KR102573565B1 - Flavonoids compound and antiviral agent containing the same as an active ingredient - Google Patents
Flavonoids compound and antiviral agent containing the same as an active ingredient Download PDFInfo
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- KR102573565B1 KR102573565B1 KR1020230027200A KR20230027200A KR102573565B1 KR 102573565 B1 KR102573565 B1 KR 102573565B1 KR 1020230027200 A KR1020230027200 A KR 1020230027200A KR 20230027200 A KR20230027200 A KR 20230027200A KR 102573565 B1 KR102573565 B1 KR 102573565B1
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- -1 Flavonoids compound Chemical class 0.000 title abstract description 12
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- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
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Abstract
Description
본 발명은 항바이러스제에 관한 것으로, 구체적으로 플라보노이드 계열 화합물을 유효성분으로 함유하는 항바이러스제에 관한 것이다.The present invention relates to an antiviral agent, and specifically, to an antiviral agent containing a flavonoid-based compound as an active ingredient.
중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS)은 진드기에 의해 매개되는 감염병 질환으로서, 주로 한국에도 널리 퍼져 있는 것으로 알려진 작은소참진드기(Haemaphysalis longicornis)나, 또는 참진드기류(Amblyomma testudinarium)에 의해 매개되는 중증열성혈소판감소증후군 바이러스(Dabie bandavirus, Severe Fever with Thrombocytopenia Syndrome Virus, SFTSV)의 감염에 의해 발생된다.Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease mediated by ticks, mainly caused by Haemaphysalis longicornis or Amblyomma testudinarium, known to be widespread in Korea. It is caused by infection with the Dabie bandavirus, Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), which is mediated by
SFTS는 2009년에 중국에서 최초로 보고되었고, 2012년에는 일본 및 한국에서도 질환 및 바이러스가 보고된 바 있다. SFTS의 주요 증상은 발열, 복통, 구역, 구토 혈소판 감소증 또는 백혈구 감소증 등이며, 중증인 경우 다발성 장기부전이 발생하여 사망에 이를 수도 있다. SFTS는 매년 중국, 일본 또는 한국에서 꾸준하게 발생하고 있으며, 이에 의한 치사율이 6 ~ 30%에 달하는 매우 높은 질환으로서, 진드기가 활동하는 시기인 봄에서 여름 사이의 기간에 주로 발생한다.SFTS was first reported in China in 2009, and the disease and virus were also reported in Japan and Korea in 2012. The main symptoms of SFTS are fever, abdominal pain, nausea, vomiting, thrombocytopenia or leukopenia, etc. In severe cases, multiple organ failure may occur and death may occur. SFTS occurs steadily every year in China, Japan, or Korea, and it is a very high disease with a mortality rate of 6 to 30%, and mainly occurs between spring and summer when mites are active.
SFTSV의 야생 숙주는 등줄쥐가 유력하고, 중국의 주요 발병지에서는 염소, 소, 개 또는 닭 등의 가축에서 혈청 항체가 높은 비율로 발견되어, 가축이 숙주 역할을 할 수도 있는 것으로 추정된다. 감염자의 체액을 매개로 하여 사람간 감염이 일어난 것이 보고된 바 있으나, 현재까지 SFTS를 효과적으로 치료할 수 있는 것으로 증명된 치료제 또는 예방법은 없는 실정이다.Rats are the most likely wild host of SFTSV, and serum antibodies are found at high rates in livestock such as goats, cows, dogs, or chickens in major outbreaks in China, suggesting that livestock may serve as hosts. Although it has been reported that human-to-human infection occurred through bodily fluids of an infected person, there is no therapeutic agent or preventive method that has been proven to effectively treat SFTS to date.
이에 다수 국내외 연구자들이 기존 FDA-승인 화합물, 핵산유도체(nucleoside ananlog), 단일항체, SFTS 회복환자로부터 얻은 항혈청(antisera) 등을 이용하여 SFTSV에 대한 항바이러스 효능을 연구 중에 있다. Favipiravir (T-705)는 구아노신 유도체(guanosine analog)로 RNA 바이러스의 RNA-의존 RNA 중합효소를 타겟하여 바이러스 복제를 저해한다고 알려져 있다. 현재 SFTSV 감수성 동물모델인 인터페론 수용체 결핍 마우스(C57BL/6 IFNAR-/-) 에서 항바이러스 효능을 확인하였고, 임상3상을 진행 중이다. 또한 단일 항체 Ab10은 당단백질 Gn을 타겟하며 SFTSV 항바이러스 효능을 인터페론 수용체 결핍 마우스(A129)에서 확인하였다. 하지만, In vivo 효능을 검증한 동물모델이 면역억제마우스로 온전한 인체감염 반응을 반영하지 못하고, favipiravir는 국내에서 허가되지 않아 SFTS 치료제 사용에 어려움이 있다. Accordingly, many domestic and foreign researchers are studying the antiviral efficacy against SFTSV using existing FDA-approved compounds, nucleoside ananlogs, monoclonal antibodies, and antisera obtained from recovered SFTS patients. Favipiravir (T-705) is a guanosine analog that is known to inhibit viral replication by targeting the RNA-dependent RNA polymerase of RNA viruses. Currently, the antiviral efficacy has been confirmed in an interferon receptor deficient mouse (C57BL/6 IFNAR-/-), an animal model susceptible to SFTSV, and phase 3 clinical trials are underway. In addition, the monoclonal antibody Ab10 targets the glycoprotein Gn, and the antiviral efficacy of SFTSV was confirmed in interferon receptor deficient mice (A129). However, it is difficult to use SFTS treatment because the animal model whose in vivo efficacy has been verified does not reflect the complete human infection response with immunosuppressed mice, and favipiravir is not approved in Korea.
SFTS 치료 또는 예방에 관한 선행기술로는 한국공개특허 제10-2020-0001671호 "중증 열성 혈소판 감소 증후군(SFTS) 바이러스 감염 질환 예방 또는 치료용 백신 조성물"에 면역반응을 효과적으로 유도하는 SFTS 바이러스 항원의 재조합 DNA 및 이를 포함하는 SFTS 바이러스 백신이 개시되어 있고, 한국공개특허 제10-2018-0122456호 "중증열성혈소판감소증후군 바이러스의 외막 당단백질에 결합하는 항체 및 이의 용도"에 SFTS의 병원체인 SFTSV를 검출 또는 진단하고 치료하기 위해 사용되는 SFTSV의 외막 당단백질에 특이적으로 결합하는 항체가 개시되어 있다.Prior art related to the treatment or prevention of SFTS includes Korean Patent Publication No. 10-2020-0001671, "Vaccine composition for preventing or treating severe fever with thrombocytopenia syndrome (SFTS) viral infection" of the SFTS virus antigen that effectively induces an immune response. Recombinant DNA and a SFTS virus vaccine containing the same are disclosed, and Korean Patent Publication No. 10-2018-0122456 "Antibodies that bind to outer membrane glycoproteins of severe fever with thrombocytopenia syndrome virus and uses thereof" discloses SFTSV, a pathogen of SFTS. Antibodies that specifically bind to the outer membrane glycoprotein of SFTSV for use in detection or diagnosis and treatment are disclosed.
또한, 항바이러스 효과를 가지는 화합물에 관한 선행기술로는 Tsutomu NAKANISHI et al. (Natural Medicines 52 (6) ,521-526, 1998) 에 ergosterol peroxide가 항 HIV-1 활성을 보임이 개시되어 있고, Beixian Zhou et al. (European Journal of Pharmacology 860, 2019) 에 ergosterol peroxide가 인플루엔자 A 바이러스에 의해 유도된 염증 반응을 억제하고, RIG-I 신호전달을 억제해 인플루엔자 바이러스를 치료제로 사용될 수 있음이 개시되어 있으며, Chun-Ting Su et al. (Antiviral Research 79, 62-70, 2008)에 digitoxin 화합물이 항 Herpes simplex virus type 1 (HSV-1) 활성이 있음이 개시되어 있다.In addition, as prior art related to compounds having antiviral effects, Tsutomu NAKANISHI et al. (Natural Medicines 52 (6), 521-526, 1998) discloses that ergosterol peroxide exhibits anti-HIV-1 activity, and Beixian Zhou et al. (European Journal of Pharmacology 860, 2019) discloses that ergosterol peroxide inhibits the inflammatory response induced by influenza A virus and inhibits RIG-I signal transduction, which can be used as a therapeutic agent for influenza virus. Chun-Ting Su et al. (Antiviral Research 79, 62-70, 2008) discloses that digitoxin compounds have anti-Herpes simplex virus type 1 (HSV-1) activity.
항바이러스제(antiviral agent)는 바이러스 감염 치료에 특화된 의약품을 말하며, 대부분의 바이러스제는 특정한 바이러스 감염만 치료하는 것으로 알려져 있다. 항생제(antibiotics)와는 달리. 항바이러스제는 대상 병원체(pathogen), 즉 바이러스를 파괴하지는 않고, 바이러스의 성장을 억제하는 역할을 한다. 바이러스 단백질을 직접적으로 타겟하는 치료제 개발이 중요하나, RNA 바이러스의 특성상 돌연변이 발생에 의해 개발된 치료제 효능이 달라질 수 있다. An antiviral agent refers to a drug specialized for treating a viral infection, and most viral agents are known to treat only a specific viral infection. Unlike antibiotics. Antiviral agents do not destroy target pathogens, that is, viruses, but inhibit the growth of viruses. Although it is important to develop a therapeutic agent that directly targets a viral protein, the efficacy of a developed therapeutic agent may vary due to mutations due to the characteristics of RNA viruses.
이처럼 다양하고 새롭게 발생되는 돌연변이 바이러스를 제어하기 위해 숙주-병원체의 상호작용을 이해하고 이를 기반으로 한 치료법의 개발이 필요하다. 즉, 바이러스 성장 조절에 중요한 숙주세포인자를 발굴하고 숙주세포인자에 의한 바이러스 제어법을 연구를 통해 바이러스 증식을 원천적으로 차단할 후 있는 치료제를 개발하는 것이 필요한 실정이다.In order to control these diverse and newly generated mutant viruses, it is necessary to understand the host-pathogen interaction and develop treatments based on it. That is, it is necessary to discover host cell factors important for regulating viral growth and to develop a therapeutic agent that can fundamentally block viral growth through research on virus control methods using host cell factors.
본 발명자들은 SFTS 바이러스 복제 및 증식에 관여하는 숙주세포인자를 규명하고 치료제 개발을 위한 연구자원 발굴하고자 화합물 라이브러리 스크리닝을 통해 새로운 치료후보물질을 찾아냄으로써 본 발명을 완성하였다.The present inventors completed the present invention by finding new therapeutic candidates through compound library screening in order to identify host cell factors involved in SFTS virus replication and proliferation and to discover research resources for the development of therapeutic agents.
본 발명의 목적은 항바이러스 활성, 특히 항SFTS바이러스 활성을 가지고 있는 플라보노이드 계열 화합물, 이의 용매화물, 이의 수화물 또는 이의 약학적으로 허용 가능한 염을 제공하는 것이다.An object of the present invention is to provide a flavonoid-based compound, a solvate thereof, a hydrate thereof, or a pharmaceutically acceptable salt thereof having antiviral activity, particularly antiSFTS virus activity.
상기 목적을 달성하기 위하여,In order to achieve the above purpose,
본 발명은 하기 화학식 1 및 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염 중에서 선택된 1종 이상을 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 치료용 약학적 조성물을 제공한다:The present invention relates to the prevention of diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, including at least one compound selected from compounds represented by Formulas 1 and 2 below, or pharmaceutically acceptable salts thereof. or a pharmaceutical composition for treatment:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
. .
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention is a health function for preventing or improving diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound or a pharmaceutically acceptable salt of the compound as an active ingredient A food composition is provided.
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 개선용 사료 첨가제를 제공한다.In addition, the present invention is a feed additive for preventing or improving diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound or a pharmaceutically acceptable salt of the compound as an active ingredient provides
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 개선용 음용수 첨가제를 제공한다.In addition, the present invention is a drinking water additive for preventing or improving disease caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound or a pharmaceutically acceptable salt of the compound as an active ingredient provides
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방용 소독제를 제공한다.In addition, the present invention provides a disinfectant for preventing diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound or a pharmaceutically acceptable salt of the compound as an active ingredient .
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염의 유효량을 동물에게 투여하는 것을 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 치료 방법을 제공한다.In addition, the present invention relates to the prevention or treatment of diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising administering an effective amount of the compound or a pharmaceutically acceptable salt of the compound to an animal. provides a way
본 발명의 화합물은 세포 독성이 없으면서도 항바이러스 활성, 특히 항SFTS바이러스 활성을 나타내는 바, 항바이러스제로 유용하게 사용할 수 있다.Since the compound of the present invention exhibits antiviral activity, particularly antiSFTS virus activity, without cytotoxicity, it can be usefully used as an antiviral agent.
도 1은 본 발명 화합물 잔토휴몰, 히노키플라본 및 양성대조군 T-705(Favipiravir)의 Vero E6 세포에서 항바이러스 효능을 나타낸 그림이다.
도 2는 본 발명 화합물 잔토휴몰, 히노키플라본 및 양성대조군 T-705(Favipiravir)의 Huh7 세포에서 항바이러스 효능을 나타낸 그림이다.1 is a picture showing the antiviral efficacy of the compounds of the present invention, xanthohumol, hinokiflavone, and positive control T-705 (Favipiravir) in Vero E6 cells.
Figure 2 is a picture showing the antiviral efficacy of the compounds of the present invention, xanthohumol, hinokiflavone, and positive control T-705 (Favipiravir) in Huh7 cells.
이하, 본 발명을 상세히 설명한다.Hereinafter, the present invention will be described in detail.
본 발명은 하기 화학식 1 및 2로 표시되는 화합물, 또는 이의 약학적으로 허용가능한 염 중에서 선택된 1종 이상을 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 치료용 약학적 조성물을 제공한다:The present invention relates to the prevention of diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, including at least one compound selected from compounds represented by Formulas 1 and 2 below, or pharmaceutically acceptable salts thereof. or a pharmaceutical composition for treatment:
[화학식 1][Formula 1]
[화학식 2][Formula 2]
. .
본 발명의 용어 "중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS)"는 SFTS 바이러스에 감염되어 유발되는 질병으로, 초기에 40도가 넘는 원인 불명의 발열, 피로, 식욕 저하, 구토, 설사, 복통 등의 소화기계 증상이 나타나며, 두통, 근육통, 림프절이 붓는 증상이 동반되기도 하는 질병이다. SFTS 바이러스를 매개하는 후기문진드기목 참진드기과 (Ixodidae), 작은소피참진드기 (Haemaphysalis longicornis)에 의해 전파되며, 흡혈과정에서 진드기가 보균하고 있는 바이러스가 체내로 유입되고, 증식하여 임상증상을 유발하는 질병을 말한다.The term "severe fever with thrombocytopenia syndrome (SFTS)" of the present invention is a disease caused by infection with the SFTS virus, which initially includes fever of unknown cause above 40 degrees, fatigue, loss of appetite, vomiting, diarrhea, Gastrointestinal symptoms such as abdominal pain appear, and it is a disease that is accompanied by symptoms such as headache, muscle pain, and swollen lymph nodes. It is spread by Ixodidae and Haemaphysalis longicornis, which mediate the SFTS virus. In the process of sucking blood, the virus carried by the tick enters the body, proliferates, and causes clinical symptoms. say the disease
본 발명의 용어 "SFTS 바이러스(Dabie bandavirus)"는 SFTS를 유발하는 병원체로, 지름이 80~100 nm인 공 모양으로 Phenuiviridae과, Bunyavirales목, Bandavirus속에 속한다. 유전체는 세 개의 분절(L, M, S)을 포함한 단일 가닥 RNA로서, L(large) 분절은 6,368 bp의 크기로 RNA 의존적 RNA 중합효소(RNA-dependent RNA polymerase, RdRp)를 암호화하며, M (medium) 분절은 3,378 bp로 2개의 당단백질(Gn/Gc) 그리고 S(small) 분절은 1,746 bp로 뉴클레오캡시드와 핵산단백질을 암호화하는 구조로 구성되어 있다.The term "SFTS virus (Dabie bandavirus)" of the present invention is a pathogen that causes SFTS, and has a ball shape with a diameter of 80 to 100 nm and belongs to the Phenuiviridae family, Bunyavirales order, Bandavi rus genus. The genome is a single-stranded RNA containing three segments (L, M, S). The L (large) segment is 6,368 bp in size and encodes RNA-dependent RNA polymerase (RdRp), and M ( The medium) segment is 3,378 bp and consists of two glycoproteins (Gn/Gc) and the S (small) segment is 1,746 bp and consists of a structure encoding a nucleocapsid and a nucleic acid protein.
상기 화학식 1로 표시되는 화합물은 잔토휴몰(Xanthohumol)이다. 상기 화합물의 IUPAC name은 (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-enyl)phenyl]-3-(4-hydroxyphenyl)prop-2-en-1-one이다. The compound represented by Formula 1 is xanthohumol. The IUPAC name of the compound is (E)-1-[2,4-dihydroxy-6-methoxy-3-(3-methylbut-2-enyl)phenyl]-3-(4-hydroxyphenyl)prop-2-en- It is 1-one.
본 발명의 화합물 잔토휴몰은 홉 식물(Humulus lupulus L)의 암꽃에서 추출한 프레닐화 플라보노이드로, 잠재적인 화학 예방 및 항신생물 활성이 있다고 알려져 있다. 또한 활성 산소종(ROS)을 제거하여 산화 스트레스로 인한 DNA 손상을 방지한다고 알려져 있다.The compound xanthohumol of the present invention is a prenylated flavonoid extracted from female flowers of the hop plant (Humulus lupulus L), and is known to have potential chemopreventive and anti-neoplastic activities. It is also known to prevent DNA damage caused by oxidative stress by removing reactive oxygen species (ROS).
상기 화학식 2로 표시되는 화합물은 히노키플라본(Hinokiflavone)이다. 상기 화합물의 IUPAC name은 6-[4-(5,7-dihydroxy-4-oxochromen-2-yl)phenoxy]-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one이다.The compound represented by Formula 2 is hinokiflavone. The IUPAC name of this compound is 6-[4-(5,7-dihydroxy-4-oxochromen-2-yl)phenoxy]-5,7-dihydroxy-2-(4-hydroxyphenyl)chromen-4-one.
본 발명의 화합물 히노키플라본은 6번 위치에서 4-(5,7-디하이드록시-4-옥소-4H-크로멘-2-일)페녹시 그룹으로 치환된 아피게닌인 바이플라보노이드이다. 디플라보닐 에테르는 Rhus succedanea에서 분리되었으며 상당한 세포 독성 잠재력을 가지고 있는 것으로 알려져 있다. 또한 신경보호제, 항종양제 및 대사산물로서의 역할을 한다고 알려져 있다.The compound hinokiflavone of the present invention is a biflavonoid that is apigenin substituted with a 4-(5,7-dihydroxy-4-oxo-4H-chromen-2-yl)phenoxy group at position 6. Diflavonyl ethers have been isolated from Rhus succedanea and are known to have significant cytotoxic potential. It is also known to act as a neuroprotective, antitumor and metabolite.
본 발명의 화합물은 SFTSV 복제 및 성장을 억제한다.Compounds of the present invention inhibit SFTSV replication and growth.
본 발명의 화합물은 천연물 유래 화합물이다.The compounds of the present invention are compounds derived from natural products.
본 발명에서 천연물 유래 화합물은 동물, 식물, 및 미생물과 같은 천연물에서 분리된 화합물로, 우수한 약리효과를 나타낸다. 또한, 천연 화합물은 제약 산업에서 화합물의 주요 공급원이며, 구조적 복잡성을 가진다는 특징이 있다. 또한, 천연 화합물은 천연 공급원에서 파생된 화학 물질이기 때문에 독성이 낮고 약동학적으로 우수하다.In the present invention, the compound derived from natural products is a compound isolated from natural products such as animals, plants, and microorganisms, and exhibits excellent pharmacological effects. In addition, natural compounds are a major source of compounds in the pharmaceutical industry and are characterized by their structural complexity. In addition, natural compounds have low toxicity and excellent pharmacokinetics because they are chemical substances derived from natural sources.
본 발명의 용어 "약학적으로 허용가능한 염"은, 표적 개체가 생리학적으로 수인 가능한 본 발명의 화합물의 모든 염을 의미하며, 화합물이 투여되는 유기체에 심각한 자극을 유발하지 않고 화합물의 생물학적 활성과 물성들을 손상시키지 않는 화합물의 제형임이 바람직하다. 상기 약학적 염은, 약학적으로 허용되는 음이온을 함유하는 무독성 산부가염을 형성하는 산, 예를 들어, 염산, 황산, 질산, 인산, 브롬화수소산, 요드화수소산 등과 같은 무기산, 타타르산, 포름산, 시트르산, 아세트산, 트리클로로아세트산, 트리플로로아세트산, 글루콘산, 벤조산, 락트산, 푸마르산, 말레인산, 살리신산 등과 같은 유기 카본산, 메탄설폰산, 에탄술폰산, 벤젠설폰산, p-톨루엔설폰산 등과 같은 설폰산 등에 의해 형성된 산부가염이 포함된다. 예를 들어, 약학적으로 허용되는 카르복실산 염에는, 리튬, 나트륨, 칼륨, 칼슘, 마그네슘 등에 의해 형성된 금속염 또는 알칼리 토금속 염, 라이신, 아르지닌, 구아니딘 등의 아미노산 염, 디시클로헥실아민, N-메틸-D-글루카민, 트리스(히드록시메틸) 메틸아민, 디에탄올아민, 콜린 및 트리에틸아민 등과 같은 유기염 등이 포함된다.As used herein, the term "pharmaceutically acceptable salt" refers to all salts of the compound of the present invention that are physiologically acceptable to the target organism, and does not cause serious irritation to the organism to which the compound is administered and exhibits the biological activity of the compound. A formulation of the compound that does not impair physical properties is preferred. The pharmaceutical salt is an acid that forms a non-toxic acid addition salt containing a pharmaceutically acceptable anion, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, tartaric acid, formic acid, Organic carbonic acids such as citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid, etc., methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. Acid addition salts formed with sulfonic acids and the like are included. For example, pharmaceutically acceptable carboxylic acid salts include metal salts or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium, etc., amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N organic salts such as -methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethylamine; and the like.
본 발명은 상기 화학식 1 또는 2로 표시되는 화합물 및 이의 약학적으로 허용 가능한 염뿐만이 아니라, 이로부터 제조될 수 있는 용매화물, 수화물 등을 모두 포함한다.The present invention includes not only the compounds represented by Formula 1 or 2 and pharmaceutically acceptable salts thereof, but also solvates and hydrates prepared therefrom.
본 발명의 용어 "수화물(hydrate)"은 비공유적 분자간력(non-covalent intramolecular force)에 의해 결합된 화학양론적 (stoichiometric) 또는 비화학양론적(non-stoichiometric) 량의 물을 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 본 발명의 상기 화학식 1 또는 2로 표시되는 화합물의 수화물은 비공유적 분자간 힘으로 결합되는 화학양론적 또는 비화학양론적 양의 물을 포함할 수 있다. 상기 수화물은 1 당량 이상, 바람직하게는, 1 당량 내지 5 당량의 물을 함유할 수 있다. 이러한 수화물은 물 또는 물을 함유하는 용매로부터 본 발명의 상기 화학식 1 또는 2로 표시되는 화합물 또는 이들의 약제학적으로 허용 가능한 염을 결정화시켜 제조될 수 있다.As used herein, the term "hydrate" refers to a stoichiometric or non-stoichiometric amount of water bound by non-covalent intramolecular forces. A compound of the invention or a salt thereof. The hydrate of the compound represented by Formula 1 or 2 of the present invention may contain a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The hydrate may contain at least 1 equivalent of water, preferably from 1 to 5 equivalents of water. Such a hydrate may be prepared by crystallizing the compound represented by Formula 1 or 2 or a pharmaceutically acceptable salt thereof of the present invention from water or a solvent containing water.
본 발명의 용어 "용매화물(solvate)"은 비공유적 분자간력에 의해 결합된 화학양론적 또는 비화학양론적 양의 용매를 포함하고 있는 본 발명의 화합물 또는 그것의 염을 의미한다. 그에 관한 바람직한 용매들로는 휘발성, 비독성, 및/또는 인간에게 투여되기에 적합한 용매들이 있다.The term "solvate" as used herein refers to a compound of the present invention or a salt thereof that contains a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents in this regard are those that are volatile, non-toxic, and/or suitable for administration to humans.
본 발명의 화합물은 SFTS 바이러스 증식을 억제함으로써 항바이러스 활성을 나타낸다.The compounds of the present invention exhibit antiviral activity by inhibiting SFTS virus growth.
본 발명의 용어 "유효성분으로 포함하는"은 화합물의 효능 또는 활성을 달성하는데 충분한 양을 포함하는 것을 의미한다.The term "comprising as an active ingredient" of the present invention means containing an amount sufficient to achieve the efficacy or activity of the compound.
본 발명의 약학적 조성물은 약학적으로 허용되는 첨가물을 추가로 포함할 수 있다.The pharmaceutical composition of the present invention may further contain pharmaceutically acceptable additives.
상기 첨가물은 약학적 조성물의 제조에 통상적으로 사용되는 적절한 담체, 부형제 및 희석제를 더 포함할 수 있다.The additives may further include suitable carriers, excipients and diluents commonly used in the preparation of pharmaceutical compositions.
적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed, 1995)에 상세히 기재되어 있다.Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington's Pharmaceutical Sciences (19th ed, 1995).
본 발명의 약학적 조성물은 약제학적으로 허용되는 담체를 포함할 수 있다. 상기 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 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.The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier is one commonly used in formulation, and includes lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate , microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, but are not limited thereto no.
본 발명의 약학적 조성물은 각각 통상의 방법에 따라, 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 또는 멸균 주사용액의 형태로 제형화하여 사용할 수 있다. 상세하게는 제형화할 경우 통상 사용하는 충진제, 중량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. The pharmaceutical composition of the present invention can be formulated in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or sterile injection solutions according to conventional methods. can Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, weighting agents, binders, wetting agents, disintegrants, and surfactants.
경구투여를 위한 고형 제제로는 정제, 환제, 산제, 과립제, 캡슐제 등을 포함하나, 이에 한정되는 것은 아니다. 이러한 고형 제제는 상기 유효성분 외에 적어도 하나 이상의 부형제, 예를 들면, 전분, 칼슘 카보네이트, 수크로오스, 락토오스, 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스테아레이트, 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등을 첨가하여 조제될 수 있다.Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. Such a solid preparation may be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., in addition to the active ingredient. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. It may be prepared by adding various excipients, for example, wetting agents, sweeteners, aromatics, and preservatives, in addition to liquids and liquid paraffin for oral use.
비경구 투여를 위한 제제는 멸균된 수용액, 비수성 용제, 현탁제, 유제, 동결건조 제제 및 과제를 포함한다. 비수성 용제 및 현탁제로는 프로필렌글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 오일, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔, 마크로솔, 트윈 61, 카카오지, 라우린지, 글리세로젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and tablets. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for suppositories, Witepsol, Macrosol, Tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.
본 발명의 약학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like in addition to the above components.
본 발명의 약학적 조성물은 당해 발명이 속하는 기술 분야에서 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 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 갑셀제 형태일 수 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention is prepared in unit dosage form by formulation using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily performed by those skilled in the art. or it may be prepared by incorporating into a multi-dose container. At this time, the dosage form may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or in the form of an extract, powder, granule, tablet or capsule, and may additionally contain a dispersing agent or stabilizer.
본 발명의 약학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다.The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc. can be administered.
본 발명의 약학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여시간, 투여 경로, 배설 속도 및 반응 감응성, 환자의 골 손실 정도와 같은 요인들에 따라 다르며, 당 업자에 의하여 적절하게 선택될 수 있고, 구체적으로 0.001 mg/kg 내지 50 mg/kg이며, 필요에 따라 일일 1회 내지 수회로 나누어 투여할 수 있다.A suitable dosage of the pharmaceutical composition of the present invention is determined by factors such as formulation method, administration method, patient's age, weight, sex, pathological condition, food, administration time, route of administration, excretion rate and reaction sensitivity, and the degree of bone loss of the patient. Depending on the field, it may be appropriately selected by those skilled in the art, and specifically, 0.001 mg/kg to 50 mg/kg, and may be administered once a day to several times as needed.
본 발명의 "투여 대상"은 인간, 원숭이, 소, 말, 돼지, 양, 닭, 고양이, 개, 마우스, 토끼 등을 포함하지만, 특별히 이에 제한되는 것은 아니다.The "administration target" of the present invention includes humans, monkeys, cows, horses, pigs, sheep, chickens, cats, dogs, mice, rabbits, etc., but is not particularly limited thereto.
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention is a health function for preventing or improving diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound or a pharmaceutically acceptable salt of the compound as an active ingredient A food composition is provided.
본 발명의 용어 "건강기능식품" 이란, 일상 식사에서 결핍되기 쉬운 영양소나 또는 인체에 유용한 기능을 가진 원료나 성분 (기능성 원료)을 사용하여 제조하는 것으로, 인체의 정상적인 기능을 유지하거나 생리 기능 활성화를 통하여 건강을 유지하고 개선하는 식품을 의미하나, 이에 제한되는 것은 아니다.The term "health functional food" of the present invention is manufactured using nutrients that are easily deficient in daily diet or raw materials or components (functional raw materials) having useful functions for the human body, maintaining normal functions of the human body or activating physiological functions. Means food that maintains and improves health through, but is not limited thereto.
본 발명의 건강기능식품은 당업계에 공지된 다양한 제조방법에 따라 적절한 유효 농도 범위에서 화합물을 첨가하여 제조 가능하다.The health functional food of the present invention can be prepared by adding a compound in an appropriate effective concentration range according to various manufacturing methods known in the art.
본 발명의 건강기능식품은 분말, 과립, 정제, 캡슐 또는 액체 등의 형태로 제조될 수 있다. The health functional food of the present invention may be prepared in the form of powder, granule, tablet, capsule or liquid.
본 발명의 건강기능식품 조성물은 중증열성혈소판감소증후군의 예방 또는 개선 효능을 가지므로 중증열성혈소판감소증후군의 예방 또는 개선을 목적으로 하는 개체에게 꾸준히 섭취하게 함으로써 상기 중증열성혈소판감소증후군을 예방할 수 있고, 이미 발생한 중증열성혈소판감소증후군을 개선시킬 수 있다.Since the health functional food composition of the present invention has an effect of preventing or improving severe fever with thrombocytopenia syndrome, severe fever with thrombocytopenia syndrome can be prevented by continuously ingesting it to an individual for the purpose of preventing or improving severe fever with thrombocytopenia syndrome, , can improve severe fever with thrombocytopenia syndrome that has already occurred.
상기 건강기능식품은 중증열성혈소판감소증후군의 예방 또는 개선을 목적으로 하는 개체이면 특별히 한정되지 않고, 어떠한 개체에도 적용 가능하다. 예를 들면, 원숭이, 개, 고양이, 토끼, 모르모트, 랫트, 마우스, 소, 양, 돼지, 염소 등과 같은 비 인간동물, 조류, 또는 어류 등 어떠한 개체에도 적용 가능하다.The health functional food is not particularly limited as long as it is an individual for the purpose of preventing or improving severe fever with thrombocytopenia syndrome, and can be applied to any individual. For example, it can be applied to any object such as non-human animals such as monkeys, dogs, cats, rabbits, guinea pigs, rats, mice, cows, sheep, pigs, goats, birds, or fish.
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 개선용 사료 첨가제를 제공한다.In addition, the present invention is a feed additive for preventing or improving diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound or a pharmaceutically acceptable salt of the compound as an active ingredient provides
본 발명의 용어 "유효성분으로 포함하는"은 화합물의 효능 또는 활성을 달성하는데 충분한 양을 포함하는 것을 의미한다.The term "comprising as an active ingredient" of the present invention means containing an amount sufficient to achieve the efficacy or activity of the compound.
본 발명의 용어 "사료 첨가제"란 영양소 보충 및 체중감소 예방, 사료내 섬유소의 소화 이용성 증진, 유질 개선, 번식장애 예방 및 수태율 향상, 하절기 고온 스트레스 예방 등 다양한 효과를 목적으로 사료에 첨가하는 물질을 의미한다. 본 발명에서는 SFTS 바이러스 감염의 예방 또는 개선을 목적으로 첨가되는 물질을 의미한다.The term "feed additive" as used herein refers to substances added to feed for various purposes, such as supplementation of nutrients and prevention of weight loss, enhancement of digestibility of fiber in feed, improvement of oil quality, prevention of reproductive disorders and improvement of conception rate, and prevention of high-temperature stress in summer. it means. In the present invention, it means a substance added for the purpose of preventing or improving SFTS virus infection.
상기 사료 첨가제를 공급하는 경우, 가축 등에 대하여 단독으로 공급하거나 사료에 혼합하여 공급할 수 있다.In the case of supplying the feed additive, it may be supplied alone or mixed with feed for livestock and the like.
또한, 본 발명의 사료 첨가제는 당업계에 공지된 다양한 사료 제조방법에 따라 적절한 유효 농도 범위에서 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염을 첨가하여 제조 가능하다.In addition, the feed additive of the present invention can be prepared by adding the compound or a pharmaceutically acceptable salt of the compound in an appropriate effective concentration range according to various feed manufacturing methods known in the art.
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 개선용 음용수 첨가제를 제공한다.In addition, the present invention is a drinking water additive for preventing or improving disease caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound or a pharmaceutically acceptable salt of the compound as an active ingredient provides
본 발명의 용어 "음용수 첨가제"는 영양적 또는 특정 목적을 위하여 동물을 대상으로 하는 음용수에 미량으로 첨가되는 물질을 총칭하는 것으로, 본 발명에서는 SFTS 바이러스 감염의 예방 또는 개선을 목적으로 첨가되는 물질을 의미한다. 여기에서, 동물이란 가축 및 애완동물을 포함하는 개념이다.The term "drinking water additive" of the present invention refers to substances added in small amounts to drinking water for animals for nutritional or specific purposes, and in the present invention, substances added for the purpose of preventing or improving SFTS virus infection it means. Here, the animal is a concept including livestock and pets.
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염을 유효성분으로 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방용 소독제를 제공한다.In addition, the present invention provides a disinfectant for preventing diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound or a pharmaceutically acceptable salt of the compound as an active ingredient .
본 발명의 용어 "소독”이란 병의 감염이나 전염을 예방하기 위하여 병원균을 죽이는 것을 의미한다. 또한 본 발명에 있어서, 상기 "미생물"이란 본 발명의 SFTS 바이러스의 소독제 조성물에 유효성분으로 포함되는 구성물질이 소독 효과를 나타내는 모든 세균, 진균, 효모, 조류를 포함하는 개념이다.The term "disinfection" of the present invention means killing pathogens to prevent infection or transmission of disease. In the present invention, the "microorganism" is a component included as an active ingredient in the disinfectant composition of the SFTS virus of the present invention It is a concept that includes all bacteria, fungi, yeasts and algae in which the substance exhibits a disinfecting effect.
또한, 본 발명은 상기 화합물, 또는 상기 화합물의 약학적으로 허용가능한 염의 유효량을 동물에게 투여하는 것을 포함하는, 중증열성혈소판감소증후군(severe fever with thrombocytopenia syndrome; SFTS) 바이러스에 의한 질환의 예방 또는 치료 방법을 제공한다.In addition, the present invention relates to the prevention or treatment of diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising administering an effective amount of the compound or a pharmaceutically acceptable salt of the compound to an animal. provides a way
구체적인 실시예에서 본 발명자들은 천연물 유래 화합물 라이브러리 스크리닝을 통해 SFTS 바이러스 증식을 효율적으로 억제하는 화합물(잔토휴몰(Xanthohumol), 히노키플라본(Hinokiflavone))을 선별하였다.In a specific example, the present inventors screened compounds (Xanthohumol, Hinokiflavone) that efficiently inhibit SFTS virus growth through natural product-derived compound library screening.
그리고 SFTSV를 감염시키거나 감염시키지 않은 Vero E6에 상기 화합물 및 양성대조군인 T-705를 처리한 후, 72시간에 SFTSV 성장 저해 효과(50% inhibitory concentration, IC50)와 세포 독성(50% cytotoxic concentration, CC50)를 측정하였다(도 1 참조).In addition, SFTSV growth inhibitory effect (50% inhibitory concentration, IC 50 ) and cytotoxicity (50% cytotoxic concentration , CC 50 ) was measured (see FIG. 1).
또한, Huh7 세포에 상기 화합물 및 양성대조군인 T-705를 처리한 후, 72시간에 SFTSV 성장 저해 효과(50% inhibitory concentration, IC50)와 세포 독성(50% cytotoxic concentration, CC50)를 측정하였다(도 2 참조). In addition, Huh7 cells were treated with the compound and T-705, a positive control group, and SFTSV growth inhibitory effect (50% inhibitory concentration, IC 50 ) and cytotoxicity (50% cytotoxic concentration, CC 50 ) were measured at 72 hours. (See Fig. 2).
측정된 IC50와 CC50를 기준으로 SI (selective index)를 비교한 결과, 양성대조군인 T-705(Favipiravir) 보다 SI가 높은 화합물을 선별하였으며, 상기 화합물을 SFTSV에 대한 항바이러스제로 사용할 수 있음을 확인함으로써 본 발명을 완성하였다. As a result of comparing the SI (selective index) based on the measured IC 50 and CC 50 , a compound with a higher SI than the positive control T-705 (Favipiravir) was selected, and the compound can be used as an antiviral agent for SFTSV The present invention was completed by confirming.
이하 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by examples and experimental examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 의해서 한정되는 것은 아니다.However, the following Examples and Experimental Examples are only to illustrate the present invention, and the content of the present invention is not limited by the following Examples and Experimental Examples.
<실시예 1> 천연물 유래 화합물 라이브러리를 이용한 화합물 스크리닝<Example 1> Compound screening using a natural product-derived compound library
바이러스가 감염된 Vero E6 세포에 화합물을 처리한 후, 72 시간째 세포배양액을 회수하였다. 회수한 세포배양액을 새로운 Vero E6 세포에 감염시킨 후, N 단백질 항체 이용 focus forming assay를 수행하여 progeny 바이러스의 양 측정을 통해 분석하였다. After the compound was treated with the virus-infected Vero E6 cells, the cell culture medium was recovered at 72 hours. After infecting new Vero E6 cells with the recovered cell culture medium, a focus forming assay using N protein antibody was performed and analyzed by measuring the amount of progeny virus.
기존 SFTS 성장의 저해하는 화합물로 알려진 T-705(Favipiravir)를 양성대조군으로 사용하였다. 파비피라비르(Favipiravir)는 RNA 바이러스 항바이러스제로, 인플루엔자 바이러스 치료제로 개발되었으며, RNA 바이러스의 RNA polymerase를 선택적으로 저해하기 때문에 다양한 RNA 바이러스에 적용이 가능하다. 현재 Favipiravir는 SFTSV 감염 마우스에서 항바이러스 효능이 있음이 밝혀졌으며, 일본에서 임상 3상이 진행 중인 약물이다.T-705 (Favipiravir), known as a compound that inhibits the growth of conventional SFTS, was used as a positive control. Favipiravir is an RNA virus antiviral agent, developed as an influenza virus treatment, and can be applied to various RNA viruses because it selectively inhibits RNA polymerase of RNA viruses. Currently, Favipiravir has been found to have antiviral efficacy in SFTSV-infected mice, and is currently undergoing phase 3 clinical trials in Japan.
바이러스가 감염된 Vero E6 세포에 화합물을 처리한 후, 72 시간째 세포배양액을 회수하였다. 회수한 세포배양액을 새로운 Vero E6 세포에 감염시킨 후, N 단백질 항체 이용 focus forming assay를 수행하여 progeny 바이러스의 양 측정을 통해 분석하였다.After the compound was treated with the virus-infected Vero E6 cells, the cell culture medium was recovered at 72 hours. After infecting new Vero E6 cells with the recovered cell culture medium, a focus forming assay using N protein antibody was performed and analyzed by measuring the amount of progeny virus.
분석 결과, SFTSV 성장을 저해하는 화합물 2종을 선별하였고, 이를 표 1에 나타내었다.As a result of the analysis, two compounds that inhibit SFTSV growth were selected, which are shown in Table 1.
<실험예 1> Vero E6 세포에서 SFTSV에 대한 항바이러스 활성 확인<Experimental Example 1> Confirmation of antiviral activity against SFTSV in Vero E6 cells
SFTSV를 감염시키거나 감염시키지 않은 Vero E6 세포에 상기 실시예 1의 화합물 2종과 양성대조군인 T-705를 처리한 후, 72시간에 SFTSV 성장 저해 효과(50% inhibitory concentration, IC50)와 세포 독성(50% cytotoxic concentration, CC50)를 측정하였다. 측정된 IC50와 CC50를 기준으로 SI (selective index)를 비교하였다.SFTSV growth inhibitory effect (50% inhibitory concentration, IC 50 ) and cells at 72 hours after treatment with the two compounds of Example 1 and positive control T-705 in Vero E6 cells infected or not infected with SFTSV Toxicity (50% cytotoxic concentration, CC 50 ) was measured. Based on the measured IC 50 and CC 50 , the SI (selective index) was compared.
그 결과, 도 1에서와 같이 실시예 1의 화합물 2종은 농도 의존적으로 SFTS 바이러스 증식을 억제함을 나타내었다. 기존 알려진 SFTSV 항바이러스 효능이 있는 T-705에 비해 높은 SI값은 높은 항바이러스 효능을 의미한다. 화합물 비처리군 대비, 처리군의 바이러스 증식 감소율(녹색)과 세포생존율(보라색)을 표시하였다. 화합물의 SFTS 바이러스에 대한 항바이러스 효능을 표 2에 정리하였다.As a result, as shown in FIG. 1, it was shown that the two compounds of Example 1 inhibited the growth of the SFTS virus in a concentration-dependent manner. A higher SI value compared to T-705, which has known SFTSV antiviral efficacy, means high antiviral efficacy. Compared to the compound untreated group, the virus proliferation reduction rate (green) and cell viability (purple) of the treated group are shown. The antiviral efficacy of the compounds against the SFTS virus is summarized in Table 2.
<실험예 2> Huh7 세포에서 SFTSV에 대한 항바이러스 활성 확인<Experimental Example 2> Confirmation of antiviral activity against SFTSV in Huh7 cells
SFTSV를 감염시키거나 감염시키지 않은 Huh7 세포에 상기 실시예 1의 화합물 2종과 양성대조군인 T-705를 처리한 후, 72시간에 SFTSV 성장 저해 효과(50% inhibitory concentration, IC50)와 세포 독성(50% cytotoxic concentration, CC50)를 측정하였다. 측정된 IC50와 CC50를 기준으로 SI (selective index)를 비교하였다.SFTSV growth inhibitory effect (50% inhibitory concentration, IC 50 ) and cytotoxicity at 72 hours after treatment with the two compounds of Example 1 and positive control T-705 in Huh7 cells infected or not infected with SFTSV (50% cytotoxic concentration, CC 50 ) was measured. Based on the measured IC 50 and CC 50 , the SI (selective index) was compared.
그 결과, 도 2에서와 같이 실시예 1의 화합물 2종은 농도 의존적으로 SFTS 바이러스 증식을 억제함을 나타내었다. 기존 알려진 SFTSV 항바이러스 효능이 있는 T-705에 비해 높은 SI값은 높은 항바이러스 효능을 의미한다. 화합물 비처리군 대비, 처리군의 바이러스 증식 감소율(녹색)과 세포생존율(보라색)을 표시하였다. 화합물의 SFTS 바이러스에 대한 항바이러스 효능을 표 2에 정리하였다.As a result, as shown in FIG. 2, it was shown that the two compounds of Example 1 inhibited the growth of the SFTS virus in a concentration-dependent manner. A higher SI value compared to T-705, which has known SFTSV antiviral efficacy, means high antiviral efficacy. Compared to the compound untreated group, the virus proliferation reduction rate (green) and cell viability (purple) of the treated group are shown. The antiviral efficacy of the compounds against the SFTS virus is summarized in Table 2.
상기에서 본 발명 실시예 1의 화합물 잔토휴몰(Xanthohumol), 히노키플라본(Hinokiflavone)은 SFTS 바이러스 증식을 억제함을 확인하였다. 따라서 상기 화합물들은 SFTS 바이러스에 대한 항바이러스제로 사용할 수 있다.In the above, it was confirmed that the compounds of Example 1 of the present invention, Xanthohumol and Hinokiflavone, inhibited the growth of the SFTS virus. Therefore, these compounds can be used as antiviral agents against SFTS virus.
Claims (8)
[화학식 1]
[화학식 2]
.
A pharmaceutical composition for preventing or treating diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising a compound represented by Formula 1 or 2, or a pharmaceutically acceptable salt thereof as an active ingredient Composition:
[Formula 1]
[Formula 2]
.
상기 화합물은 천연물 유래 화합물인 것을 특징으로 하는, 약학적 조성물.
According to claim 1,
Characterized in that the compound is a natural product-derived compound, a pharmaceutical composition.
A health functional food composition for preventing or improving diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound of claim 1 as an active ingredient.
A feed additive for preventing or improving diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound of claim 1 as an active ingredient.
A drinking water additive for preventing or improving diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound of claim 1 as an active ingredient.
A disinfectant for preventing diseases caused by severe fever with thrombocytopenia syndrome (SFTS) virus, comprising the compound of claim 1 as an active ingredient.
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