로프 파괴제를 제공하는 것이다. 또, 본 발명의 유효 성분인 모과의 추출물은 안전성이 높기 때문에, 마스크, 에어콘 필터, 의류, 웨트 티슈, 스프레이액 등에 흡착, 함침, 첨가함으로써, 인플루엔자 바이러스 감염 억제용품으로서 일상 생활에서 널리 이용할 수 있다. 또한 추잉껌, 캔디, 정과(錠菓), 음료 등의 음식물에 첨가하여, 항인플루엔자 바이러스 작용을 갖는 음식물로서 일상적으로 이용, 섭취하는 것도 가능하다. 본 발명품은 인플루엔자 바이러스의 감염 예방이나, 인플루엔자 바이러스에서 기인하는 질병의 치료에 유효하다.The present invention uses an extract of a high-fidelity quince as an active ingredient, an influenza virus adsorption inhibitor that is strong against influenza viruses, a virus mRNA synthesis inhibitor in influenza virus infected cells, a virus vRNA synthesis inhibitor in influenza virus infected cells, and an influenza virus infection To provide a virus replication inhibitor in a cell, a hemolytic inhibitor in a viral membrane fusion activity test and an envelope destroyer of influenza virus. Moreover, since the extract of the Chinese quince which is an active ingredient of the present invention has high safety, it can be widely used in daily life as an influenza virus infection suppressing product by adsorbing, impregnating and adding to masks, air conditioner filters, clothes, wet tissues, and spray liquids. . In addition, it can be added to foods such as chewing gum, candy, tablets, and beverages, and can be used and consumed daily as foods having an anti-influenza virus action. The present invention is effective for preventing infection of influenza virus and for treating diseases caused by influenza virus.
도 1 은 모과 추출물의 바이러스 엔벨로프막에 대한 파괴 활성을 나타낸다.
도 2 는 모과 추출물의 흡착 억제 활성 및 vRNA 합성 억제 활성, mRNA 합성 억제 활성, cRNA 합성 억제 활성을 나타낸다.
도 3 은 모과 추출물의 용혈 억제 활성을 나타낸다.Figure 1 shows the disruptive activity of the quince extract against the viral envelope membrane.
2 shows adsorption inhibitory activity, vRNA synthesis inhibitory activity, mRNA synthesis inhibitory activity, cRNA synthesis inhibitory activity of Chinese quince extract.
3 shows the hemolytic inhibitory activity of Chinese quince extract.
본 발명품의 원료가 되는 모과에서는 그 열매를 사용하는 것이 바람직하다.In the Chinese quince which becomes a raw material of this invention, it is preferable to use the fruit.
상기 식물의 분쇄물로부터 본 발명의 추출물을 얻는 방법에 대해서는 특별히 한정되지 않지만, 물, 메탄올, 에탄올, n-프로판올 및 n-부탄올 등의 저급 알코올, 에테르, 아세트산 에틸, 아세톤, 글리세린, 프로필렌글리콜 등의 유기 용제의 1 종 또는 2 종 이상의 혼합 용매를 첨가하여, 종래 행해지고 있는 추출 방법에 의해 추출한다. 그러나, 본 발명의 항인플루엔자 바이러스제를 경구로 섭취하는 것을 고려하면, 안전성 면에서 물, 에탄올 또는 그 혼합액을 이용하여 추출하는 것이 바람직하다.The method for obtaining the extract of the present invention from the pulverized product of the plant is not particularly limited, but lower alcohols such as water, methanol, ethanol, n-propanol and n-butanol, ether, ethyl acetate, acetone, glycerin, propylene glycol and the like 1 type, or 2 or more types of mixed solvent of the organic solvent of is added, and it extracts by the extraction method conventionally performed. However, in consideration of oral ingestion of the anti-influenza virus agent of the present invention, it is preferable to extract using water, ethanol or a mixture thereof from the viewpoint of safety.
추출 조건으로서는 특별히 제한은 없지만, 50?90 ℃ 에서 1?5 시간 정도가 바람직하다. 추출액을 여과하여, 추출 용제를 증류 제거한 후, 감압하에서 농축 또는 동결 건조한 것을 사용할 수 있다. 또한, 이들 추출물을 유기 용제 분획, 칼럼 크로마토그래피 등에 의해 분획 정제한 것도 사용할 수 있다.There is no restriction | limiting in particular as extraction conditions, About 1 to 5 hours are preferable at 50-90 degreeC. The extract is filtered, the extractant is distilled off, and then concentrated or lyophilized under reduced pressure can be used. Moreover, what refine | purified these extracts by the organic solvent fraction, column chromatography, etc. can also be used.
본 발명품의 이용 형태에 대해서는 특별히 제한은 없고, 유효 성분으로서 예시한 식물 추출물에 용제, 분산제, 제제용 담체, 유화제, 희석제, 안정제 등을 첨가함으로써, 산제, 정제, 트로치제, 흡입제, 구강 세척약, 함수제, 좌제, 주사제 등 임의의 제제로서 조제하는 것이 가능하며, 투여 경로로서 경구 투여, 기도 투여, 정맥내 투여, 직장 투여, 피하 투여, 피내 투여 등을 예시할 수 있다. 이 경우 성인에 대한 투여량은 각 추출물에서 10?2000 mg/일이 바람직하지만, 이 값에 제한되는 것은 아니다. 각종 제제에 대한 추출물의 첨가량으로는, 그 제제의 형태에 따라 상이하지만, 0.001 중량% 이상, 바람직하게는 약 0.01 중량% 이상의 비율이 되도록 첨가하는 것이 바람직하다.There is no restriction | limiting in particular about the usage form of this invention, A powder, a tablet, a troche, an inhalant, and mouthwashes are added to a plant extract illustrated as an active ingredient by adding a solvent, a dispersing agent, a preparation carrier, an emulsifier, a diluent, a stabilizer, etc. It can be prepared as any preparation, such as a water-containing, suppository, injection, etc., and examples of the route of administration include oral administration, airway administration, intravenous administration, rectal administration, subcutaneous administration, intradermal administration and the like. In this case, the dosage for adults is preferably 10-2000 mg / day in each extract, but is not limited to this value. The amount of the extract added to the various formulations varies depending on the form of the formulation, but is preferably added at a ratio of at least 0.001% by weight, preferably at least about 0.01% by weight.
또, 본 발명을 마스크, 에어콘 필터, 의류, 웨트 티슈, 스프레이액 등에 흡착, 함침, 첨가함으로써, 인플루엔자 예방에 기여할 수 있는 감염 억제용품을 제공할 수 있다. 이들 용도에서의 식물 추출물의 흡착, 첨가량은 그 감염 억제용품의 형태에 따라 상이하여, 일률적으로 규정할 수는 없지만, 0.001?5 중량% 의 비율이 되도록 첨가하는 것이 바람직하다.In addition, by adsorbing, impregnating, and adding the present invention to a mask, air conditioner filter, clothing, wet tissue, and spray solution, an infection suppressing article that can contribute to influenza prevention can be provided. The amount of adsorption and addition of the plant extract in these applications differs depending on the form of the infection suppressing article, and cannot be defined uniformly, but it is preferably added in a ratio of 0.001-5% by weight.
또 본 발명은 안전성이 높은 점에서, 예를 들어 추잉껌, 캔디, 정과, 구미젤리, 초콜릿, 비스킷 등의 과자, 아이스크림, 샤벳 등의 빙과, 음료, 스프, 잼 등의 음식물에 배합하여 일상적으로 이용하는 것이 가능하다. 첨가량으로서는, 그 이용 형태 및 추출물의 정미성 (呈味性) 에 따라 상이하지만, 음식품에 대해서 0.001?5 중량%, 바람직하게는 약 0.01?1 중량% 의 비율이 되도록 첨가하는 것이 바람직하다.In addition, since the present invention has high safety, for example, chewing gum, candy, sweets, gummi jelly, chocolate, biscuits, confectionery, ice cream, sherbet, ice cream, beverages, soups, jams, and the like are commonly used. It is possible. As addition amount, although it changes with the usage form and the taste of the extract, it is preferable to add so that it may become 0.001-5 weight% with respect to food-drinks, Preferably it is about 0.01-1 weight%.
이하에서 실시예, 시험예를 들어 본 발명을 구체적으로 설명하지만 본 발명은 이들에 한정되는 것은 아니다.Although an Example and a test example are given to the following and this invention is concretely demonstrated to it, this invention is not limited to these.
실시예 1Example 1
(모과 추출물의 조제)(Preparation of Chinese quince extract)
모과의 건조 분쇄물을 50% EtOH 추출한 후 다이아이온 HP-20 을 이용하여 분획하고, 5개의 분획물 (CSD1?5) 을 얻었다. 이들 분획물 중, 가장 활성이 높았던 CSD3 (40% EtOH 용출 획분) 을 시료로 했다.The dry pulverized product of Chinese quince was extracted with 50% EtOH, and then fractionated using Diion HP-20, and five fractions (CSD1-5) were obtained. Among these fractions, CSD3 (40% EtOH eluted fraction) having the highest activity was used as a sample.
즉, 모과 과실 건조물 300 g 과 50 % 에탄올 3000 ㎖ 를 첨가한 플라스크에 환류 냉각기를 장착하고, 1 시간 환류하면서 추출한다. 얻어진 추출액을 여과 분리하여 용매를 제거한 후, 동결 건조시킴으로써 추출물을 69 g 얻었다.That is, the reflux condenser was attached to the flask to which 300 g of quince fruit dried products and 3000 ml of 50% ethanol were attached, and it extracts, refluxing for 1 hour. The obtained extract was separated by filtration to remove the solvent, and then freeze-dried to obtain 69 g of the extract.
상기 모과 50 % 에탄올 추출물을 Diaion HP20 (미츠비시 화성 제조) 칼럼에 제공했다. 물, 20 % 에탄올, 40 % 에탄올, 60 % 에탄올의 순서로 용출시켰다. 이 에탄올 농도 40% 수용액으로 용출한 성분 (CSD3) 을 채취했다. 본 분획물의 수확량은 건조 중량으로서 약 8.6 g 이었다. 본품의 바닐린 염산법에 의한 페놀 함량은 54 % [(-)-에피카테킨을 표준으로서]이며, 페놀성의 물질을 주로 함유하고 있는 것이 확인되었다.The
실시예 2Example 2
CSD3 에 의한 바이러스의 흡착 억제 효과, vRNA 합성 억제 효과, mRNA 합성 억제 효과, cRNA 합성 억제 효과는 바이러스 RNA 를 추출하여 RT-PCR 법으로 해석했다. CSD3 을 50 ㎎/㎖ 가 되도록 50 % 에탄올로 용해한 것을 시료 원액으로 했다. 시료 원액을 Tris-Glucose-Saline (TGS) 으로 적절히 희석하고 (102 내지 106 배 희석까지), 이들의 시료 희석액 50 ㎕ 와 바이러스액 (4×104 내지 4×106 PFU (plaque forming unit)/㎖) 50 ㎕ 를 혼합하여 실온에서 10 분간 반응시켰다. 이 0.1 ㎖ 를 TGS 가 0.4 ㎖ 첨가되어 있는 Madin-Darby canine kidney (MDCK) 세포의 단층 배양 (6 구멍 플레이트) 에 접종하고, 바이러스를 실온에서 30분간 흡착시키고, 반응 후 상청액을 제거하여, 0.5 ㎖ 의 배양액을 첨가하고, 37 ℃ 에서 0, 1, 2, 3, 4, 6, 8, 12 시간 배양 후, 감염 세포 중의 바이러스 게놈 RNA 를 티오시안산 구아니딘 용해 25% 에탄올 침전법에 의해 회수했다. 이하에서 각 시험법에서의 RNA 로부터의 cDNA 합성법 및 PCR 증폭법에 대해 상세를 나타낸다.Virus adsorption inhibitory effect, vRNA synthesis inhibitory effect, mRNA synthesis inhibitory effect, and cRNA synthesis inhibitory effect by CSD3 were extracted and analyzed by RT-PCR method. What dissolved CSD3 in 50% ethanol so that it might become 50 mg / mL was used as the sample stock solution. Dilute the sample stock with Tris-Glucose-Saline (TGS) (up to 10 2 to 10 6- fold dilution), 50 μl of these sample dilutions and virus solution (4 × 10 4 to 4 × 10 6 PFU (plaque forming unit) 50 µl of the mixture was reacted at room temperature for 10 minutes. 0.1 ml of this was inoculated into a monolayer culture (6-hole plate) of Madin-Darby canine kidney (MDCK) cells to which 0.4 ml of TGS was added. The virus was adsorbed at room temperature for 30 minutes, and the supernatant was removed after the reaction. Culture medium was added, and after culturing at 37 ° C for 0, 1, 2, 3, 4, 6, 8 and 12 hours, the viral genomic RNA in the infected cells was recovered by
(인플루엔자 바이러스의 흡착 억제 시험 및 vRNA 합성 억제 시험)(Adsorption inhibition test and vRNA synthesis inhibition test of influenza virus)
흡착 억제 시험 및 vRNA 합성 억제 시험에서는, 회수한 0.5?5 ㎍ 의 RNA 로부터, 첨부된 설명서에 따라, Super Script III (인비트로젠사) 역전사 효소 및 T7 cRNA (1-12) 프라이머를 사용하여 역전사 반응을 실시하고, vRNA 의 cDNA 를 합성했다. 합성한 cDNA 를 주형으로 하여 바이러스 (Udorn) NP 유전자 특이적인 1 세트의 올리고 뉴클레오티드 프라이머에 의해 PCR 의 증폭을 실시했다. PCR은 SYBR Premix taq polymeraseII (인비트로젠사) 를 사용하여 45 사이클 (5 초, 95 ℃, 34 초, 64 ℃) 실시했다.In the adsorption inhibition test and the vRNA synthesis inhibition test, reverse transcription was performed from the recovered 0.5-5 μg RNA using Super Script III (Invitrogen) reverse transcriptase and T7 cRNA (1-12) primers according to the attached instructions. The reaction was carried out to synthesize cDNA of vRNA. PCR was amplified by using a set of oligonucleotide primers specific for the virus (Udorn) NP gene using the synthesized cDNA as a template. PCR was performed for 45 cycles (5 seconds, 95 degreeC, 34 second, 64 degreeC) using SYBR Premix taq polymeraseII (Invitrogen).
얻어진 각 구멍당 vRNA 의 카피수를 도 2 에 나타낸다. CSD3 미처리 바이러스의 0 시간시의 흡착 카피수는 6.7×108/구멍인 것에 대해서, 1 ㎍/㎖ 의 CSD3 처리에 의해 2.2×108/구멍이며 약 1/3로 흡착은 억제되었다. 또, CSD3 미처리 바이러스의 vRNA 합성량은 2.2×1010/구멍 (배양 12 시간 후) 인 것에 대해서, 1 ㎍/㎖ 의 CSD3 처리에서는 3.2×108/구멍이며, vRNA 합성량은 약 1/70 로 감소했다.The copy number of the vRNA per each obtained hole is shown in FIG. The adsorption copy number at
(mRNA 합성 억제 시험)(mRNA synthesis inhibition test)
CSD3 에 의한 바이러스의 1 차/2 차 전사 억제 시험에서는, 역전사 효소 및 T7T (18) VN 프라이머를 사용하여 역전사 반응을 실시하고, mRNA 의 cDNA 를 합성했다. 합성한 cDNA 를 주형으로 하여 NP 유전자 특이적인 1 세트의 올리고 뉴클레오티드 프라이머에 의해 PCR 의 증폭을 실시했다. PCR 은 SYBR Premix taq polymeraseII (인비트로젠사) 를 사용하여 45 사이클 (5 초, 95 ℃, 34 초, 64 ℃) 실시했다.In the primary / secondary transcriptional inhibition test of virus by CSD3, reverse transcriptase reaction was carried out using reverse transcriptase and T7T (18) VN primers to synthesize cDNA of mRNA. PCR was amplified by using a set of oligonucleotide primers specific for NP gene using the synthesized cDNA as a template. PCR was performed for 45 cycles (5 second, 95 degreeC, 34 second, 64 degreeC) using SYBR Premix taq polymeraseII (Invitrogen).
얻어진 각 구멍당 mRNA 의 카피수를 도 2 에 나타낸다. CSD3 미처리 바이러스의 mRNA 의 카피수는 2.6×1010/구멍 (배양 12 시간 후) 인 것에 대해서, 1 ㎍/㎖ 의 CSD3 처리에서는 4.3×107/구멍이며, mRNA 합성량은 약 1/600 로 감소했다.The copy number of mRNA per each obtained hole is shown in FIG. The copy number of mRNA of CSD3 untreated virus was 2.6 × 10 10 / holes (12 hours after incubation), whereas in 1 μg / ml CSD3 treatment, 4.3 × 10 7 / holes and mRNA synthesis amount was about 1/600. Decreased.
(cRNA 합성 억제 시험)(cRNA synthesis inhibition test)
CSD3 에 의한 바이러스의 복제 단계 억제 시험에서는, 역전사 효소 및 T7 vRNA (1-13) 프라이머를 사용하여 역전사 반응을 실시하고, cRNA 의 cDNA 를 합성했다. 합성한 cDNA 를 주형으로 하여 NP 유전자 특이적인 1 세트의 올리고 뉴클레오티드 프라이머에 의해 PCR 의 증폭을 실시했다. PCR 은 SYBR Premix taq polymeraseII (인비트로젠사) 를 사용하여 45 사이클 (5 초, 95 ℃, 34 초, 64 ℃) 실시했다. 얻어진 각 구멍당 cRNA 의 카피수를 도 2 에 나타낸다. CSD3 미처리 바이러스의 cRNA 의 카피수는 9.7×106/구멍 (배양 8 시간 후) 인 것에 대해서, 1 ㎍/㎖ 의 CSD3 처리에서는 2.5×104/구멍이며, cRNA 합성량은 약 1/400 로 감소했다.In the replication step inhibition test of the virus by CSD3, reverse transcription was performed using a reverse transcriptase and a T7 vRNA (1-13) primer to synthesize cDNA of cRNA. PCR was amplified by using a set of oligonucleotide primers specific for NP gene using the synthesized cDNA as a template. PCR was performed for 45 cycles (5 second, 95 degreeC, 34 second, 64 degreeC) using SYBR Premix taq polymeraseII (Invitrogen). The copy number of the cRNA per each obtained hole is shown in FIG. The copy number of cRNA of the CSD3 untreated virus was 9.7 × 10 6 / holes (after 8 hours of culture), whereas in 1 μg / ml CSD3 treatment, it was 2.5 × 10 4 / holes, and the cRNA synthesis amount was about 1/400. Decreased.
실시예 3Example 3
(용혈 억제 시험)(Hemolysis inhibition test)
CSD3 를 5 % 에탄올에 용해 (5 ㎎/㎖) 한 것을 시료 원액으로 했다. 인플루엔자 바이러스 (10 HA 내지 320 HA) 와 CSD3 (시료 원액을 TGS 로 102 내지 106 배 희석) 을 10 분간 실온하에서 인큐베이트했다. 반응 후, CSD3 으로 처리한 인플루엔자 바이러스와 10% 닭 적혈구 100 ㎕ 를 혼합하여, 30 분간 실온에서 유지했다. 적혈구를 원심 분리하여 모으고, 침전을 pH 5.3 의 완충액 (136 mM NaCl, 2.68 mM KCl, 10 mM CH3COONa) 에 현탁시켰다. 현탁액을 37 ℃ 에서 30 분간 인큐베이트 후, 원심 분리했다. 상청액의 409 nm 의 흡광도를 측정하고, 모과 미처리 바이러스의 흡광도를 1 로 하여 모과 첨가에 의한 용혈 활성을 평가했다.A sample stock solution was obtained by dissolving CSD3 in 5% ethanol (5 mg / ml). Influenza virus (10 HA to 320 HA) and CSD3 (10 2 to 10 6 fold dilution of sample stock with TGS) were incubated at room temperature for 10 minutes. After the reaction, influenza virus treated with CSD3 and 100 µl of 10% chicken erythrocytes were mixed and maintained at room temperature for 30 minutes. Erythrocytes were collected by centrifugation and the precipitate was suspended in a buffer of pH 5.3 (136 mM NaCl, 2.68 mM KCl, 10 mM CH 3 COONa). The suspension was incubated at 37 ° C. for 30 minutes and then centrifuged. The absorbance at 409 nm of the supernatant was measured, and the hemolytic activity by the addition of the Chinese quince was evaluated with the absorbance of the Chinese quince untreated virus as 1.
얻어진 결과를 도 3 에 나타낸다.The obtained result is shown in FIG.
실시예 4Example 4
바이러스 (16000 HA) 에 CSD3 을 첨가하여, 실온하, 1 시간 유지했다. 바이러스 입자의 전자 현미경 관찰은 2% 아세트산 우라늄에 의한 네거티브 염색법에 의해 실시했다.CSD3 was added to the virus (16000 HA) and maintained at room temperature for 1 hour. Electron microscopy of the virus particles was carried out by a negative staining method with 2% uranium acetate.
이들 결과를 도 1 에 나타낸다.These results are shown in FIG.
도 1 은 모과 추출물 (CSD3) 의 바이러스 엔벨로프막에 대한 파괴 활성을 나타낸 전자 현미경 이미지로서, (a) 는 모과 추출물을 첨가한 경우를 나타내고, (b) 는 모과 추출물을 미첨가한 경우를 나타낸다.1 is an electron microscope image showing the disruptive activity of the quince extract (CSD3) against the viral envelope membrane, (a) shows the case where the quince extract is added, and (b) shows the case without addition of the quince extract.
CSD3 로 처리된 바이러스의 전자 현미경 이미지에서는 입자 표면의 HA?NA 스파이크의 외측에 약 2 nm 폭의 CSD3 으로 보이는 부착층이 관찰되고, 또 엔벨로프에 손상 지점이 있어, 입자 내부에 염색제가 침투하여, 내부 구조가 가시화되어 있었다 (도 1 (a)).Electron microscopy images of the virus treated with CSD3 showed an adhesion layer of about 2 nm wide CSD3 on the outside of the HA-NA spike on the surface of the particle, and there was a point of damage to the envelope, which allowed the dye to penetrate into the particle. The internal structure was visualized (FIG. 1 (a)).
(결론)(conclusion)
모과 추출물 (CSD3) 처리 바이러스에서는 1 차 전사보다 전단계에서 바이러스 증식이 정지하는 것으로 나타났다. 바이러스의 흡착?막융합 단계에서의 불활성화도 나타났지만, 그 이상으로 RNA 의 합성이 억제되어 있고, 막융합으로부터 1 차 전사까지의 과정에 관한 어떠한 결함이 있는 것이 시사되었다. 전자 현미경에서 나타난 엔벨로프의 손상이 이 결함의 원인으로 되어 있을 가능성이 있다.In the Chinese quince extract (CSD3) treated virus, virus proliferation was stopped at an earlier stage than primary transcription. Inactivation at the adsorption-membrane fusion step of the virus also appeared, but further, the synthesis of RNA was suppressed, suggesting that there was any defect in the process from membrane fusion to primary transcription. The damage to the envelope seen in the electron microscope may be the cause of this defect.
실시예 1 에서 조제한 모과 추출물을 사용하여, 구강 세척약, 흡입제, 트로치제, 스프레이액, 추잉껌, 캔디, 정과, 음료, 분말제, 정제, 함수제, 구미젤리, 초콜릿, 비스킷, 아이스, 샤벳, 스프, 잼, 웨트 티슈, 마스크를 조제했다. 이하에서 실시예로서 그 처방을 나타냈다.Using the Chinese quince extract prepared in Example 1, mouthwashes, inhalants, troches, sprays, chewing gums, candies, fruits, beverages, powders, tablets, water solubles, gummi jelly, chocolate, biscuits, ice, sherbet, Soup, jam, wet tissue and mask were prepared. The prescription is shown as an Example below.
실시예 5Example 5
구강 세척약의 처방Prescription of mouthwash
에탄올 2.0 중량% Ethanol 2.0 wt%
향료 1.0 중량%1.0% by weight fragrance
사카린 0.05 중량%Saccharin 0.05 wt%
염산 클로르헥시딘 0.01 중량%0.01% by weight of chlorhexidine hydrochloride
CSD3 0.5 중량%CSD3 0.5 wt%
물 나머지 Water rest
100.0 중량%100.0 wt%
실시예 6Example 6
흡입제의 처방Prescription of inhalants
에탄올 5.0 중량%Ethanol 5.0 wt%
CSD3 1.0 중량%CSD3 1.0 wt%
물 나머지 Water rest
100.0 중량%100.0 wt%
실시예 7Example 7
트로치제의 처방Prescription of troche
포도당 72.3 중량%Glucose 72.3 wt%
락토오스 19.0 중량%Lactose 19.0 wt%
아라비아고무 6.0 중량%Arabian rubber 6.0 wt%
향료 1.0 중량%1.0% by weight fragrance
모노플루오로 인산 나트륨 0.7 중량%0.7% by weight sodium monofluorophosphate
CSD3 1.0 중량%CSD3 1.0 wt%
100.0 중량%100.0 wt%
실시예 8Example 8
스프레이액의 처방Prescription of Spray
에탄올 25.0 중량%Ethanol 25.0 wt%
시트르산 1.5 중량%Citric acid 1.5 wt%
시트르산 3 나트륨 1.0 중량%Sodium citrate 1.0% by weight
CSD3 0.5 중량%CSD3 0.5 wt%
물 나머지Water rest
100.0 중량%100.0 wt%
실시예 9Example 9
추잉껌의 처방Chewing Gum Prescription
껌 베이스 20.0 중량%Gum base 20.0 wt%
설탕 54.7 중량%54.7 wt% sugar
글루코오스 15.0 중량%15.0% by weight glucose
물엿 9.3 중량%Starch syrup 9.3 wt%
향료 0.5 중량%0.5% by weight fragrance
CSD3 0.2 중량%CSD3 0.2 wt%
100.0 중량%100.0 wt%
실시예 10Example 10
캔디의 처방Candy prescription
설탕 50.0 중량%50.0 wt% sugar
물엿 34.0 중량%Starch syrup 34.0 wt%
시트르산 1.0 중량%Citric Acid 1.0 wt%
향료 0.2 중량%Fragrance 0.2 wt%
CSD3 0.4 중량%CSD3 0.4 wt%
물 나머지 Water rest
100.0 중량%100.0 wt%
실시예 11Example 11
정과의 처방Prescription
설탕 76.1 중량%Sugar 76.1 wt%
글루코오스 19.0 중량%Glucose 19.0 wt%
자당 지방산 에스테르 0.2 중량%0.2% by weight sucrose fatty acid ester
향료 0.2 중량%Fragrance 0.2 wt%
CSD3 0.5 중량%CSD3 0.5 wt%
물 나머지Water rest
100.0 중량%100.0 wt%
실시예 12Example 12
음료의 처방Prescription of drink
오렌지 과즙 30.00 중량%Orange Juice 30.00% by weight
이성화당 15.24 중량%15.24% by weight of isomerized
시트르산 0.10 중량%Citric Acid 0.10 wt%
비타민 C 0.04 중량%Vitamin C 0.04 wt%
향료 0.10 중량%Perfume 0.10% by weight
CSD3 0.10 중량%CSD3 0.10 wt%
물 나머지Water rest
100.00 중량%100.00 wt%
실시예 13Example 13
분말제의 처방Powder prescription
옥수수 전분 55.0 중량%Corn starch 55.0 wt%
카르복시 셀룰로오스 40.0 중량%Carboxy cellulose 40.0 wt%
CSD3 5.0 중량%CSD3 5.0 wt%
100.0 중량%100.0 wt%
실시예 14Example 14
정제의 처방Prescription of tablets
락토오스 70.0 중량%Lactose 70.0 wt%
결정성 셀룰로오스 15.0 중량%15.0 wt% crystalline cellulose
스테아르산 마그네슘 5.0 중량%Magnesium Stearate 5.0% by weight
CSD3 10.0 중량%CSD3 10.0 wt%
100.0 중량%100.0 wt%
실시예 15Example 15
함수제의 처방Prescription of Hydrant
에탄올 2.00 중량% Ethanol 2.00 wt%
향료 1.00 중량%1.00% by weight
사카린 0.05 중량%Saccharin 0.05 wt%
염산 클로르헥시딘 0.01 중량%0.01% by weight of chlorhexidine hydrochloride
CSD3 0.50 중량%CSD3 0.50 wt%
물 나머지Water rest
100.00 중량% 100.00 wt%
실시예 16Example 16
구미젤리의 처방Gumi jelly prescription
젤라틴 60.00 중량%Gelatin 60.00 wt%
물엿 23.00 중량%Starch syrup 23.00 wt%
설탕 8.50 중량%8.50 wt% sugar
식물 유지 4.50 중량%4.50 wt% plant fat
만니톨 2.95 중량%Mannitol 2.95 wt%
레몬 과즙 1.00 중량%Lemon Juice 1.00% by weight
CSD3 0.05 중량%CSD3 0.05 wt%
100.00 중량%100.00 wt%
본 출원은 2009 년 9 월 24 일에 출원된 일본국 특허 출원 제2009-218643호 및 2009 년 12 월 8 일에 출원된 일본국 특허 출원 제2009-278462호로부터의 우선권을 주장하는 것으로서, 그 내용을 인용하여 본 출원의 일부로 하는 것이다.This application claims the priority from Japanese Patent Application No. 2009-218643 for which it applied on September 24, 2009, and Japanese Patent Application No. 2009-278462 for which it applied on December 8, 2009, The content is Is incorporated herein by reference.
Claims (9)
Applications Claiming Priority (5)
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JPJP-P-2009-218643 | 2009-09-24 | ||
JP2009218643 | 2009-09-24 | ||
JP2009278462 | 2009-12-08 | ||
JPJP-P-2009-278462 | 2009-12-08 | ||
PCT/JP2010/005762 WO2011036883A1 (en) | 2009-09-24 | 2010-09-24 | Anti-influenza virus agent |
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CN100544750C (en) * | 2006-10-13 | 2009-09-30 | 解会元 | Medicated wine composition |
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