KR20210116153A - Composition for preventing or treating corona virus comprising Levistilide A - Google Patents
Composition for preventing or treating corona virus comprising Levistilide A Download PDFInfo
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- KR20210116153A KR20210116153A KR1020200055400A KR20200055400A KR20210116153A KR 20210116153 A KR20210116153 A KR 20210116153A KR 1020200055400 A KR1020200055400 A KR 1020200055400A KR 20200055400 A KR20200055400 A KR 20200055400A KR 20210116153 A KR20210116153 A KR 20210116153A
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- coronavirus
- sars
- levistilide
- present
- infection
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Abstract
Description
본 발명은 레비스틸라이드 A(Levistilide A) 또는 이의 약학적으로 허용 가능한 염을 포함하는 코로나바이러스(CoV)에 대한 항바이러스 용도에 관한 것으로, 구체적으로, 본 발명은 레비스틸라이드 A(Levistilide A) 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 코로나바이러스에 대한 항바이러스용 약학 조성물; 코로나바이러스 감염질환의 예방 또는 치료용 약학 조성물; 및 코로나바이러스 감염질환의 예방 또는 개선용 건강기능식품 조성물 및 사료 조성물에 관한 것이다.The present invention relates to an antiviral use for coronavirus (CoV) comprising Levitilide A or a pharmaceutically acceptable salt thereof, and specifically, the present invention relates to Levistilide A (Levistilide A) Or a pharmaceutical composition for antiviral against coronavirus comprising a pharmaceutically acceptable salt thereof as an active ingredient; A pharmaceutical composition for the prevention or treatment of a coronavirus infectious disease; And it relates to a health functional food composition and feed composition for preventing or improving coronavirus infectious diseases.
코로나 바이러스(coronavirus)는 1937년 닭에서 처음 발견된 뒤 개, 돼지, 조류 등의 동물을 거쳐 1965년에는 사람에게서도 발견되었다. 개기일식 때 태양의 광구가 달에 가려졌을 때 그 둘레에서 하얗게 빛나는 현상인 코로나 현상과 생김새가 비슷하여 이러한 이름이 붙여졌다.Coronavirus was first discovered in chickens in 1937, followed by animals such as dogs, pigs, and birds, and then in humans in 1965. During a total solar eclipse, when the sun's photosphere is obscured by the moon, it is given this name because its appearance is similar to the corona phenomenon, which is a phenomenon that glows white around the moon.
코로나바이러스는 사람과 동물에서 주로 폐렴과 장염을 유발하는 것으로 알려져 있으며, 간혹 신경계 감염과 간염을 유발하는 것으로도 알려져 있다. 코로나바이러스는 코로나바이러스과(Coronaviridae)에 속하며 구형의 외막을 가지는, 약 100-120 nm 크기의 positive sense RNA 바이러스이다(Master, 2006). 코로나바이러스는 가장 외각에 있는 spike 단백질 (S), hemagglutinin-esterase (HE) 단백질, transmembrane (M) 단백질, small membrane (E) 단백질 및 nucleocapsid (N) 단백질 등 총 5개의 구조 단백질로 이루어져 있다(Lai and Homes, 2001. Fields Virology). 이 중 spike 단백질은 세포 수용체와 결합하는 리간드 역할을 하며, 숙주세포와 바이러스간의 융합을 유도하는 단백질로 가장 변이가 심한 단백질로 알려져 있다.Coronaviruses are known to mainly cause pneumonia and enteritis in humans and animals, and are also known to occasionally cause nervous system infections and hepatitis. Coronavirus belongs to the coronaviridae and is a positive sense RNA virus with a spherical outer membrane and a size of about 100-120 nm (Master, 2006). Coronavirus consists of a total of five structural proteins, including the outermost spike protein (S), hemagglutinin-esterase (HE) protein, transmembrane (M) protein, small membrane (E) protein, and nucleocapsid (N) protein (Lai). and Homes, 2001. Fields Virology). Among them, the spike protein acts as a ligand that binds to the cell receptor and induces fusion between the host cell and the virus, and is known as the most mutable protein.
지금까지 코로나바이러스는 사람에게는 거의 감염되지 않고 주로 개, 돼지, 소 등의 동물에 감염되는 병원균으로 인식되어 왔다. 사람에게 감염될 때에도 호흡기 증상을 유발하는 여러 바이러스 가운데 하나로서 단순한 감기를 유발하거나 어린이에게 위험성이 그리 높지 않은 설사 등의 장 질환을 일으키는 경우가 있을 뿐이었다. 그러나 세계적으로 수백명이 넘는 사망자와 수천여 명의 환자를 발생시킨 중증 급성 호흡기 증후군(사스;SARS)의 원인균 및 중동 호흡기 증후군(메르스;MERS), 및 코로나바이러스감염증-19(coronavirus disease 2019; COVID-19)의 원인균이 신종(변종) 코로나바이러스인 것으로 알려지면서 점차적으로 주목받기 시작하였다.So far, coronavirus has been recognized as a pathogen that rarely infects humans and mainly infects animals such as dogs, pigs, and cattle. It is one of several viruses that cause respiratory symptoms even when infecting humans, and only causes a simple cold or intestinal disease such as diarrhea, which is not a high risk for children. However, the causative agent of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS), which has caused over hundreds of deaths and thousands of cases worldwide, and coronavirus disease 2019; COVID- 19), as it became known that the causative bacterium was a novel (mutated) coronavirus, it gradually began to attract attention.
사스는 2002년 11월 중국 남부 광둥(廣東)성에서 발생, 홍콩을 거쳐 세계로 확산된 전염병으로, 갑작스런 발열, 기침 및 호흡곤란이 주 증상이며, 심한 경우 폐렴으로 진행돼 죽음에 이를 수도 있는 질환이다. 전파되는 경로는 아직 완전히 밝혀지지 않았지만 대기 중에 떠다니는 고체나 액체의 미세한 입자에 의해 전파되는 것으로 추측하고 있다. 사스는 2003년 7월까지 유행하였으며, 약 7개월 동안 32개국에서 총 8,096명의 감염자가 발생하고 그 가운데 774명이 사망한 것으로 알려져 있다.SARS is an infectious disease that originated in Guangdong Province in southern China in November 2002 and spread to the world through Hong Kong. am. The path of propagation is not yet fully elucidated, but it is speculated that it is propagated by fine particles of solid or liquid floating in the atmosphere. The SARS epidemic lasted until July 2003, and in about 7 months, a total of 8,096 infections were reported in 32 countries, and 774 of them were known to have died.
메르스는 2012년 사우디아라비아에서 처음 발견되었고, 고열, 기침 및 호흡곤란 등 심한 호흡기 증상을 나타내며, 심한 경우 합병증이 동반되면서 사망에 이르기도 하는 질환이다. 명확한 감염원과 감염경로는 확인되지 않았으나, 중동 지역의 낙타와의 접촉을 통해 감염될 가능성이 크고 사람 간 밀접접촉에 의한 전파가 가능하다고 보고되었다. 주로 중동 지역에서 환자가 집중적으로 발생하였다가 2015년 5월부터 우리나라 전역에서 100명이 넘는 감염자가 발생한 바 있다.MERS was first discovered in Saudi Arabia in 2012, and it presents severe respiratory symptoms such as high fever, cough and shortness of breath. In severe cases, it is accompanied by complications, leading to death. Although the exact source and route of infection have not been identified, it has been reported that infection is highly likely to be transmitted through contact with camels in the Middle East and transmission through close human contact is possible. The cases were mainly concentrated in the Middle East, but since May 2015, more than 100 cases have been reported across Korea.
COVID-19는 2019년 말 중국 후베이 지방의 수도인 우한에서 처음 확인되어 전세계로 확산되어 진행성 팬데믹을 초래한 질환으로, 사스-코로나바이러스-2에 의해 유발되는 감염성 질환이다. 2020년 5월 7일을 기준으로 3.75백만 케이스 이상이 187개국에서 보고되었고, 사망자는 263천명에 이르며, 1.24백만명이 회복되었다. 보편적인 증상은 발열(fever), 기침(cough), 피로(fatigue), 호흡곤란(shortness of breath) 및 후각 및 미각의 상실이다. 대부분의 경우 증상이 경미하나 몇몇은 바이러스성 폐렴(viral pneumonia), 다중기관부전(multi-organ failure) 및 사이토카인 폭풍(cyrokine storm)으로 진행한다. 증상의 발현으로부터 발병까지의 시간은 일반적으로 약 5일이지만 2 내지 14일 사이일 수 있다. 바이러스는 주로 밀접접촉하는 동안, 때로는 기침, 재채기 및 대화시 발생하는 비말을 통해 사람 간에 전파된다. 증상 발현 후 처음 3일 동안 가장 전염성이 높으며, 증상이 나타나기 전이나 질환의 말기에라도 전파될 수 있다. 이를 진단하는 표준 방법은 비인두 면봉검사(nasopharyngeal swab)로부터의 실시간 역전사 PCR(real-time reverse transcription polymerase chain reaction; rRT-PCR)을 이용한다.COVID-19 is an infectious disease caused by SARS-coronavirus-2, a disease that was first identified in Wuhan, the capital of China's Hubei province, at the end of 2019 and spread worldwide, resulting in a progressive pandemic. As of May 7, 2020, more than 3.75 million cases were reported in 187 countries, with 263,000 deaths and 1.24 million recoveries. Common symptoms are fever, cough, fatigue, shortness of breath and loss of smell and taste. In most cases, symptoms are mild, but some progress to viral pneumonia, multi-organ failure, and a cytokine storm. The time from onset of symptoms to onset is usually about 5 days, but can be between 2 and 14 days. The virus is spread from person to person primarily during close contact, and sometimes through droplets that occur when coughing, sneezing and talking. It is most contagious during the first 3 days after onset of symptoms and can be spread before symptoms appear or even late in the disease. A standard method for diagnosing it is using real-time reverse transcription polymerase chain reaction (rRT-PCR) from a nasopharyngeal swab.
앞서 언급한대로, 메르스 및 사스는 모두 베타 코로나바이러스(Beta coronavirus) 속에 속하는 변종 코로나바이러스(메르스-코로나바이러스, 사스-코로나바이러스, 및 사스-코로나바이러스-2)가 원인이 되는 것으로 알려져 있다. 따라서 메르스-코로나바이러스, 사스-코로나바이러스, 및 사스-코로나바이러스-2는 임상 증상, 병인 및 감염 등에 있어서 유사한 특성을 공유한다. 계통수(phylogenetic tree)에서, 사스-코로나바이러스 및 사스-코로나바이러스-2는 박쥐 사스-유사 코로나바이러스와 다른 박쥐 유래의 코로나바이러스를 포함하는 계통 B에 속하며, 메르스-코로나바이러스는 박쥐 유래의 코로나바이러스를 포함하는 계통 C에 속한다(Trends Microbiol 24:490-502; https://nextstrain.org/groups/blab/sars-like-cov?f_virus_type=SARS-CoV-2).As mentioned earlier, both MERS and SARS are known to be caused by variant coronaviruses (MERS-coronavirus, SARS-coronavirus, and SARS-coronavirus-2) belonging to the genus Beta coronavirus. Therefore, MERS-coronavirus, SARS-coronavirus, and SARS-coronavirus-2 share similar characteristics in clinical symptoms, etiology and infection. In the phylogenetic tree, SARS-coronavirus and SARS-coronavirus-2 belong to strain B, which includes bat SARS-like coronaviruses and other bat-derived coronaviruses, and MERS-coronaviruses are bat-derived coronaviruses. Belongs to strain C containing the virus (Trends Microbiol 24:490-502; https://nextstrain.org/groups/blab/sars-like-cov?f_virus_type=SARS-CoV-2).
메르스-코로나바이러스, 사스-코로나바이러스, 및 사스-코로나바이러스-2는 모두 다양한 코로나바이러스의 1차적인 보유 숙주인 박쥐로부터 유래한 것으로 여겨지며(Antiviral Res 101:45-56), 그 정확한 감염 경로에 대해서는 아직 완전히 밝혀지지 않았다. 한편, 사향 고양이(palm civet) 및 단봉낙타(dromedary camel)에 대한 상기 바이러스의 종간 전염은 인간에 대해 인수 공통 감염의 가능성을 증가시켰고(Nat Rev Microbiol 14:523-534), 병원 내 감염은 인간과 인간 사이의 메르스-코로나바이러스 및 사스-코로나바이러스 감염의 주된 원인으로 여겨진다(BMC Med13:1-12).MERS-coronavirus, SARS-coronavirus, and SARS-coronavirus-2 are all believed to originate from bats, which are the primary carriers of various coronaviruses (Antiviral Res 101:45-56), and their exact route of infection has not yet been fully elucidated. On the other hand, interspecies transmission of the virus to palm civet and dromedary camel increased the likelihood of zoonotic infections in humans (Nat Rev Microbiol 14:523-534), and nosocomial infections in humans It is believed to be the main cause of MERS-coronavirus and SARS-coronavirus infections between and humans (BMC Med13:1-12).
한편, 레비스틸라이드 A는 당귀에서 분리동정한 것으로, 당귀(Angelica sinensis)는 미나리과에 속하는 다년생 풀인 당귀의 뿌리를 말린 것으로, 맛은 달고 매우며 성질은 따뜻하다. 당귀의 효능에는 피가 부족할 때 피를 생성해주는 보혈작용이 있으며, 당귀는 관상동맥의 혈류량을 촉진시키고, 적혈구 생성을 왕성하게 한다고 알려져 있다. 그러나 상기 레비스틸라이드 A의 코로나바이러스의 예방, 치료 또는 개선 효과는 알려진 바가 없었으며, 본 발명자에 의하여 최초로 규명되었다.On the other hand, Levistilide A is isolated and identified from Angelica sinensis, and Angelica sinensis is a dried root of Angelica sinensis, a perennial grass belonging to the Asteraceae family. Angelica is known to have a bohyeol effect that produces blood when there is not enough blood, and it promotes blood flow in the coronary arteries and stimulates the production of red blood cells. However, the preventive, therapeutic or ameliorating effect of levistilide A on coronavirus was not known, and was first identified by the present inventors.
현재까지 개발된 항바이러스들은 심한 부작용을 나타내고 있으므로, 그 응용에 있어서 많은 주의가 필요하다. 이러한 치료제는 효과적이지 못하며 부작용 또한 나타나고 있는 실정이다. 그러므로 코로나바이러스의 발생을 예방하고 치료하기 위한 감염 억제 효과가 뛰어나고 독성이 적은 우수한 새로운 코로나 바이러스제의 개발의 필요성이 증가하고 있다.Since the antivirals developed to date show severe side effects, much attention is required in their application. These treatments are not effective and side effects are also present. Therefore, there is an increasing need for the development of excellent novel coronavirus agents with excellent anti-infection effects and low toxicity for preventing and treating coronavirus outbreaks.
이러한 배경 하에, 본 발명자들은, 신규한 코로나바이러스 치료제를 개발하기 위한 노력을 계속한 결과, 당귀에서 추출한 레비스틸라이드 A가 메르스-코로나바이러스, 사스-코로나바이러스, 및 사스-코로나바이러스-2의 증식을 억제하는 우수한 효과가 있음을 확인함으로써, 본 발명을 완성하였다.Under this background, the present inventors continued their efforts to develop novel coronavirus therapeutics, and as a result, levistilide A extracted from Angelica keiskei was MERS-coronavirus, SARS-coronavirus, and SARS-coronavirus-2. By confirming that there is an excellent effect of inhibiting proliferation, the present invention was completed.
본 발명의 하나의 목적은 레비스틸라이드 A 또는 이의 약학적으로 허용 가능한 염을 포함하는 코로나바이러스에 대한 항바이러스용 약학 조성물을 제공하는 것이다.One object of the present invention is to provide a pharmaceutical composition for antiviral against coronavirus comprising levistilide A or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 레비스틸라이드 A 또는 이의 약학적으로 허용 가능한 염을 포함하는 코로나바이러스 감염질환의 예방 또는 치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a coronavirus infection disease comprising levistilide A or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 레비스틸라이드 A 또는 이의 식품학적으로 허용 가능한 염을 포함하는 코로나바이러스 감염질환의 예방 또는 개선용 건강기능식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a health functional food composition for preventing or improving a coronavirus infection disease, comprising levistilide A or a pharmaceutically acceptable salt thereof.
본 발명의 또 다른 목적은 레비스틸라이드 A 또는 이의 식품학적으로 허용 가능한 염을 포함하는 코로나바이러스 감염질환의 예방 또는 개선용 사료 조성물을 제공하는 것이다.Another object of the present invention is to provide a feed composition for preventing or improving a coronavirus infectious disease, comprising levistilide A or a pharmaceutically acceptable salt thereof.
상기 목적을 달성하기 위한 본 발명의 일 실시 양태는 레비스틸라이드 A 또는 이의 약학적으로 허용 가능한 염을 포함하는 항바이러스용 약학 조성물을 제공한다:One embodiment of the present invention for achieving the above object provides a pharmaceutical composition for antiviral comprising levistilide A or a pharmaceutically acceptable salt thereof:
[화학식 1][Formula 1]
상기 목적을 달성하기 위한 본 발명의 다른 실시 양태는 상기 화학식 I로 표시되는 화합물 또는 이의 약학적으로 허용 가능한 염을 유효성분으로 포함하는 코로나바이러스 감염질환의 예방 또는 치료용 약학 조성물을 제공한다.Another embodiment of the present invention for achieving the above object provides a pharmaceutical composition for preventing or treating a coronavirus infection disease comprising the compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient.
구체적으로, 본 발명의 약학 조성물은 코로나바이러스를 억제하는 효과를 나타내므로, 이를 개체에 투여하는 단계를 포함하는 본 발명의 방법은 코로나바이러스에 의한 감염질환의 예방 또는 치료에 유용하게 활용될 수 있다.Specifically, since the pharmaceutical composition of the present invention exhibits an effect of inhibiting coronavirus, the method of the present invention comprising the step of administering it to an individual can be usefully utilized for the prevention or treatment of infectious diseases caused by coronavirus. .
상기 코로나바이러스는 메르스-코로나바이러스, 사스-코로나바이러스, 및 사스-코로나바이러스-2로 이루어진 군에서 선택된 하나 이상일 수 있다.The coronavirus may be at least one selected from the group consisting of MERS-coronavirus, SARS-coronavirus, and SARS-coronavirus-2.
본 발명의 용어, “레비스틸라이드 A(Levistilide A)”는 하기 화학식 I의 구조를 갖는 화합물을 의미한다. 상기 레비스틸라이드 A는 이에 한정되지는 않으나 당귀로부터 분리 동정한 것일 수 있다. 상기 레비스틸라이드 A의 코로나바이러스의 예방, 치료 또는 개선 효과는 알려진 바가 없었으며, 본 발명자에 의하여 최초로 규명되었다:As used herein, the term “Levistilide A” refers to a compound having the structure of the following formula (I). The levistilide A is not limited thereto, but may be isolated and identified from Angelica. The preventive, therapeutic or ameliorating effect of levistilide A on coronavirus was not known, and was first identified by the present inventors:
[화학식 I][Formula I]
레비스틸라이드 A를 포함하는 조성물은 레비스틸라이드 A에서 일부 당업자가 예상 가능한 범위의 유도체가 포함될 수 있으며, 본 발명에서의 동일한 효과가 있는 한 제한 없이 포함된다. 레비스틸라이드 A는 이를 포함하는 추출물에서 수득될 수 있다. 또한, 공지의 방법으로 합성해서 사용 가능하다.The composition comprising levistilide A may include a range of derivatives expected by some skilled in the art from levistilide A, and is included without limitation as long as the same effect is obtained in the present invention. Levistilide A can be obtained from an extract comprising it. Moreover, it can be synthesize|combined and used by a well-known method.
본 발명의 용어, “메르스-코로나바이러스(MERS-CoV)”는 2012년 9월 24일에 새롭게 발견된 베타 코로나바이러스 속에 속하는 ssRNA 바이러스로, 5′-복제효소-구조 단백질(spikeenvelope-membrane-nucleocapsid)-poly(A)-3′[5′-ORF1a/b-S-E-M-N-poly(A)]의 구조를 갖는다. 메르스-코로나바이러스 게놈은 계통 발생적으로 계통군 A, 계통군 B로 분류되는데, 초기 메르스 사례들은 계통군 A였고(EMC/2012 and Jordan-N3/2012), 새로 보고된 사례들은 유전적으로 별개인 계통군 B이다(Emerging Infectious Diseases, Vol. 20, No. 6, June 2014).As used herein, the term "MERS-coronavirus (MERS-CoV)" is an ssRNA virus belonging to the genus beta-coronavirus newly discovered on September 24, 2012, and 5'-replicate-structural protein (spikeenvelope-membrane- It has the structure of nucleocapsid)-poly(A)-3'[5'-ORF1a/bSEMN-poly(A)]. The MERS-Coronavirus genome is phylogenetically classified into clade A and clade B. Early MERS cases were clade A (EMC/2012 and Jordan-N3/2012), and newly reported cases are genetically distinct. Individual clade B (Emerging Infectious Diseases, Vol. 20, No. 6, June 2014).
본 발명의 용어, “사스-코로나바이러스(SARS-CoV)”는 외피를 지닌 베타 코로나바이러스 속에 속하는 ssRNA 바이러스이다. 전체 게놈이 29,727 뉴클레오타이드로 구성되며, 현재까지 알려진 RNA 바이러스 중에서 가장 큰 게놈을 갖는 바이러스이다. 사스-코로나바이러스의 게놈은 11개의 오픈 리딩 프레임 (open reading frame, ORF)을 갖고 있으며 23종에 달하는 단백질을 코딩하고 있는 것으로 알려졌다. 사스-코로나바이러스의 주요 구조 단백질은 뉴클레오캡시드 (nucleocapsid, N), 스파이크 (spike, S), 멤브레인 (membrane, M), 스몰 엔벨로프 (small envelope, E) 단백질임이 밝혀졌다.As used herein, the term "SARS-coronavirus (SARS-CoV)" is an ssRNA virus belonging to the genus beta-coronavirus with an envelope. The entire genome consists of 29,727 nucleotides, and it is the virus with the largest genome among RNA viruses known to date. The SARS-coronavirus genome has 11 open reading frames (ORFs) and is known to encode 23 types of proteins. It has been found that the major structural proteins of SARS-coronavirus are nucleocapsid (N), spike (S), membrane (M), and small envelope (E) proteins.
이들 단백질에 대한 염기서열 분석결과, 사스-코로나바이러스가 다른 코로나바이러스와 비교하여 약 40 ~ 50% 정도의 매우 낮은 서열 상동성을 가짐이 밝혀졌다. 코로나바이러스의 항원성에 따른 계통발생학적 분류에 따르면, 사스 코로나바이러스는 Ⅰ, Ⅱ 및 Ⅲ그룹 중 Ⅱ그룹과 유연관계가 높은 것으로 나타났다.As a result of sequencing of these proteins, it was found that SARS-coronavirus has a very low sequence homology of about 40-50% compared to other coronaviruses. According to the phylogenetic classification according to the antigenicity of the coronavirus, the SARS coronavirus was found to be highly related to group II among groups I, II and III.
본 발명의 용어, "사스-코로나바이러스-2(SARS-CoV-2)"는 호흡기 질환인 코로나바이러스감염증-19(coronavirus disease 2019; COVID-19)를 야기하는 바이러스 균주이다. 국립보건원(National Institutes of Health; NIH)에 의해 공지된 바와 같이, 사스-코로나바이러스(SARS-CoV)의 계승자(successor)이다. SARS-CoV-2는 양성 단일가닥 RNA 바이러스(positive-sense single-stranded RNA virus)이다. 인간에서 전염성이 있으며(contagious), 세계보건기구(World Health Organization; WHO)는 국제적 공중보건 비상사태(Public Health Emergency of International Concern; PHEIC)로 COVID-19의 진행성 팬데믹(ongoing pandemic)을 선언하였다. SARS-CoV-2는 분류학적으로 SARS-CoV의 계통(strain)으로, 동물원성 감염증의 기원(zoonotic origins)을 가지며, 박쥐 코로나바이러스와 근접한 유전적 유사성을 갖는 것으로 간주된다. 상기 SARS-CoV-2는 주로 사람들 간의 긴밀한 접촉을 통해 및/또는 기침이나 재채기시 발생하는 비말을 통해 전파되며, 주로 수용체 안지오텐신 전환 효소 2(receptor angiotensin converting enzyme 2; ACE2)에 결합하여 인간 세포에 진입한다.As used herein, the term "SARS-CoV-2" is a virus strain that causes coronavirus disease 2019 (COVID-19), a respiratory disease. As known by the National Institutes of Health (NIH), it is the successor of SARS-CoV. SARS-CoV-2 is a positive-sense single-stranded RNA virus. Contagious in humans, the World Health Organization (WHO) has declared the ongoing pandemic of COVID-19 as a Public Health Emergency of International Concern (PHEIC). . SARS-CoV-2 is a taxonomic strain of SARS-CoV, has zoonotic origins, and is considered to have close genetic similarity to bat coronavirus. The SARS-CoV-2 is mainly transmitted through close contact between people and/or through droplets generated during coughing or sneezing, and mainly binds to receptor angiotensin converting enzyme 2 (ACE2) to bind to human cells. enter
본 발명에서, 상기 레비스틸라이드 A를 포함하는 코로나바이러스 감염질환에 대한 예방 또는 치료용 약학 조성물은 코로나바이러스 감염질환, 예컨대 메르스-코로나바이러스, 사스-코로나바이러스, 및 사스-코로나바이러스-2로 이루어진 군에서 선택된 하나 이상의 바이러스를 억제하는 것을 특징으로 한다. 구체적으로, 본 발명의 일 실시예에서는 상기 레비스틸라이드 A가 메르스-코로나바이러스, 사스-코로나바이러스, 및 사스-코로나바이러스-2의 감염 억제능을 가지는 것을 확인하고, 이를 양성 대조군 로피나비어와 비교하였다(도 1 내지 5).In the present invention, the pharmaceutical composition for preventing or treating a coronavirus infection comprising the levistilide A is a coronavirus infectious disease, such as MERS-coronavirus, SARS-coronavirus, and SARS-coronavirus-2. It is characterized in that it inhibits one or more viruses selected from the group consisting of. Specifically, in one embodiment of the present invention, it was confirmed that the levistilide A has the ability to inhibit infection of MERS-Coronavirus, SARS-Coronavirus, and SARS-Coronavirus-2, and the positive control lopinavir and were compared ( FIGS. 1 to 5 ).
본 발명의 용어, "약학적으로 허용 가능한 염"은 양이온과 음이온이 정전기적 인력에 의해 결합하고 있는 물질인 염 중에서도 약학적으로 사용될 수 있는 형태의 염을 의미하며, 통상적으로 금속염, 유기염기와의 염, 무기산과의 염, 유기산과의 염, 염기성 또는 산성 아미노산과의 염 등이 될 수 있다. 예를 들어, 금속염으로는 알칼리 금속염(나트륨염, 칼륨염 등), 알칼리 토금속염(칼슘염, 마그네슘염, 바륨염 등), 알루미늄염 등이 될 수 있고; 유기염기와의 염으로는 트리에틸아민, 피리딘, 피콜린, 2,6-루티딘, 에탄올아민, 디에탄올아민, 트리에탄올아민, 시클로헥실아민, 디시클로헥실아민, N,N-디벤질에틸렌디아민 등과의 염이 될 수 있으며; 무기산과의 염으로는 염산, 브롬화수소산, 질산, 황산, 인산 등과의 염이 될 수 있고; 유기산과의 염으로는 포름산, 아세트산, 트리플루오로아세트산, 프탈산, 푸마르산, 옥살산, 타르타르산, 말레인산, 시트르산, 숙신산, 메탄술폰산, 벤젠술폰산, p-톨루엔술폰산 등과의 염이 될 수 있으며; 염기성 아미노산과의 염으로는 아르기닌, 라이신, 오르니틴 등과의 염이 될 수 있고; 산성 아미노산과의 염으로는 아스파르트산, 글루탐산 등과의 염이 될 수 있다.As used herein, the term "pharmaceutically acceptable salt" refers to a salt in a form that can be used pharmaceutically among salts, which are substances in which cations and anions are bonded by electrostatic attraction. salts, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. For example, the metal salt may be an alkali metal salt (sodium salt, potassium salt, etc.), alkaline earth metal salt (calcium salt, magnesium salt, barium salt, etc.), an aluminum salt or the like; Salts with organic bases include triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N,N-dibenzylethylenediamine salts with, etc.; salts with inorganic acids may be salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like; Salts with organic acids may be salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like; Salts with basic amino acids may be salts with arginine, lysine, ornithine and the like; The salt with an acidic amino acid may be a salt with aspartic acid, glutamic acid, or the like.
본 발명의 용어, "감염질환"은 감염에 의해 발병되는 질환을 의미한다.As used herein, the term "infectious disease" refers to a disease caused by infection.
상기 용어, “감염”은 병원성 미생물이 숙주가 되는 생물체의 체내에 침입하여, 발육?증식한 상태를 의미한다.As used herein, the term “infection” refers to a state in which a pathogenic microorganism invades the body of a host organism and develops and proliferates.
본 발명의 용어, "예방"은 본 발명에 따른 약학 조성물의 투여에 의해 코로나바이러스에 의한 감염질환의 발병을 억제시키거나 또는 지연시키는 모든 행위를 의미한다.As used herein, the term "prevention" refers to any action that inhibits or delays the onset of an infectious disease caused by a coronavirus by administration of the pharmaceutical composition according to the present invention.
본 발명의 용어, "치료"는 상기 약학 조성물의 투여에 의해 코로나바이러스 감염질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 변경되는 모든 행위를 의미한다.As used herein, the term "treatment" refers to any action in which the symptoms of a suspected and onset individual of a coronavirus infection are improved or beneficially changed by administration of the pharmaceutical composition.
본 발명의 약학적 조성물은, 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있는데, 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다.The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent, which may include a non-naturally occurring carrier.
보다 구체적으로, 상기 약학적 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 폴리카프로락톤(polycaprolactone), 폴리락틱액시드(Poly Lactic Acid), 폴리-L-락틱액시드(poly-L-lactic acid), 광물유 등을 들 수 있다.More specifically, carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate , calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, polycaprolactone, polylactic acid (Poly Lactic Acid), poly-L-lactic acid, mineral oil, and the like.
상기 약학적 조성물은 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있으며, 담체의 형태로는 각종 부정형의 담체, 마이크로 스피어, 나노파이버 등을 포함할 수 있다.The pharmaceutical composition may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc., oral dosage forms, external preparations, suppositories, and sterile injection solutions according to conventional methods, respectively. The carrier may include various amorphous carriers, microspheres, nanofibers, and the like.
제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다.In the case of formulation, it can be prepared using a diluent or excipient such as a filler, extender, binder, wetting agent, disintegrant, surfactant, etc. commonly used.
경구투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형 제제는 상기 추출물과 이의 분획물들에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘 카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용될 수 있다.Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract and its fractions, for example, starch, calcium carbonate, It may be prepared by mixing sucrose or lactose, gelatin, or the like. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used.
경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다.Liquid formulations for oral administration include suspensions, solutions, emulsions, syrups, etc. In addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, and preservatives may be included. have.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조 제제, 좌제 등이 포함될 수 있다. 비수성용제, 현탁제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다.Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Non-aqueous solvents and suspending agents include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate.
본 발명의 약학적 조성물에 포함된 레비스틸라이드 A의 함량은 특별히 제한되지 않는다.The content of levistilide A included in the pharmaceutical composition of the present invention is not particularly limited.
상기 목적을 달성하기 위한 본 발명의 또 다른 실시 양태는 레비스틸라이드 A 또는 이의 식품학적으로 허용 가능한 염을 포함하는 코로나바이러스 감염질환의 예방 또는 개선용 건강기능식품 조성물을 제공한다.Another embodiment of the present invention for achieving the above object provides a health functional food composition for the prevention or improvement of coronavirus infection disease comprising levistilide A or a pharmaceutically acceptable salt thereof.
이때, 상기 “레비스틸라이드 A”, “약학적으로 허용 가능한 염”, “코로나바이러스”, “감염질환” 및 “예방”에 대한 설명은 상기에서 서술한 바와 같다.In this case, the descriptions of “levistilide A”, “pharmaceutically acceptable salt”, “coronavirus”, “infectious disease” and “prevention” are the same as described above.
본 발명에 따른 레비스틸라이드 A는 우수한 코로나바이러스 억제 효과를 나타내므로, 코로나바이러스에 의한 감염질환의 예방 또는 개선을 목적으로 식품 조성물에 포함될 수 있으며, 상기 식품 조성물은 일상적으로 섭취하는 것이 가능하기 때문에 코로나바이러스에 의한 감염의 예방 또는 개선에 대하여 높은 효과를 기대할 수 있다.Since levistilide A according to the present invention exhibits an excellent coronavirus-inhibiting effect, it may be included in a food composition for the purpose of preventing or improving infectious diseases caused by coronavirus, and the food composition can be consumed on a daily basis. A high effect can be expected for prevention or improvement of infection caused by coronavirus.
본 발명의 용어, “개선”은 본 발명에 따른 약학 조성물을 투여로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term “improvement” refers to any action that at least reduces a parameter related to a condition to be treated, for example, the severity of symptoms by administering the pharmaceutical composition according to the present invention.
본 발명의 용어, "건강기능식품"은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 의미하며, '기능성'은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻는 것을 의미한다. 한편, 건강식품은 일반식품에 비해 적극적인 건강유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품은 건강 보조 목적의 식품을 의미하는데, 경우에 따라, 건강기능식품, 건강식품, 건강보조식품의 용어는 혼용될 수 있다.As used herein, the term "health functional food" means a food manufactured and processed using raw materials or ingredients useful for the human body according to Act No. 6727 of the Health Functional Food Act, and 'functionality' refers to the structure of the human body. and regulating nutrients for function or obtaining useful effects for health applications such as physiological action. On the other hand, health food refers to food that has an active health maintenance or promotion effect compared to general food, and health supplement refers to food for the purpose of health supplementation. can be mixed.
본 발명의 레비스틸라이드 A는 그대로 첨가되거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다.The levistilide A of the present invention may be added as it is or used together with other foods or food ingredients, and may be appropriately used according to a conventional method.
본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조 가능하며, 상기 제조 시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 구체적으로, 상기 식품 조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 않으며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다. 또한, 상기 식품 조성물은 방부제, 살균제, 산화방지제, 착색제, 발색제, 표백제, 조미료, 감미료, 향료, 팽창제, 강화제, 유화제, 증점제, 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용될 수 있다.The food of the present invention can be prepared by a method commonly used in the art, and at the time of manufacture, it can be prepared by adding raw materials and components commonly added in the art. Specifically, the food composition may further include a physiologically acceptable carrier, the type of carrier is not particularly limited and any carrier commonly used in the art may be used. In addition, the food composition contains food additives such as preservatives, fungicides, antioxidants, colorants, coloring agents, bleaching agents, seasonings, sweeteners, flavoring agents, expanding agents, strengthening agents, emulsifiers, thickeners, filming agents, gum base agents, foam inhibitors, solvents, and improving agents. may include The additive may be selected according to the type of food and used in an appropriate amount.
또한, 상기 식품의 제형은 식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고 휴대성이 뛰어나므로, 본 발명의 식품은 코로나바이러스에 의한 감염질환의 예방 또는 개선의 효과를 증진시키기 위한 보조제로 섭취가 가능하다.In addition, the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food. The composition for food of the present invention can be prepared in various forms, and unlike general drugs, it has the advantage that there are no side effects that may occur during long-term administration of the drug using food as a raw material, and is excellent in portability, so the present invention Foods of can be consumed as a supplement to enhance the effect of prevention or improvement of infectious diseases caused by coronavirus.
본 발명의 레비스틸라이드 A는 코로나바이러스에 의한 감염질환의 예방 또는 개선 효과를 나타낼 수 있다면 식품조성물에 다양한 중량%로 포함될 수 있다. 구체적으로 식품 조성물의 총 중량 대비 0.00001 내지 100 중량% 또는 0.01 내지 80 중량%로 포함될 수 있으나, 이에 제한되지 않는다. 건강 및 위생을 목적으로 장기간 섭취할 경우에는 상기 범위 이하의 함량을 포함할 수 있으며, 안전성 면에서 아무런 문제가 없기 때문에 유효성분은 상기 범위 이상의 양으로도 사용될 수 있다.The levistilide A of the present invention may be included in various weight % in the food composition if it can exhibit the effect of preventing or improving infectious diseases caused by coronavirus. Specifically, it may be included in an amount of 0.00001 to 100% by weight or 0.01 to 80% by weight relative to the total weight of the food composition, but is not limited thereto. When ingested for a long period of time for health and hygiene purposes, it may contain an amount below the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount above the above range.
상기 목적을 달성하기 위한 본 발명의 또 다른 실시 양태는 레비스틸라이드 A 또는 이의 식품학적으로 허용 가능한 염을 포함하는 코로나바이러스 감염질환의 예방 또는 개선용 사료 조성물을 제공한다.Another embodiment of the present invention for achieving the above object provides a feed composition for preventing or improving a coronavirus infection disease comprising levistilide A or a pharmaceutically acceptable salt thereof.
이때, 상기 “레비스틸라이드 A”, “약학적으로 허용 가능한 염”, “코로나바이러스”,, “감염질환”, “예방” 및 “개선”에 대한 설명은 상기에서 서술한 바와 같다.In this case, the descriptions of “levistilide A”, “pharmaceutically acceptable salt”, “coronavirus”, “infectious disease”, “prevention” and “improvement” are the same as described above.
본 발명에 따른 레비스틸라이드 A는 우수한 코로나바이러스 억제 효과를 나타내므로, 코로나바이러스에 의한 감염질환의 예방 또는 개선을 목적으로 사료 조성물에 포함될 수 있으며, 상기 사료 조성물은 동물이 일상적으로 섭취하는 것이 가능하기 때문에 코로나바이러스에 의한 감염질환의 예방 또는 개선에 대하여 높은 효과를 기대할 수 있다.Since levistilide A according to the present invention exhibits an excellent coronavirus inhibitory effect, it may be included in a feed composition for the purpose of preventing or improving infectious diseases caused by coronavirus, and the feed composition can be routinely consumed by animals. Therefore, a high effect can be expected for the prevention or improvement of infectious diseases caused by coronavirus.
본 발명의 용어, "사료"는 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분을 의미한다.As used herein, the term "feed" means any natural or artificial diet, meal, etc., or a component of said meal, intended for or suitable for eating, ingestion, and digestion by an animal.
상기 사료의 종류는 특별히 제한되지 아니하며, 당해 기술 분야에서 통상적으로 사용되는 사료를 사용할 수 있다. 상기 사료의 비제한적인 예로는, 곡물류, 근과류, 식품 가공 부산물류, 조류, 섬유질류, 제약 부산물류, 유지류, 전분류, 박류 또는 곡물 부산물류 등과 같은 식물성 사료; 단백질류, 무기물류, 유지류, 광물성류, 유지류, 단세포 단백질류, 동물성 플랑크톤류 또는 음식물 등과 같은 동물성 사료를 들 수 있다. 이들은 단독으로 사용되거나 2종 이상을 혼합하여 사용될 수 있다.The type of feed is not particularly limited, and feed commonly used in the art may be used. Non-limiting examples of the feed include plant feeds such as grains, root fruits, food processing by-products, algae, fibers, pharmaceutical by-products, oils and fats, starches, gourds or grain by-products; and animal feeds such as proteins, inorganic materials, oils and fats, minerals, oils and fats, single cell proteins, zooplankton or food. These may be used alone or in mixture of two or more.
본 발명의 레비스틸라이드 A는 메르스-코로나바이러스, 사스-코로나바이러스, 및 사스-코로나바이러스-2와 같은 코로나바이러스의 감염을 억제하는 효과를 나타내므로, 상기 바이러스 질환을 예방 또는 치료를 위한 항바이러스제 개발에 이용될 수 있다.Since levistilide A of the present invention exhibits an effect of inhibiting infection of coronaviruses such as MERS-coronavirus, SARS-coronavirus, and SARS-coronavirus-2, antibacterial agents for preventing or treating the viral diseases It can be used for the development of viral agents.
도 1은 레비스틸라이드 A의 농도에 따른 메르스-코로나바이러스 억제 효능을 나타내는 그래프이다.
도 2는 로피나비어의 농도에 따른 메르스-코로나바이러스 억제 효능을 나타내는 그래프이다.
도 3은 레비스틸라이드 A의 농도에 따른 사스-코로나바이러스 억제 효능을 나타내는 그래프이다.
도 4는 로피나비어의 농도에 따른 사스-코로나바이러스 억제 효능을 나타내는 그래프이다.
도 5는 레비스틸라이드 및 대조군 로피나비어의 중증급성호흡기증후군 코로나바이러스-2(Severe acute respiratory syndrome-related coronavirus 2; SARS-CoV-2)에 대한 용량 의존적 항바이러스 활성을 나타내는 그래프이다.1 is a graph showing the MERS-coronavirus inhibitory efficacy according to the concentration of levistilide A.
2 is a graph showing the MERS-coronavirus inhibitory efficacy according to the concentration of lopinavir.
3 is a graph showing the SARS-coronavirus inhibitory efficacy according to the concentration of levistilide A.
4 is a graph showing the SARS-coronavirus inhibitory efficacy according to the concentration of lopinavir.
5 is a graph showing the dose-dependent antiviral activity of levistilide and the control lopinavir against severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2).
이하, 하기 실시예에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail by way of Examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.
실시예 1: 화합물의 준비Example 1: Preparation of compounds
레비스틸라이드 A(Levistilide A)를 DMSO에 용해시켜 10mM 농도의 원액으로 -80℃에 보관하고, 실험시 2% DMEM 배지를 이용하여 원하는 농도로 희석하여 사용하였다.Levistilide A (Levistilide A) was dissolved in DMSO and stored at -80 ℃ as a stock solution of 10 mM concentration, and used after dilution to the desired concentration using 2% DMEM medium during the experiment.
실시예 2: 메르스-코로나바이러스 감염 억제 확인Example 2: Confirmation of inhibition of MERS-coronavirus infection
실시예 2-1: 세포주 및 바이러스 준비Example 2-1: Cell line and virus preparation
본 발명에 사용한 베로 세포(vero cell)는 American Type Culture Collection (ATCC, CCL-81; Manassas, VA)는 10% 열 불활성화 소 태아 혈청 및 1x Antibiotic-Antimycotic (Gibco/Thermo Fisher Scientific, Waltham, MA)가 포함된 Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea)에 담아 37℃에서 5% 이산화탄소 하에서 배양하였다. 또한, 메르스-코로나바이러스 한국 분리주 (MERS-CoV/KOR/KNIH/002_05_2015, Genbank accession no. KT029139.1 [Kim et al., 2015 doi:10.1128/genomeA.00787-15])를 한국 질병관리본부, 국립보건원으로부터 제공받아, 선행 문헌(Kim et al., 2016 doi:10.1093/cid/ciw239)에 제시된 방법에 따라 vero cell에서 증식하였다. 메르스-코로나바이러스를 사용한 모든 실험은 한국질병관리본부부터 승인 받은 국립보건원의 강화된 생물 안전 등급 3단계 (Biosafety Level 3, BL-3) 봉쇄 절차를 준수한 한국 파스퇴르 연구소에서 수행하였다.The vero cells used in the present invention were obtained from the American Type Culture Collection (ATCC, CCL-81; Manassas, VA) with 10% heat-inactivated fetal bovine serum and 1x Antibiotic-Antimycotic (Gibco/Thermo Fisher Scientific, Waltham, MA). ) containing Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea) and incubated at 37°C under 5% carbon dioxide. In addition, the MERS-coronavirus Korean isolate (MERS-CoV/KOR/KNIH/002_05_2015, Genbank accession no. KT029139.1 [Kim et al., 2015 doi:10.1128/genomeA.00787-15]) was used in the Korea Centers for Disease Control and Prevention. , provided by the National Institutes of Health, and proliferated in vero cells according to the method presented in the prior literature (Kim et al., 2016 doi:10.1093/cid/ciw239). All experiments using MERS-Coronavirus were performed at the Pasteur Institute in Korea in compliance with the National Institutes of Health's enhanced Biosafety Level 3 (BL-3) containment procedures approved by the Korea Centers for Disease Control and Prevention.
실시예 2-2: 면역형광 어세이를 이용한 메르스-코로나바이러스 감염 억제 확인Example 2-2: MERS-Coronavirus infection inhibition confirmation using immunofluorescence assay
본 발명의 레비스틸라이드 A의 메르스-코로나바이러스 감염 억제능을 확인하기 위하여 면역형광 어세이를 이용하여 확인하였다.In order to confirm the MERS-coronavirus infection inhibitory ability of levistilide A of the present invention, it was confirmed using an immunofluorescence assay.
보다 구체적으로, 검은 384-웰 마이크로플레이트에 각 웰당 1.2 x 10⁴베로 세포를 접종하고 L-Glutamine 및 1 × Antibiotic-Antimycotic을 처리하여 24시간동안 37℃, 5% 이산화탄소 조건에서 배양하였다. 24시간 후, DMSO에 녹인 본 발명의 레비스틸라이드 A를 농도별로 첨가한 뒤, 메르스-코로나바이러스에 감염시켰다. 감염 후 24시간 뒤, PFA로 감염을 고정하고 Alexa Fluor 488 및 Hoechst 33342를 사용하여 염색하고, 염색된 세포는 20x 배율의 형광 이미징 시스템으로 이미지화 하여 감염억제율을 확인하였다. 또한, 양성 대조군으로는 로피나비어를 사용하였다.More specifically, 1.2 x 10⁴ Vero cells per well were inoculated in a black 384-well microplate, treated with L-Glutamine and 1 x Antibiotic-Antimycotic, and cultured at 37°C and 5% carbon dioxide for 24 hours. After 24 hours, levistilide A of the present invention dissolved in DMSO was added by concentration, and then infected with MERS-coronavirus. Twenty-four hours after infection, the infection was fixed with PFA, stained using Alexa Fluor 488 and Hoechst 33342, and the stained cells were imaged with a fluorescence imaging system at 20x magnification to confirm the inhibition of infection. In addition, lopinavir was used as a positive control.
그 결과, 도 1 내지 2에서 볼 수 있듯이, 레비스틸라이드 A의 50%의 저해 농도를 나타내는 IC50은 19.472μM이었고, 50%의 세포 독성을 나타내는 CC50은 >100μM인 것으로 측정되었다. 또한, 대조군인 로피나비어의 50%의 저해 농도를 나타내는 IC50은 16.29μM이었고, 50%의 세포 독성을 나타내는 CC50은 >50μM인 것으로 측정되었다.As a result, as shown in FIGS. 1 and 2 , the IC 50 representing the 50% inhibitory concentration of levistilide A was 19.472 μM, and the CC 50 representing 50% cytotoxicity was measured to be >100 μM. In addition, the IC 50 representing the 50% inhibitory concentration of lopinavir as a control was 16.29 μM, and the CC 50 representing 50% cytotoxicity was measured to be >50 μM.
이를 통해, 본 발명의 레비스틸라이드 A가 양성 대조군과 유사하게 효과적으로 메르스-코로나바이러스의 감염을 억제하는 것을 확인하였다. Through this, it was confirmed that levistilide A of the present invention effectively inhibited MERS-coronavirus infection, similar to the positive control.
실시예 3: 사스-코로나바이러스 감염 억제 확인Example 3: Confirmation of SARS-coronavirus infection inhibition
실시예 3-1: 세포주 및 바이러스 준비Example 3-1: Cell line and virus preparation
본 발명에 사용한 베로 세포(Vero cell) 및 베로E6 세포(VeroE6 cell)는 10% 열 불활성화 소 태아 혈청 및 1x 항생제-항진균제(Antibiotic-Antimycotic, Gibco/Thermo Fisher Scientific, Waltham, MA)가 포함된 Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea)에 담아 37℃에서 5% 이산화탄소 하에서 배양하였다. 사스-코로나바이러스 HK39849를 홍콩대학교의 말릭 패리스 박사님으로부터 제공받아 Peiris JS et al., 2003 doi: 10.1016/s0140-6736(03)13077-2 (PMID : 12711465)에 제시된 방법에 따라 베로 E6 세포에서 증식하였다. 사스-코로나바이러스를 사용한 모든 실험은 한국질병관리본부부터 승인 받은 국립보건원의 강화된 생물 안전 등급 3단계 (Biosafety Level 3, BL-3) 봉쇄 절차를 준수한 한국 파스퇴르 연구소에서 수행하였다.Vero cells and VeroE6 cells used in the present invention were prepared with 10% heat-inactivated fetal bovine serum and 1x antibiotic-antimycotic (Gibco/Thermo Fisher Scientific, Waltham, MA). Incubated in Dulbecco's modified Eagle's medium (DMEM; Welgene, Gyeongsan, Korea) at 37°C under 5% carbon dioxide. SARS-coronavirus HK39849 was provided by Dr. Malik Parris of the University of Hong Kong and propagated in Vero E6 cells according to the method presented in Peiris JS et al., 2003 doi: 10.1016/s0140-6736(03)13077-2 (PMID: 12711465). did. All experiments using SARS-coronavirus were performed at the Pasteur Institute in Korea, which complied with the National Institutes of Health's enhanced Biosafety Level 3 (BL-3) containment procedures approved by the Korea Centers for Disease Control and Prevention.
실시예 3-2: 면역형광 어세이를 이용한 사스-코로나바이러스 감염 억제 확인Example 3-2: Confirmation of SARS-coronavirus infection inhibition using immunofluorescence assay
본 발명의 레비스틸라이드 A의 사스-코로나바이러스 억제능을 확인하기 위하여 면역형광 어세이를 이용하여 확인하였다.In order to confirm the SARS-coronavirus inhibitory ability of levistilide A of the present invention, it was confirmed using an immunofluorescence assay.
보다 구체적으로, 검은 384-웰 마이크로플레이트에 각 웰당 1.2 × 10⁴ 베로E6 세포를 접종하고 소 태아 혈청 및 1 × Antibiotic-Antimycotic을 처리하여 24시간동안 37℃, 5% 이산화탄소 조건에서 배양하였다. 24시간 후, 2% DMEM에 녹인 본 발명의 레비스틸라이드 A를 농도별로 첨가한 뒤, 사스-코로나바이러스에 감염시켰다. 감염 후 24시간 뒤, PFA로 감염을 고정하고 Alexa Fluor 488 및 Hoechst 33342를 사용하여 염색하였다. 염색된 세포는 20x 배율의 형광 이미징 시스템으로 이미지화 하여 감염억제율을 확인하였다. 또한, 양성 대조군으로는 로피나비어를 사용하였다.More specifically, 1.2 × 10⁴ Vero E6 cells per well were inoculated into a black 384-well microplate, treated with fetal bovine serum and 1 × Antibiotic-Antimycotic, and cultured at 37°C and 5% carbon dioxide for 24 hours. After 24 hours, levistilide A of the present invention dissolved in 2% DMEM was added by concentration, followed by SARS-coronavirus infection. Twenty-four hours after infection, the infection was fixed with PFA and stained using Alexa Fluor 488 and Hoechst 33342. The stained cells were imaged with a fluorescence imaging system at 20x magnification to confirm the inhibition of infection. In addition, lopinavir was used as a positive control.
그 결과, 도 3 내지 4에서 볼 수 있듯이, 레비스틸라이드 A의 50%의 저해 농도를 나타내는 IC50은 28.241μM이었고, 50%의 세포 독성을 나타내는 CC50은 >100μM인 것으로 측정되었다. 또한, 로피나비어의 50%의 저해 농도를 나타내는 IC50은 16.7μM이었고, 50%의 세포 독성을 나타내는 CC50은 >50μM인 것으로 측정되었다.As a result, as can be seen in FIGS. 3 to 4 , the IC 50 indicating the 50% inhibitory concentration of levistilide A was 28.241 μM, and the CC 50 indicating 50% cytotoxicity was measured to be >100 μM. In addition, the IC 50 representing the 50% inhibitory concentration of lopinavir was 16.7 μM, and the CC 50 representing 50% cytotoxicity was measured to be >50 μM.
이를 통해, 본 발명의 레비스틸라이드 A가 양성 대조군과 유사하게 사스-코로나바이러스를 효과적으로 억제하는 것을 확인하였다.Through this, it was confirmed that levistilide A of the present invention effectively inhibited SARS-coronavirus, similar to the positive control.
실시예 4: 사스-코로나바이러스-2 감염 억제 확인Example 4: Confirmation of SARS-coronavirus-2 infection inhibition
실시예 4-1: 세포주 및 바이러스 준비Example 4-1: Cell line and virus preparation
본 발명에 사용한 베로 세포(Vero cell)는 American Type Culture Collection(ATCC, CCL-81, Manassas, VA)으로부터 구매하여 사용하였으며, 10% 열 불활성화 소태아혈청 및 1×항생제-항진균제(Gibco)가 포함된 DMEM에 담아 37℃에서 5% 이산화탄소 하에서 배양하였다. 사스-코로나바이러스-2(βCoV/KOR/KCDC03/2020)를 한국질병관리본부(Korea Centers for Disease Control and Prevention; KCDC)로부터 제공받아 베로 세포에서 증식시켰다. 바이러스 역가는 베로 세포에서 플라크 어세이에 의해 결정되었다. 사스-코로나바이러스-2를 사용한 모든 실험은 한국질병관리본부부터 승인 받은 국립보건원의 강화된 생물 안전 등급 3단계 (Biosafety Level 3, BL-3) 봉쇄 절차를 준수한 한국 파스퇴르 연구소에서 수행하였다.Vero cells used in the present invention were purchased from the American Type Culture Collection (ATCC, CCL-81, Manassas, VA), and 10% heat-inactivated fetal bovine serum and 1× antibiotic-antifungal (Gibco) were used. It was placed in the included DMEM and incubated at 37°C under 5% carbon dioxide. SARS-coronavirus-2 (βCoV/KOR/KCDC03/2020) was provided from the Korea Centers for Disease Control and Prevention (KCDC) and propagated in Vero cells. Viral titers were determined by plaque assay in Vero cells. All experiments using SARS-coronavirus-2 were performed at the Pasteur Institute in Korea, which complied with the National Institutes of Health's enhanced Biosafety Level 3 (BL-3) containment procedures approved by the Korea Centers for Disease Control and Prevention.
실시예 4-2: 시약 준비Example 4-2: Reagent Preparation
로피나비어 (LPV; S1380)는 SelleckChem(Houston, TX)에서 구매하여, 선별을 위해 DMSO에 용해시켰다. 항-사스-코로나바이러스-2 N 단백질 항체는 Sino Biological Inc.(Beijing, China)로부터 구매하였다. Alexa Fluor 488 goat anti-rabbit IgG (H+L) 이차 항체 및 Hoechst 33342는 MolecularProbes에서 구매하였다. 또한, 32% PFA 수용액과 정상염소 혈청은 각각 Electron Microscopy Sciences(Hatfield, PA) 및 Vector Laboratories, Inc.(Burlingame, CA)에서 구매하였다.Lopinavir (LPV; S1380) was purchased from SelleckChem (Houston, TX) and dissolved in DMSO for selection. Anti-SARS-coronavirus-2 N protein antibody was purchased from Sino Biological Inc. (Beijing, China). Alexa Fluor 488 goat anti-rabbit IgG (H+L) secondary antibody and Hoechst 33342 were purchased from MolecularProbes. In addition, 32% PFA aqueous solution and normal goat serum were purchased from Electron Microscopy Sciences (Hatfield, PA) and Vector Laboratories, Inc. (Burlingame, CA), respectively.
실시예 4-3: 면역형광어세이를 이용한 사스-코로나바이러스-2 감염 억제 확인Example 4-3: Confirmation of SARS-coronavirus-2 infection inhibition using immunofluorescence assay
본 발명의 레비스틸라이드 A의 사스-코로나바이러스-2 억제능을 확인하기 위하여 면역형광어세이를 이용하여 확인하였다.In order to confirm the SARS-coronavirus-2 inhibitory ability of levistilide A of the present invention, it was confirmed using an immunofluorescence assay.
각 시료에 대해 10 포인트 용량 반응 곡선(dose-response curves; DRCs)을 작성하였다. 구체적으로, 검은 색, 384-웰, μClear 플레이트(Greiner Bio-One)에 각 웰당 1.2×104개의 베로 세포를 접종하고 실험에 앞서 24시간 동안 2% 소태아혈청 및 1×항생제-항진균제를 포함하는 DMEM에 배양하였다. 0.05 내지 50 μM의 화합물 농도 범위에서 10 포인트 DRCs를 작성하였다. 바이러스 감염을 위해, 플레이트를 BSL-3 수용 시설로 옮기고, 사스-코로나바이러스-2를 0.0125의 감염다중도(multiplicity of infection; MOI)로 첨가하였다. 감염 후 24시간 뒤(24 hpi), 4% PFA로 세포를 고정하고, 면역형광으로 분석하였다. 세포 수 및 감염율(infection ratio)을 정량하기 위하여, 자체 개발한(in-house) 소프트웨어를 사용하여 획득한 이미지를 분석하였으며, 항-바이러스 활성은 각 어세이 플레이트에서 양성(mock) 및 음성(0.5% DMSO) 대조군에 대해 XLfit 4 소프트웨어 또는 프리즘 7을 사용하여 다음의 방정식으로 정상화하였다:10-point dose-response curves (DRCs) were generated for each sample. Specifically, inoculate 1.2×10 4 Vero cells per well in a black, 384-well, μClear plate (Greiner Bio-One) and contain 2% fetal bovine serum and 1× antibiotic-antifungal for 24 h prior to the experiment. incubated in DMEM. Ten point DRCs were generated in the range of compound concentrations from 0.05 to 50 μM. For viral infection, plates were transferred to a BSL-3 receiving facility and SARS-coronavirus-2 was added at a multiplicity of infection (MOI) of 0.0125. 24 hours after infection (24 hpi), cells were fixed with 4% PFA and analyzed by immunofluorescence. In order to quantify the cell number and infection ratio, the acquired images were analyzed using in-house software, and anti-viral activity was positive (mock) and negative (0.5) in each assay plate. % DMSO) controls were normalized to the following equation using XLfit 4 software or Prism 7:
상기 IC50 값은 정상화된 활성 데어터데이터 세트-최적화된 곡선으로부터 계산되었다. 모든 IC50 및 CC50 값은 중복하여 측정하고, 각 어세이의 퀄리티는 Z'-인자와 변동계수 백분율(coefficient of variation in percent; %CV)로 조절하였다.The IC 50 values were calculated from normalized activity data data set-optimized curves. All IC 50 and CC 50 values were measured in duplicate, and the quality of each assay was adjusted by Z'-factor and coefficient of variation in percent (%CV).
그 결과, 도 5에서 볼 수 있듯이, 레비스틸라이드 A의 50% 저해 농도를 나타내는 IC50은 45.51μM이었고, 50%의 세포 독성을 나타내는 CC50은 >50μM인 것으로 측정되었다. 또한, 대조군인 로피나비어의 IC50은 12.998μM 이었고, CC50은 >50μM인 것으로 측정되었다.As a result, as shown in FIG. 5 , the IC 50 representing the 50% inhibitory concentration of levistilide A was 45.51 μM, and the CC 50 representing 50% cytotoxicity was measured to be >50 μM. Also, the control group lopinavir had an IC 50 of 12.998 μM and a CC 50 of >50 μM.
이를 통해, 본 발명의 레비스틸라이드 A가 양성 대조군에 비해 우수한 사스-코로나바이러스-2 억제 효과를 나타내는 것을 확인하였다.Through this, it was confirmed that the levistilide A of the present invention exhibited an excellent SARS-coronavirus-2 inhibitory effect compared to the positive control.
이상의 설명으로부터, 본 발명이 속하는 기술 분야의 당업자는 본 발명이 그 기술적 사상이나 필수적 특징을 변경하지 않고서 다른 구체적인 형태로 실시될 수 있다는 것을 이해할 수 있을 것이다. 이와 관련하여, 이상에서 기술한 실시 예들은 모든 면에서 예시적인 것이며 한정적인 것이 아닌 것으로서 이해해야만 한다. 본 발명의 범위는 상기 상세한 설명보다는 후술하는 특허 청구범위의 의미 및 범위 그리고 그 등가 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the claims described below and their equivalents.
Claims (5)
[화학식 I]
A pharmaceutical composition for antiviral against coronavirus comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
[Formula I]
The pharmaceutical composition of claim 1, wherein the coronavirus is at least one selected from the group consisting of MERS-coronavirus, SARS-coronavirus, and SARS-coronavirus-2.
[화학식 I]
A pharmaceutical composition for preventing or treating a coronavirus infection disease comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
[Formula I]
[화학식 I]
A health functional food composition for the prevention or improvement of a coronavirus infectious disease comprising a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
[Formula I]
[화학식 I]
[Formula I]
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