KR101934199B1 - Composition for preventing or treating middle east respiratory syndrome-coronavirus (MERS-CoV) infection - Google Patents
Composition for preventing or treating middle east respiratory syndrome-coronavirus (MERS-CoV) infection Download PDFInfo
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Abstract
본 발명은 중동호흡기증후군 코로나바이러스(middle east respiratory syndrome-coronavirus, MERS-CoV)의 파파인 유사 단백질 분해효소(papain-like protease) 억제 활성을 갖는 화합물을 유효성분으로 포함하는 조성물에 관한 것으로, 상기 화합물은 중동호흡기증후군 코로나바이러스의 전사와 복제에 중요한 역할을 하는 파파인 유사 단백질 분해효소의 억제제로서 중동호흡기증후군 코로나바이러스의 예방 또는 치료용 약학 조성물, 또는 중동호흡기증후군 코로나바이러스 예방 또는 개선용 건강식품으로 유용하게 활용될 수 있다.The present invention relates to a composition comprising, as an active ingredient, a compound having a papain-like protease inhibitory activity of a middle east respiratory syndrome-coronavirus (MERS-CoV) Is an inhibitor of papain-like protease that plays an important role in transcription and replication of the Middle East respiratory syndrome coronavirus, and is useful as a pharmaceutical composition for prevention or treatment of coronavirus of the Middle East Respiratory Syndrome or as a health food for preventing or improving coronavirus of the Middle East Respiratory Syndrome .
Description
본 발명은 중동호흡기증후군 코로나바이러스(middle east respiratory syndrome-coronavirus, MERS-CoV)의 파파인 유사 단백질 분해효소(papain-like protease) 억제 활성을 갖는 화합물을 유효성분으로 포함하는 중동호흡기증후군 코로나바이러스 감염증 예방 또는 치료용 조성물에 관한 것이다.The present invention relates to a medicament for preventing respiratory syndrome coronavirus infection in a Middle East respiratory syndrome which comprises a compound having an activity of inhibiting papain-like protease of a middle east respiratory syndrome-coronavirus (MERS-CoV) Or therapeutic compositions.
중동호흡기증후군 코로나바이러스(middle east respiratory syndrome-coronavirus, MERS-CoV)는 중동 지역에서 집중적으로 발생한 바이러스로, 2012년 사우디아라비아에서 처음 발견되었고, 중증급성호흡기증후군 코로나바이러스(severe acute respiratory syndrome-coronavirus, SARS-CoV) 보다 심각한 발병 증상을 나타내어 세계적으로 주목받는 질병 중 하나가 되었다. MERS-CoV는 주로 인간 대 인간을 통해서 감염되며, 고열, 기침, 호흡곤란 등 폐와 전신 질병을 야기하고, 때때로 설사와 구토를 포함한 위장 증상을 나타내기도 한다. MERS-CoV에 감염된 대부분의 환자는 신부전, 당뇨, 심장질환을 겪으며, 연령대에 따라 50%가 넘는 높은 치사율을 보인다. 보고에 따르면, MERS-CoV에 감염된 환자의 평균 연령은 49세이고, 잠복기는 2 내지 11일, 평균 2 내지 13일 사이로 알려져 있다. (MERS-CoV) was first detected in Saudi Arabia in 2012 and is a severe acute respiratory syndrome-coronavirus (MERS-CoV) SARS-CoV) and became one of the world's most notable diseases. MERS-CoV is predominantly infected through human-to-human transmission, causing lung and systemic diseases such as high fever, coughing, and dyspnea, and occasionally gastrointestinal symptoms including diarrhea and vomiting. Most patients infected with MERS-CoV suffer from kidney failure, diabetes and heart disease, with a mortality rate of over 50%, depending on the age group. According to reports, the average age of patients infected with MERS-CoV is 49 years, with a latency of 2 to 11 days, an average of 2 to 13 days.
코로나바이러스는 코로나바이러스 과(coronaviridae family)와 코로나바이러스 아과(coronaviridae subfamily)에 속하는 바이러스로, 포유류 및 조류에 존재하며 α, β, γ 및 δ로 분류된다. 인간 코로나바이러스 SARS-CoV와 MERS-CoV는 β5 속이며, 각각 유전적으로 계통 B와 C에 아형이다. Coronaviruses belong to the coronaviridae family and the coronaviridae subfamily. They are present in mammals and birds and are classified as α, β, γ and δ. The human coronaviruses SARS-CoV and MERS-CoV are in the β5 genus, and are genetically subtype to lines B and C, respectively.
코로나바이러스는 모든 RNA 바이러스(27 내지 32Kb) 중에서 가장 큰 바이러스 게놈(genome)을 갖는 양성 가닥 RNA 바이러스이다. 상기 게놈 RNA는 뉴클레오캡시드(nucleocapsid) 단백질로 커버되고, 폴리아데닐화(polyadenylation)되며, 캡 결합된다. 상기 바이러스는 외피를 보유하고 거대 스파이크(spike) 당단백질을 운반한다. 모든 코로나바이러스는 공통의 게놈 조직을 이용하며, 이 조직에서 복제효소(replicase) 유전자는 상기 게놈에서 5'의 3분의 2를 포함하고, 2개의 중복되는 개방 판독 프레임(open reading frame, ORF)인 ORF1a 및 ORF1b로 구성된다.Corona virus is a positive strand RNA virus with the largest viral genome among all RNA viruses (27 to 32 Kb). The genomic RNA is covered with a nucleocapsid protein, polyadenylated, and capped. The virus retains the envelope and carries a large spike glycoprotein. All coronaviruses utilize a common genomic organization in which the replicase gene contains two thirds of the 5 'in the genome, two overlapping open reading frames (ORFs) ORF1a and ORF1b.
MERS-CoV 게놈은 30,119 뉴클레오타이드(nucleotide)와 11개 개방 판독 프레임을 포함한다. 단일 양성 가닥 RNA 게놈은 각각 278과 300 뉴클레오타이드 길이의 5'와 3' 번역되지 않은 영역(untranslated region, UTRs)을 가진다. 5' 말단은 2개의 다단백질(polyprotein) 1a(pp1a) 및 다단백질 1ab(pp1ab)로 번역되는 2개의 중복되는 개방 판독 프레임 ORF1a 및 ORF1b로 구성된다. 이 다단백질은 2개의 바이러스성 단백질 분해효소인 파파인 유사 단백질 분해효소(papain-like protease, PLpro)와 3CLpro(3C-like protease)의 단백질 분해 활성에 의해 16개의 기능적 비 구조 단백질(nonstructural proteins, NSPs)로 분해된다. MERS-CoV 다단백질의 단백질 분해 과정은 바이러스성 복제 활성을 위해 요구된다.The MERS-CoV genome contains 30,119 nucleotides and 11 open reading frames. The single positive strand RNA genome has 5 'and 3' untranslated regions (UTRs) of 278 and 300 nucleotides in length, respectively. The 5 'terminus consists of two overlapping open reading frames ORF1a and ORF1b translated into two polyprotein 1a (pp1a) and a polyprotein 1ab (pp1ab). This multiprotein is composed of 16 nonstructural proteins (NSPs) by the proteolytic activity of two viral proteases papain-like protease (PLpro) and 3CLpro (3C-like protease) ). Protein degradation of MERS-CoV proteins is required for viral replication activity.
상기 2개의 단백질 분해효소 외에 2개의 ORF는 바이러스성 RNA 의존 RNA 폴리머라제 활성(nsp12), RNA 헬리카제(helicase) 활성(nsp13), 엑소리보뉴클레아제(exoribonuclease) 활성(nsp14) 및 메틸트렌스퍼레이즈 활성(nsp16)에 관여하는 다른 비 구조 단백질을 암호화한다. nsp14는 돌연변이율(mutation rate) 모니터링에 의한 교정에 관여하는 것으로 알려져 있다. ORF1ab의 다운스트림(downstream)에는 구조적 단백질 및 악세서리(accessory) 단백질을 암호화하는 많은 유전자들이 있다. 스파이크(S), 동봉(envelope)(E), 막(membrane)(M) 및 뉴클레오캡시드(N)는 모두 구조적 단백질이며, 악세서리 단백질과 달리 바이러스 계통에 특이적이며, ORF3, ORF4a, ORF4b, ORF5 및 ORF8b에 의해 암호화된다. MERS-CoV는 S 단백질을 통해 CD26 또는 디펩티딜 펩티다제 4(dipeptidyl peptidase 4, DPP4)에 의해서 인식된다. 악세서리 단백질의 기능은 아직 정확하게 알려지지 않았으나, 최근 몇몇 연구에서 숙주 면역 반응을 회피하는 중요한 역할을 하는 것으로 나타났다.In addition to the two proteolytic enzymes, the two ORFs are composed of a viral RNA-dependent RNA polymerase activity (nsp12), an RNA helicase activity (nsp13), an exoribonuclease activity (nsp14) And encodes other nonstructural proteins involved in raising activity (nsp16). nsp14 is known to be involved in the correction by monitoring the mutation rate. Downstream of ORF1ab is a number of genes that encode structural and accessory proteins. Spike (S), envelope (E), membrane (M), and nucleocapsid (N) are all structural proteins, unlike accessory proteins, specific to the viral system and include ORF3, ORF4a, ORF4b, ORF5 and ORF8b. MERS-CoV is recognized by CD26 or dipeptidyl peptidase 4 (DPP4) through the S protein. The function of accessory proteins is not yet known, but recent studies have shown that they play an important role in avoiding host immune responses.
바이러스성 다단백질의 처리 과정은 MERS-CoV의 게놈의 복제와 전사에 관여하기 때문에 성숙한(mature) 단백질의 방출을 위해 필수적이다. 이것은 nsp3와 nsp5에 위치한 2개의 바이러스성 단백질 분해효소인 PLpro 및 3CLpro에 의해 이루어진다. 이 단백질 분해효소는 여러 위치에 pp1a 및 pp1ab를 절단한다. 처음에는 2개의 단백질 분해효소가 자동 단백질 분해 과정에 의해 미숙한 형태로 방출된다. 다단백질의 처리 과정은 바이러스성 성숙을 위해 필수적이기 때문에, MERS-CoV PLpro는 유망한 항바이러스 타켓으로 간주된다. The processing of viral polyproteins is essential for the release of mature proteins because they are involved in the replication and transcription of the genome of MERS-CoV. This is accomplished by two viral proteases, PLpro and 3CLpro, located in nsp3 and nsp5. This protease cleaves pp1a and pp1ab at several positions. Initially, two proteases are released in an immature form by an automatic proteolytic process. Because the processing of multiproteins is essential for viral maturation, MERS-CoV PLpro is considered a promising antiviral target.
오늘날까지 임상적으로 중동호흡기증후군에 대해 승인 받은 약물이 없으며, in silico와 in vitro 방법을 이용하여 PLpro 억제제를 확인하였다. 대부분의 억제제가 기능적 의미(functional significance)를 가지지 않는 시스테인(cysteine) 잔기를 공유결합으로 변형하기 때문에 특징적이지 않아 중동호흡기질환증후군 코로나바이러스 PLpro와 같은 시스테인 단백질 분해효소를 개발하는 것은 많은 어려움이 있는 실정이다.To date, no medicines have been approved clinically for respiratory syndrome in the Middle East, and PLpro inhibitors have been identified using in silico and in vitro methods. Most inhibitors are not characteristic because they transform cysteine residues that do not have functional significance into covalent bonds. Developing cysteine proteases such as the middle respiratory syndrome coronavirus PLpro is difficult. to be.
본 발명의 목적은 파파인 유사 단백질 분해효소(papain-like protease, PLpro) 억제 활성을 갖는 화합물을 유효성분으로 포함하는 중동호흡기증후군 코로나바이러스 감염증 예방 또는 치료용 약학 조성물을 제공하는 데에 있다.It is an object of the present invention to provide a pharmaceutical composition for preventing or treating a coronavirus infectious disease of the Middle East Respiratory Syndrome, which comprises, as an active ingredient, a compound having a papain-like protease (PLpro) inhibitory activity.
본 발명의 또 다른 목적은 파파인 유사 단백질 분해효소 억제 활성을 갖는 화합물을 유효성분으로 포함하는 중동호흡기증후군 코로나바이러스 감염증 예방 또는 개선용 건강식품 조성물을 제공하는 데에 있다.It is another object of the present invention to provide a health food composition for preventing or ameliorating a coronavirus infection of the respiratory tract syndrome of Middle East comprising a compound having a papain-like protease inhibitory activity as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 하기 화학식 1 내지 화학식 5로 표시되는 화합물에서 선택된 하나 이상의 화합물을 유효성분으로 포함하는 중동호흡기증후군 코로나바이러스 감염증 예방 또는 치료용 약학 조성물 및 중동호흡기증후군 코로나바이러스 감염증 예방 또는 개선용 건강식품 조성물을 제공한다:In order to achieve the above object, the present invention provides a medicinal composition for preventing or treating a respiratory syndrome coronavirus infection comprising at least one compound selected from compounds represented by Chemical Formulas 1 to 5 as an active ingredient, and a medicinal composition for preventing respiratory syndrome coronavirus infection Prevention or amelioration of the following diseases:
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
본 발명의 화학식 1 내지 화학식 5로 표시되는 화합물은 중동호흡기증후군 코로나바이러스의 전사와 복제에 중요한 역할을 하는 파파인 유사 단백질 분해효소(papain-like protease, PLpro)의 억제제로서, 파파인 유사 단백질 분해효소를 억제하여 중동호흡기증후군 코로나바이러스의 예방 또는 치료용 약학 조성물, 또는 중동호흡기증후군 코로나바이러스 예방 또는 개선용 건강식품으로 유용하게 활용될 수 있다.The compounds represented by Chemical Formulas 1 to 5 of the present invention are inhibitors of papain-like protease (PLpro), which plays an important role in transcription and replication of the coronavirus of the respiratory syndrome of the Middle East. To prevent or treat coronavirus of the Middle East Respiratory Syndrome, or as a health food for prevention or improvement of coronavirus of the Middle East Respiratory Syndrome.
도 1은 MERS-CoV의 게놈을 도시하여 나타낸 것이다.
도 2는 본 발명의 흐름도로 MERS-CoV PLpro 억제제인 PL-4의 확인 단계를 도시하여 나타낸 것이다.
도 3은 PL-4의 분자 도킹 포즈(molecular docking pose)가 AutoDock Vina를 통해 얻은 MERS-CoV PLpro에 결합하는 것을 보여주는 것으로, 어두운 녹색 점선은 강한 수소결합을 나타낸 것이며, 밝은 녹색 점선은 약한 수소결합을 나타낸 것이다.
도 4는 HEK 293T 세포를 이용하여 후보 화합물에 의한 세포 생존율을 분석한 것으로, HEK 293T 세포에 각 후보 화합물을 농도 별로 처리하여 배양한 후, 490 nm에서 광학 밀도를 측정하여 대조구와 비교한 세포 생존율을 히스토그램으로 나타낸 것이다.
도 5는 HEK 293T 세포를 이용하여 MERS-CoV PLpro에 대한 후보 화합물의 억제 효과를 이중 루시퍼라제 분석(dual luciferase assay)으로 확인한 것이다Figure 1 shows the genome of MERS-CoV.
FIG. 2 is a flow chart of the present invention showing the identification step of PL-4, which is a MERS-CoV PLpro inhibitor.
Figure 3 shows that the molecular docking pose of PL-4 binds to the MERS-CoV PLpro obtained via AutoDock Vina, with the dark green dotted line showing strong hydrogen bonding and the bright green dotted line showing weak hydrogen bonding Lt; / RTI >
FIG. 4 is a graph showing the cell survival rate of candidate compounds using HEK 293T cells. After incubation of HEK 293T cells with each candidate compound in a concentration-dependent manner, the optical density at 490 nm was measured, As a histogram.
FIG. 5 shows the inhibitory effect of candidate compounds on MERS-CoV PLpro using a dual luciferase assay using HEK 293T cells
본 발명에서 사용된 용어 "예방"은 조성물에 의해 중동호흡기증후군 코로나바이러스 감염을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.The term "prophylactic, " as used herein, refers to any action that inhibits or delay the onset of a respiratory syndrome coronavirus infection by a composition.
본 발명에서 사용된 용어 "치료"는 조성물에 의해 중동호흡기증후군 코로나바이러스 감염의 증세가 호전되거나 이롭게 변경하는 모든 행위를 의미한다.The term "treatment" as used herein refers to any action that improves or alleviates symptoms of a respiratory syndrome coronavirus infection by a composition.
본 발명에서 사용된 용어 "MERS-CoV"는 중동호흡기증후군 코로나바이러스로 코로나바이러스 과(coronaviridae family)와 코로나바이러스 아과(coronaviridae subfamily)에 속하는 단일 가닥 RNA의 신종 베타 코로나바이러스이며, 독감, 감기, 인후염, 기관지염 및 폐렴의 질환을 야기하고, 때때로 설사와 구토를 포함한 위장 증상을 나타내는 전신질환을 의미한다. As used herein, the term "MERS-CoV" is a new beta-coronavirus of the single-stranded RNA belonging to the coronaviridae family and the coronaviridae subfamily of the respiratory syndrome coronavirus, , Bronchitis and pneumonia, and occasionally gastrointestinal symptoms including diarrhea and vomiting.
본 발명에서 사용된 용어 "파파인 유사 단백질 분해효소(papain-like protease, PLpro)"는 면역계로부터 바이러스를 은폐하는 역할을 하며, 바이러스의 전사와 복제에 필수적인 단백질들이 하나로 묶인 다단백질을 절단하는 역할을 함으로써 코로나바이러스 제어용 타겟으로 사용된다.As used herein, the term "papain-like protease (PLpro)" plays a role in concealing viruses from the immune system, and plays a role in cleavage of proteins bound together by proteins necessary for transcription and replication of viruses Thereby being used as a target for controlling coronavirus.
본 발명의 스크리닝 방법을 언급하면서 사용되는 용어 "후보 화합물"은 유전자의 발현량에 영향을 미치거나, 단백질의 발현 또는 활성에 영향을 미치는지 여부을 검사하기 위하여 스크리닝에서 이용되는 미지의 후보 물질을 의미한다. 상기 후보 물질은 화합물 및 뉴클레오타이드를 포함하나, 이에 한정되는 것은 아님을 명시한다.The term "candidate compound " used in reference to the screening method of the present invention means an unknown candidate substance used in screening in order to examine whether it affects the expression level of a gene or affects the expression or activity of a protein . Such candidate materials include, but are not limited to, compounds and nucleotides.
본 발명은 하기 화학식 1 내지 화학식 5로 표시되는 화합물에서 선택된 하나 이상의 화합물을 유효성분으로 포함하는 중동호흡기증후군 코로나바이러스 감염증 예방 또는 치료용 약학 조성물을 제공한다. 상세하게는, 상기 화합물은 파파인 단백질 분해효소의 활성을 억제할 수 있다.The present invention provides a pharmaceutical composition for preventing or treating a respiratory syndrome coronavirus infection comprising at least one compound selected from the group consisting of compounds represented by Chemical Formulas 1 to 5 as an active ingredient. Specifically, the compound can inhibit the activity of the papain protease.
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
본 발명의 조성물은 투여를 위하여, 상기 기재한 성분 이외에 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 포함할 수 있다. 상기 담체, 부형제 및 희석제로는 락토오스, 덱스트로오스, 수크로오스, 소르비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오스, 메틸 셀룰로오스, 미정질 셀룰로오스, 폴리비닐피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다.The composition of the present invention may contain, for administration, a pharmaceutically acceptable carrier, excipient or diluent in addition to the components described above. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, microcrystalline cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
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. 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. 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.The pharmaceutical compositions of the present invention may be formulated in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols or the like, oral preparations, suppositories or sterilized injection solutions according to a conventional method have. In detail, when formulating, it can be prepared using diluents or excipients such as fillers, weights, binders, humectants, disintegrants, surfactants and the like which are usually used. Solid form 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 excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like in addition to the active ingredient. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration, liquid paraffin, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and tasks. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. As a base for suppositories, it is possible to use witepsol, macrosole, tween 61, cacao paper, laurin, glycerogelatin and the like.
상기 약학 조성물은 증상 정도에 따라 투여 방법이 결정되는데, 통상적으로는 국소 투여 방식이 바람직하다. 또한, 상기 약학 조성물의 유효성분의 유효량은 질환의 예방 또는 치료 요구되는 양을 의미한다. 따라서, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효 성분 및 다른 성분의 종류 및 함량, 제형의 종류 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료 기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 이에 제한되는 것은 아니나, 예컨대, 성인의 경우, 1일 1회 내지 수회 투여 시, 본 발명의 억제제는 1일 1회 내지 수회 투여 시, 화합물일 경우 0.1 mg/kg~100 mg/kg, 폴리펩타이드, 단백질 또는 항체일 경우 0.1 mg/kg~100 mg/kg, 안티센스 뉴클레오타이드, siRNA, shRNAi, miRNA일 경우 0.1 mg/kg~100 mg/kg의 용량으로 투여할 수 있다. The method of administration of the pharmaceutical composition is determined depending on the severity of symptoms, and local administration is generally preferred. The effective amount of the active ingredient of the above pharmaceutical composition means an amount required for prevention or treatment of the disease. Accordingly, the present invention is not limited to the particular type of the disease, the severity of the disease, the kind and amount of the active ingredient and other ingredients contained in the composition, the type of formulation and the patient's age, body weight, general health status, sex and diet, Rate of administration, duration of treatment, concurrent medication, and the like. For example, in the case of an adult, once to several times a day, the inhibitor of the present invention may be administered at a dose of 0.1 mg / kg to 100 mg / kg for a compound once to several times a day, , 0.1 mg / kg to 100 mg / kg for protein or antibody, 0.1 mg / kg to 100 mg / kg for antisense nucleotide, siRNA, shRNAi and miRNA.
본 발명은 하기 화학식 1 내지 화학식 5로 표시되는 화합물에서 선택된 하나 이상의 화합물을 유효성분으로 포함하는 중동호흡기증후군 코로나바이러스 감염증 예방 또는 개선용 건강식품 조성물을 제공한다. 상세하게는, 상기 화합물은 파파인 단백질 분해효소의 활성을 억제할 수 있다.The present invention provides a health food composition for preventing or ameliorating a respiratory syndrome coronavirus infection comprising at least one compound selected from compounds represented by the following Chemical Formulas (1) to (5) as an active ingredient. Specifically, the compound can inhibit the activity of the papain protease.
[화학식 1][Chemical Formula 1]
[화학식 2](2)
[화학식 3](3)
[화학식 4][Chemical Formula 4]
[화학식 5][Chemical Formula 5]
상기 건강식품 조성물은 분말, 과립, 정제, 캡슐, 시럽 또는 음료의 형태로 제공될 수 있으며, 상기 건강식품 조성물은 상기 유효성분 이외에 다른 식품 또는 식품 첨가물과 함께 사용되고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효성분의 혼합양은 그의 사용 목적 예를 들어 예방, 건강 또는 치료적 처치에 따라 적합하게 결정될 수 있다.The health food composition may be provided in the form of powder, granules, tablets, capsules, syrups or beverages. The health food composition may be used in combination with other food or food additives other than the active ingredient, . The amount of the active ingredient to be mixed can be suitably determined according to its use purpose, for example, prevention, health or therapeutic treatment.
상기 건강식품 조성물에 함유된 유효용량은 상기 약학 조성물의 유효용량에 준해서 사용할 수 있으나, 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 범위 이하일 수 있으며, 유효성분은 안전성 면에서 아무런 문제가 없기 때문에 상기 범위 이상의 양으로도 사용될 수 있음은 확실하다.The effective dose contained in the health food composition may be used in accordance with the effective dose of the pharmaceutical composition, but may be less than the above range for health and hygiene purposes or long-term intake for health control purposes, and may be effective It is clear that the component can be used in an amount of more than the above range since there is no problem in terms of safety.
상기 건강식품의 종류에는 특별한 제한이 없고, 예로는 육류, 소세지, 빵, 초콜릿, 캔디류, 스넥류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알콜 음료 및 비타민 복합제 등을 들 수 있다.There is no particular limitation on the kind of the above health food and examples thereof include dairy products including meat, sausage, bread, chocolate, candy, snack, confectionery, pizza, ramen and other noodles, gums, ice cream, Drinks, alcoholic beverages and vitamin complexes.
또한, 상기 건강식품 조성물은 식품첨가물을 추가로 포함할 수 있으며, 식품첨가물로서의 적합 여부는 다른 규정이 없는 한 식품의약품안전처에 승인된 식품첨가물공전의 총칙 및 일반 시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.In addition, the health food composition may further include a food additive, and the suitability of the food additive as a food additive is not limited to those described in the General Rules and General Test Methods approved by the Food and Drug Administration Standards and standards.
상기 식품첨가물공전에 수재된 품목으로 예를 들어, 케톤류, 글리신, 구연산 칼륨, 니코틴산, 계피산 등의 화학적 합성품, 감색소, 감초추출물, 결정셀룰로오스, 고랭색소, 구아검 등의 천연첨가물, L-글루타민산나트륨 제제, 면류 첨가 알칼리제, 보존료제제, 타르색소 제제 등의 혼합 제제류 등을 들 수 있다.Examples of the above-mentioned food additives include natural products such as ketones, chemical products such as glycine, potassium citrate, nicotinic acid and cinnamic acid, detainable extracts, licorice extracts, crystalline cellulose, high-melting dyes and guar gum, A mixed preparation such as a sodium preparation, a noodle-added alkaline preparation, a preservative preparation, a tar coloring preparation and the like.
이때, 건강식품 조성물을 제조하는 과정에서 식품에 첨가되는 본 발명에 따른 조성물은 필요에 따라 그 함량을 적절히 가감할 수 있다.At this time, the composition according to the present invention, which is added to foods in the course of manufacturing a health food composition, can be appropriately increased or decreased as needed.
이하에서는 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
실시예 1 : PLpro를 억제하는 후보 화합물의 스크리닝Example 1: Screening of candidate compounds inhibiting PLpro
MERS-CoV PLpro 구조(PDB ID: 4RNA)는 가상 스크리닝에 사용되었고, 공동 결정화(co-crystallization) 리간드는 MOE 2013.08를 사용하여 제거되었다. 전체 효소는 스크리닝을 위한 결합 부위로 지정되었다. 리간드는 .mdb 형식으로 저장되었다. 각 리간드의 1000 포즈(pose)에서 가장 좋은 하나의 포즈를 제외하고, 기본 설정으로 화합물을 스크리닝하였다. Yasara에서 실행된 AutoDock(AD) Vina에서 선택된 포즈의 분자 도킹(docking)을 위해, 전체 단백질은 수용체에서 그리드(grid)로 지정되었고, SCE 형식으로 저장되었다. 반면에, 리간드는 PDB 형식으로 변환하여 저장되었다. dock_runscreening 프로토콜을 적용하였고, AMBER03 force field는 입력 구조로 전하를 할당하기 위해 YASARA 구조에서 사용되었다. 각 리간드는 dock_play 프로토콜을 사용하여 100 도킹 실행이 실시되었고, 연관 에너지 값 및 육안 검사에 기초하여 각각의 리간드 분자에 가장 좋은 dock 형태를 검색하였다.The MERS-CoV PLpro structure (PDB ID: 4 RNA) was used for virtual screening and the co-crystallization ligand was removed using MOE 2013.08. The entire enzyme was designated as the binding site for screening. The ligand was stored in .mdb format. Compounds were screened with default settings, except for one best pose at 1000 pose of each ligand. In order to dock the selected pose in the AutoDock (AD) Vina run at Yasara, the entire protein was designated as a grid at the receptor and stored in the SCE format. On the other hand, ligands were converted to PDB format and stored. The dock_runscreening protocol was applied, and the AMBER03 force field was used in the YASARA structure to assign charge to the input structure. Each ligand was subjected to 100 docking runs using the dock_play protocol and retrieved the best dock form for each ligand molecule based on the associated energy values and visual inspection.
MERS-CoV PLpro 효소는 단백질 분해 기능뿐만 아니라 탈-유비퀴틴(de-ubiquitylation) 및 탈-ISGylation(de-ISGylation) 활성을 나타낸다. ISG는 유비퀴틴이나 유비퀴틴 유사 단백질과 비슷한 방법으로 단백질을 변형시키며 이를 ISGylation이라고 부른다. 따라서, 좋은 약동학적 특성을 가지는 MERS-CoV PLpro 억제제와 같은 약물의 개발이 효과적이다. MERS-CoV PLpro의 고해상도 결정 구조에 대한 접근은 억제제를 확인하기 위한 가상 스크리닝을 용이하게 한다. 따라서, 효과적인 PLpro 억제제를 발견하기 위해, 결정 구조를 갖는 화학 라이브러리를 스크리닝할 수 있다. 약물을 설계하고 슈퍼 확산 감염성 질환을 위해 승인을 받는 과정은 적절하지 않다. 즉각적으로 치료에 사용하기 위해, 주로 천연 화합물 (158086)과 FDA 승인된 (2924) 화합물을 스크리닝하였다. 분자가 FDA 승인 약물로부터 PLpro 억제제로서 입증된 경우에는 직접적으로 MERS에 감염된 환자에게 시험될 수 있다. 본 발명에서는 유망한 분자를 분리하기 위해, 분자 도킹은 두 개의 프로그램 MOE 2013.08 및 AD Vina로 수행되었다. 선도 화합물(lead compound) PL-4를 확인하기 위해, MERS-CoV PLpro의 결정 구조 4RNA을 사용하였다. 본 발명의 타켓은 기질 결합 부위 또는 알로스테릭 사이트(allosteric site)에 결합할 수 있는 화합물을 얻는 것이었다. 따라서, 결합 부위로 전체 효소를 설정하고 화합물이 결합하기 위한 결합 영역을 제한하지 않았다. The MERS-CoV PLpro enzyme exhibits de-ubiquitylation and de-ISGylation as well as proteolytic function. ISG modifies proteins in a similar way to ubiquitin or ubiquitin-like proteins and is called ISGylation. Therefore, the development of drugs such as MERS-CoV PLpro inhibitors with good pharmacokinetic properties is effective. The approach to high resolution crystal structure of MERS-CoV PLpro facilitates virtual screening to identify inhibitors. Therefore, in order to find an effective PLpro inhibitor, a chemical library having a crystal structure can be screened. The process of designing drugs and obtaining approval for superfluous infectious diseases is not appropriate. For immediate therapeutic use, we screened predominantly natural compounds (158086) and FDA approved (2924) compounds. If the molecule is proven to be a PLpro inhibitor from an FDA-approved drug, it can be tested directly in patients infected with MERS. In the present invention, to separate promising molecules, molecular docking was performed with two programs MOE 2013.08 and AD Vina. To identify the lead compound PL-4, the
가장 좋은 100 도킹 포즈는 AD Vina로 redock 되었고, 6개의 후보 화합물은 결합점수와 육안 검사에 기초하여 in vitro 실험을 위해 선택되었으며, 이들 후보 화합물의 이차 구조는 하기 표 1에 나열하였다. MERS-CoV PLpro 억제제로 PL-4 화합물과 MERS PLpro의 억제 메카니즘을 확인하였다. MERS-CoV PLpro의 촉매 자리는 Cys111, His278 및 Asp293를 포함하는 세작용기 촉매(catalytic triad)를 포함한다. 기질에 결합하는 MERS-CoV PLpro의 잔기는 Leu106-Tyr112 및 Gly161-Arg168, Phe269-Tyr279, Pro250 및 Thr308이다. AD Vina를 사용하여 분자 도킹을 통해 PL-4의 결합 포즈를 예상하였고, 이를 도 3에 나타내었다. The best 100 docking pose was redocked to AD Vina and six candidate compounds were selected for in vitro experiments based on binding scores and visual inspection and the secondary structure of these candidate compounds is listed in Table 1 below. The inhibitory mechanism of PL-4 compound and MERS PLpro was confirmed by MERS-CoV PLpro inhibitor. The catalytic site of MERS-CoV PLpro includes a catalytic triad comprising Cys111, His278 and Asp293. Residues of MERS-CoV PLpro that bind to the substrate are Leu106-Tyr112 and Gly161-Arg168, Phe269-Tyr279, Pro250 and Thr308. The binding pose of PL-4 was predicted by molecular docking using AD Vina, which is shown in Fig.
실시예Example 2 : 2 : HEKHEK 293T 세포의 형질 전환 Transformation of 293T cells
세포 형질 전환을 위해, HEK 293T 세포는 10% 우태아혈청(fetal bovine serum, FBS), 1% L-글루타민(L-glutamine)을 함유하는 DMEM 배지(dulbecco’s modified eagle’s medium)에서 배양하였다. 형질 전환 실험을 위해, 세포를 24 웰 플레이트(24 well plate) (Thermo Fisher Scientific Inc., Waltham, MA, USA)에서 배양하였고, 세포가 약 80% 포화상태가 되면, TransIT-LT1 transfecting reagent (Mirus Bio LLC., Madison, WI, USA)를 이용하여 제조업체가 제공한 프로토콜을 따라 형질 전환을 수행하였다.For cell transformation, HEK 293T cells were cultured in DMEM medium (dulbecco's modified eagle's medium) containing 10% fetal bovine serum (FBS), 1% L-glutamine. For transfection experiments, cells were cultured in 24-well plates (Thermo Fisher Scientific Inc., Waltham, Mass., USA) and the transIT-LT1 transfecting reagent (Mirus Bio LLC., Madison, Wis., USA) according to the protocol provided by the manufacturer.
실시예Example 3 : 3: PLpro를PLpro 억제하는 후보 화합물의 세포 독성 실험 Cytotoxicity test of candidate compound inhibiting
세포 생존 능력을 측정하기 위해, HEK 293T 세포를 96 웰 플레이트(BD Biosciences. , San Diego, CA, USA)에 하룻밤 배양하고, 화합물을 농도 별로(100 nM, 1 μM, 10 μM, 50 μM) 처리한 다음 24시간 동안 배양하였다. AQueous One Solution Cell Proliferation Assay의 4, 5-dimethylthiazol-2-yl)-5 (3-carboxymethonyphenol)-2-(4-sulfophenyl)-2H-tetrazolium(MTS) (Promega Corporation., Madison WI, USA)를 이용하여 HEK 293T 세포에 MTS 용액을 웰 당 10 μl처리한 후, 3시간 동안 37℃, 5% CO2 인큐베이터에서 배양하였다. 배양 후, 세포 생존율은 마이크로 플레이트 분광 광도계 시스템(Molecular Devices Inc., Sunnyvale, CA, USA)을 이용하여 490 nm에서 측정하였다.HEK 293T cells were cultured overnight in 96-well plates (BD Biosciences., San Diego, Calif., USA) and the compounds were treated at different concentrations (100 nM, 1 μM, 10 μM, 50 μM) And then cultured for 24 hours. 5-dimethylthiazol-2-yl) -5- (3-carboxymethonyphenol) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) (Promega Corporation, Madison Wis., USA) of AQueous One Solution Cell Proliferation Assay HEK 293T cells were treated with 10 μl of MTS solution per well and cultured in a 5% CO 2 incubator at 37 ° C. for 3 hours. After incubation, cell viability was measured at 490 nm using a microplate spectrophotometer system (Molecular Devices Inc., Sunnyvale, Calif., USA).
그 결과, 도 4를 참조하여 보면, 후보 화합물들은 시험 농도에서 세포 독성을 유발하지 않는 것을 확인하였다.As a result, referring to FIG. 4, it was confirmed that the candidate compounds did not cause cytotoxicity at the test concentration.
실시예Example 4 : 4 : PLpro를PLpro 억제하는 후보 화합물의 Of inhibiting candidate compounds PLproPLpro 활성 확인 실험 Activity verification experiment
후보 화합물에 의한 MERS-CoV PLpro의 억제 활성을 확인하기 위해, 2013년 Andy Kilianski 등에 의해 보고된 MERS-CoV PLpro 활동 바이오센서 종료점 분석(biosensor endpoint assay)을 수행하였다. In order to confirm the inhibitory activity of MERS-CoV PLpro by the candidate compound, the MERS-CoV PLpro activity biosensor endpoint assay reported by Andy Kilianski et al. In 2013 was performed.
HEK 293T 세포는 100 ng의 pMERS-CoV PLpro-야생형(WT) 또는 pMERS-CoV PLpro-돌연변이(mutant) 플라스미드(plasmid)와 100 ng의 pGlo-30F-RLKGG와 2 ng의 pRL-TK(Promega, Madison, WI, USA)을 이용하여 형질 전환시켰다. 형질 전환 48시간 후, 세포에 MERS-CoV PLpro의 후보 화합물을 10 μM로 처리하고 24시간 동안 배양하였다. 그 후, 세포는 1X passive lysis buffer(Promega)로 용해시키고, 20 μl의 용해물(lysate)을 이용하여 96 웰 흰색 바닥 플레이트(96 well white bottom plate) (Greiner Bio-One, Frickenhausen, Germany) 및 이중 루시퍼라제 활성화 시약(dual luciferase activationg reatent) (Promega)을 사용하여 MERS-CoV PLpro 활성을 분석하였다.HEK 293T cells were treated with 100 ng of pMERS-CoV PLpro-wild type (WT) or pMERS-CoV PLpro-mutant plasmid, 100 ng of pGlo-30F-RLKGG and 2 ng of pRL-TK (Promega, Madison , WI, USA). Forty-eight hours after the transformation, the cells were treated with 10 μM of the candidate compound of MERS-CoV PLpro and cultured for 24 hours. Cells were then lysed with 1X passive lysis buffer (Promega) and resuspended in 96 well white bottom plates (Greiner Bio-One, Frickenhausen, Germany) using 20 μl of lysate and MERS-CoV PLpro activity was assayed using a dual luciferase activation reagent (Promega).
그 결과, 도 5를 참조하여 보면, PL-4 화합물이 MERS-CoV PLpro 활성을 약 73% 억제하는 것을 확인하였다. 세포주에서 실험한 PL-5는 SARS-CoV PLpro 및 MERS-CoV PLpro에 대한 이중 억제제이지만 어떠한 억제 활성도 보이지 않았다. PL-4는 첫 번째 MERS-CoV PLpro 억제제로 카나마이신(kanamycin)이라고 불리는 FDA 승인된 약이며, 이 약은 박테리아 스트렙토 마이세스(Streptomyces)로부터 추출한 약물로 필수 의약품의 세계 보건기구(world health organization, WHO) 목록에 있다. As a result, referring to FIG. 5, it was confirmed that the PL-4 compound inhibits MERS-CoV PLpro activity by about 73%. PL-5, which was tested in cell lines, was a double inhibitor against SARS-CoV PLpro and MERS-CoV PLpro but showed no inhibitory activity. PL-4, the first MERS-CoV PLpro inhibitor, is an FDA-approved drug called kanamycin. It is a drug extracted from the bacterium Streptomyces and used by the world health organization WHO ) Is on the list.
이상으로 본 발명의 특정한 부분을 상세히 기술한 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
본 발명의 범위는 후술하는 특허청구범위에 의하여 나타내어지며, 특허청구범위의 의미 및 범위 그리고 그 균등 개념으로부터 도출되는 모든 변경 또는 변형된 형태가 본 발명의 범위에 포함되는 것으로 해석되어야 한다.The scope of the present invention is defined by the appended claims, and all changes or modifications derived from the meaning and scope of the claims and their equivalents should be construed as being included within the scope of the present invention.
Claims (4)
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
[화학식 1]
[화학식 2]
[화학식 3]
[화학식 4]
[화학식 5]
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
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