KR20190070629A - A composition for preventing or treating MERS-CoV virus comprising HBD2 (human beta-defensin 2) or an fusion protein comprising epitope protein of MERS-CoV virus and the HBD2L - Google Patents
A composition for preventing or treating MERS-CoV virus comprising HBD2 (human beta-defensin 2) or an fusion protein comprising epitope protein of MERS-CoV virus and the HBD2L Download PDFInfo
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Abstract
Description
본 발명은 HBD2(human beta-defensin 2) 또는 상기 유전자와 융합된 메르스 바이러스의 에피토프 단백질을 포함하는 메르스 코로나바이러스의 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to a composition for the prophylaxis or treatment of mars coronavirus comprising human beta-defensin 2 (HBD2) or an epitope protein of mers virus fused with the gene.
백신은 자연 감염을 모방하여 특이적인 후천성 면역반응을 유도할 수 있어야하는데, 일반적으로 약독화 생백신 또는 사백신의 경우에는 pathogen-cell wall product 등 병원체 유래 물질들이 병원체-연관 분자패턴(pathogen-associated molecular pattern, PAMP)으로 작용하여 병원체 침입에 대하여 1 차적으로 반응하는 선천면역을 유도하며, 아울러 후천성 면역반응을 유도할 수 있는 내인성 보조제를 포함하고 있다. 그러나 재조합 단백질을 기반으로 하는 항원백신의 경우에는 이러한 선천면역 유도체가 내제되어 있지 않은 상태로, 효과적으로 항원특이적인 면역반응을 유도하기 위하여 선천 면역을 활성화 시켜 숙주의 방어면역을 활성화 시켜 숙주의 방어면역을 유도하는데 도움을 줄 수 있는 백신 보조제로서 면역 중강제가 필요하다. Vaccines should be able to mimic natural infections and induce a specific acquired immune response. In the case of attenuated live vaccines or vaccines, pathogen-associated molecular patterns of pathogen-cell wall products, such as pathogen-cell wall products, , PAMP) to induce innate immunity, which primarily responds to pathogen invasion, as well as an endogenous adjuvant that can induce acquired immune response. However, in the case of an antigen vaccine based on a recombinant protein, these innate immunity derivatives are not incorporated, and in order to induce an antigen-specific immune response effectively, innate immunity is activated, thereby activating the defense immunity of the host, Immunostimulant is needed as a vaccine adjuvant that can help to induce.
HBD2(human beta-defensin 2)는 사람의 점액성 표피세포와 대식세포에서 주로 발현되는 항균 펩타이드 중 하나로, 이들 펩타이드 항균물질은 자연 분해가 잘 되어 인체에서나 자연계에 잔류성의 위험이 없는 환경 친화적인 항생물질로 기존 항생제를 대체할 새로운 후보물질로 활발하게 연구가 진행되고 있다. 지금까지 곤충, 갑각류, 양서류, 포유동물 식물 및 세균 등으로부터 약 500여종의 발견되었고, 디펜신은 사람 및 포유동물 유래의 항균 펩타이드 중 대표적인 물질로 병원균의 침입을 막아주는 선천성 면역시스템의 일부로 알려졌다. HBD2 (human beta-defensin 2) is one of the antimicrobial peptides mainly expressed in mucous epidermal cells and macrophages of humans. These peptide antimicrobial substances are environmentally friendly antibiotics Research is actively underway as a new candidate to replace conventional antibiotics as a substance. So far, about 500 species have been found from insects, crustaceans, amphibians, mammalian plants, and bacteria. Diphencin is a representative of antimicrobial peptides derived from humans and mammals, and is known to be part of a congenital immune system that prevents pathogens from entering.
메르스(MERS, 중동호흡기증후군)는 잠복기가 1주일가량이며 발열을 동반한 기침, 호흡곤란, 숨 가쁨, 가래 등 호흡기 증상을 주로 보이며 그 이외에도 두통, 오한, 콧물, 근육통뿐만 아니라 식욕부진, 메스꺼움, 구토, 복통, 설사 등 소화기 증상도 나타날 수 있다. 다만 사스와는 달리 급성 신부전증을 동반한다. 사스보다 치사율 이 6배가량 높다는 조사 결과가 나오기도 하는 등 더 치명적인 양상을 보이고 있다. 연령대에 따라 치사율은 50%가 넘는다. 현재까지 중동호흡기증후군 바이러스 치료를 위한 항바이러스 제는 개발되지 않았고 증상에 대한 치료를 위주로 하게 되며 중증의 경우 인공호흡기나 인공혈액투석 등을 받아야 되는 경우도 있다. 명확한 감염원과 감염경로는 확인되지 않았으나, 중동 지역의 낙타와의 접촉을 통해 감염될 가능성이 높고 사람 간 밀접접촉에 의한 전파가 가능하다고 보고되었다. MERS-CoV는 코로나바이러스 중에서 베타코로나바이러스의 일종으로, 유전자 길이는 다양하지만 약 30 kb에 해당 하며, 11개의 ORF(open reading frame)를 지닌다. MERS-CoV의 구조 단백질은 S(spike), E(envelope), M(matrix) 및 NP(nucleocapsid) 단백질이 존재한다. MERS (MERS, respiratory syndrome) has a latency period of about 1 week. It has respiratory symptoms such as cough, dyspnea, shortness of breath and sputum with fever. In addition to headache, chills, runny nose, muscle aches, , Vomiting, abdominal pain, diarrhea and other symptoms of digestive problems may also occur. Unlike SARS, acute renal failure is accompanied. There are also reports that the death rate is six times higher than that of SARS. The mortality rate is over 50% depending on the age group. Until now, antiviral agents for the treatment of respiratory syndrome virus in the Middle East have not been developed and the treatment of symptoms is mainly focused. In some cases, it is necessary to receive artificial respiration or artificial hemodialysis. Although clear infectious agents and routes of infection have not been identified, it has been reported that contact with camelids in the Middle East is highly likely to be transmitted and possible to spread by close contact between humans. MERS-CoV is a type of beta-coronavirus among coronaviruses. It has a gene length of about 30 kb and 11 open reading frames (ORFs). The structural proteins of MERS-CoV are S (spike), E (envelope), M (matrix) and NP (nucleocapsid) proteins.
이러한 배경 하에서, 본 발명자들은 HBD2(human beta-defensin 2)의 항바이러스 활성, 선천면역의 증진 및 면역 증가제 효과를 연구 노력한 결과, HBD2(human beta-defensin 2)이 IFN-β, IFN-γ, TNF-α, CXCL-10, IL-1β, IL-6, MCP-1, MIP-1α, PANTES 등 특이적인 면역반응 유도에 필요한 선천면역반응을 유도됨을 확인하였고, 염증성 사이토카인의 발현을 유도하고 host defense에 중요한 viral pattern recognition receptor로 생각되고 있는 NOd2와 RNA viruses의 증식 억제에 관여한다고 알려진 MxA, PKR, RNase L도 증가하는 되는 것을 확인하였다. 나아가, HBD2(human beta-defensin 2)를 메르스 코로나바이러스의 숙주세포 수용체에 결합하는 부위인 S-RBD에 융합하여 처리한 결과, S-RBD 단독 사용 시와 비교하여 HBD2에 의한 항원 특이적인 항체 증가 및 anti-body mediated inbition assay를 통하여 유도된 항체의 메르스 바이러스 방어능을 확인하였다. 상기의 결과들을 통해, HBD2(human beta-defensin 2)가 항바이러스 활성, 선천면역의 증진 및 면역증가제 효과를 확인함으로서, 본 발명을 완성하였다. Under these circumstances, the inventors of the present invention have found that HBD2 (human beta-defensin 2) inhibits IFN-β, IFN-γ , TNF-α, CXCL-10, IL-1β, IL-6, MCP-1, MIP-1α and PANTES and induces the expression of inflammatory cytokines PKR and RNase L, which are known to be involved in the inhibition of NOd2 and RNA viruses, which are thought to be important viral pattern recognition receptors in host defense, are also increased. Furthermore, as a result of the fusion treatment with S-RBD, a site that binds to the host cell receptor of mers coronavirus, HBD2 (human beta-defensin 2) was treated with HBD2 antigen-specific antibody And anti-body mediated inbition assays. The above results confirmed that HBD2 (human beta-defensin 2) has antiviral activity, innate immunity enhancement and immunity enhancer effect, thus completing the present invention.
본 발명은 상기와 같은 문제점을 해결하기 위하여 안출된 것으로, 본 발명자들은 HBD2(human beta-defensin 2)를 이용하여 항 바이러스 활성, 선천면역의 증진 및 면역증가제 효과를 확인함으로써, 본 발명을 완성하였다. Disclosure of the Invention The present invention has been conceived to solve the above-mentioned problems. The present inventors have completed the present invention by confirming the antiviral activity, innate immunity enhancement and immunity enhancer effect using HBD2 (human beta-defensin 2) Respectively.
상기와 같은 본 발명의 과제를 달성하기 위해서, 본 발명 HBD2 (human beta-defensin 2)를 포함하는 선천면역 증진, 또는 바이러스 감염에 대한 예방 또는 치료용 약학 조성물을 제공하는 것이다. In order to achieve the object of the present invention, there is provided a pharmaceutical composition for preventing or treating congenital immune enhancement or virus infection comprising HBD2 (human beta-defensin 2).
상기 바이러스는 메르스 코로나 바이러스(MERS-CoV virus)일 수 있다. The virus may be MERS-CoV virus.
상기 HBD2는 서열번호 1의 아미노산 서열을 포함하는 것을 특징으로 할 수 있다. The HBD2 may be characterized in that it comprises the amino acid sequence of SEQ ID NO: 1.
본 발명은 또 다른 목적을 달성하기 위해, HBD2 (human beta-defensin 2)를 포함하는 선천면역 증진, 또는 바이러스 감염에 대한 예방 또는 개선용 건강기능식품 조성물을 제공한다. In order to accomplish still another object of the present invention, there is provided a health functional food composition for preventing or ameliorating congenital immune enhancement or viral infection comprising HBD2 (human beta-defensin 2).
상기 바이러스는 메르스 코로나 바이러스(MERS-CoV virus)일 수 있다. The virus may be MERS-CoV virus.
상기 HBD2는 서열번호 1의 아미노산 서열을 포함하는 것을 특징으로 할 수 있다. The HBD2 may be characterized in that it comprises the amino acid sequence of SEQ ID NO: 1.
본 발명은 다른 목적을 달성하기 위해, 서열번호 2의 아미노산 서열로 구성되는 메르스 코로나 바이러스 에피토프 단백질을 제공한다. In order to achieve another object, the present invention provides a mammalian coronavirus epitope protein consisting of the amino acid sequence of SEQ ID NO: 2.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 에피토프을 포함하는 메르스 코로나 바이러스의 항원을 제공한다. In order to achieve another object, the present invention provides an antigen of a mars coronavirus comprising the epitope described above.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 에피토프 단백질을 암호화하는 유전자를 포함하는 재조합 벡터를 제공한다. In order to achieve another object, the present invention provides a recombinant vector comprising a gene encoding the epitope protein described above.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 재조합 벡터로 형질전화된 형질전화체를 제공한다. In order to achieve another object, the present invention provides a transgenic transformed plant transformed with the above-mentioned recombinant vector.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 형질전환체의 단백질 추출물 또는 상기 형질전화체로 부터 분리된 재조합 메르스 코로나 바이러스 에피토프 단백질을 포함하는 메르스 코로나 바이러스 감염에 대한 예방 또는 치료용 약학적 조성물을 제공한다. In order to accomplish another object of the present invention, there is provided a pharmaceutical composition for preventing or treating a corn virus infection comprising a protein extract of the above-mentioned transformant or a recombinant mars coronavirus epitope protein isolated from the transformant Lt; / RTI >
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 술한 형질전환체의 단백질 추출물 또는 상기 형질전화체로 부터 분리된 재조합 메르스 코로나 바이러스 에피토프 단백질을 포함하는 메르스 코로나 바이러스 감염에 대한 예방 또는 개선용 건강기능식품조성물을 제공한다. In order to accomplish another object of the present invention, there is provided a pharmaceutical composition for preventing or ameliorating a mors coronavirus infection comprising a protein extract of the transformant described above or a recombinant maize coronavirus epitope protein isolated from the transformant Functional food composition.
본 발명의 HBD2(human beta-defensin 2)이 IFN-β, IFN-γ, TNF-α, CXCL-10, IL-1β, IL-6, MCP-1, MIP-1α, PANTES 등 특이적인 면역반응 유도에 필요한 선천면역반응을 유도하고, 염증성 사이토카인의 발현을 유도하고 host defense에 중요한 viral pattern recognition receptor로 생각되고 있는 NOd2와 RNA viruses의 증식 억제에 관여한다고 알려진 MxA, PKR, RNase L도 증가시키며, HBD2(human beta-defensin 2)를 메르스 코로나바이러스의 숙주세포 수용체에 결합하는 부위인 S-RBD에 융합하여 처리한 결과, S-RBD 단독 사용 시와 비교하여 HBD2에 의한 항원 특이적인 항체 증가 및 anti-body mediated inbition assay를 통하여 유도된 항체의 메르스 바이러스 방어하는 효과를 가진다. 즉 HBD2(human beta-defensin 2)는 항바이러스 활성, 선천면역의 증진 및 면역증가제 효과가 있다.The present invention relates to the use of the human beta-defensin 2 (HBD2) as a specific immune response such as IFN- ?, IFN- ?, TNF- ?, CXCL-10, IL-1 ?, IL-6, MCP-1, MIP- Induces the innate immune response necessary for induction, induces the expression of inflammatory cytokines, and increases MxA, PKR, and RNase L, which are known to be involved in the proliferation inhibition of NOd2 and RNA viruses, which are thought to be important viral pattern recognition receptors for host defense , And S-RBD, a site that binds to the host cell receptor of mers coronavirus HBD2 (human beta-defensin 2). As a result, compared to S-RBD alone, HBD2- And an anti-body mediated inbition assay. In other words, HBD2 (human beta-defensin 2) has antiviral activity, innate immunity enhancement and immunity enhancement effect.
도 1은 본 발명의 항원 단백질(MERS-CoV S-RBD)에 HBD2가 융합된 유전자 염기서열 및 구조이다.
도 2는 본 발명의 HBD2에 의한 항원(MERS-CoV S-RBD) 특이적인 면역반응의 결과이다.
도 3은 본 발명의 HBD2에 의하여 유도된 중화항체 반응 및 바이러스 반어능을 확인한 결과이다.
도 4은 본 발명의 HBD2에 의하여 항바이러스 면역반응과 연계된 선천면역 증가효과를 확인 결과이다. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a gene sequence and structure in which HBD2 is fused to an antigen protein (MERS-CoV S-RBD) of the present invention.
Figure 2 shows the results of an antigen (MERS-CoV S-RBD) specific immune response by HBD2 of the present invention.
FIG. 3 shows the result of confirming the neutralizing antibody reaction and the virus hemolytic activity induced by HBD2 of the present invention.
FIG. 4 shows the results of confirming the concomitant immunity increase effect associated with the antiviral immune response by the HBD2 of the present invention.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명의 목적은 상기와 같은 본 발명의 과제를 달성하기 위해서, 본 발명은 HBD2 (human beta-defensin 2)를 포함하는 선천면역 증진, 또는 바이러스 감염에 대한 예방 또는 치료용 약학적 조성물을 제공한다. In order to accomplish the object of the present invention, the present invention provides a pharmaceutical composition for preventing or treating congenital immune enhancement or viral infection comprising HBD2 (human beta-defensin 2) .
본 발명의 서열번호 1의 아미노산 서열로 구성되는 HBD2는 개체의 선천면역을 증가시켜 바이러스의 감염 및 증식을 억제하는 효과가 있을 뿐만 아니라, 세포 독성이나 부작용을 거의 나타내지 않으므로 장기간 복용시에도 안심하고 사용할 수 있는 것을 특징으로 한다. 병원체의 감염 시 선천 면역의 방어 기작의 하나로 면역 인자가 분비되는데, 이들 면역 인자들(TNF-α, IL-6 및 IFN-β)의 분비가 병원체를 방어하므로, 적정한 수준의 사이토카인의 반응 유도는 다양한 전염병 병원체에 대한 예방 및 치료 방법이 될 수 있다. 특히 바이러스에 대한 면역력을 증강시킬 수 있는 것이다. The HBD2 consisting of the amino acid sequence of SEQ ID NO: 1 of the present invention increases the innate immunity of the individual to inhibit infection and proliferation of the virus, and exhibits little cytotoxicity or side effects. Therefore, . The secretion of these immune factors (TNF-α, IL-6, and IFN-β) protects the pathogen, so that the appropriate level of cytokine induction Can be a preventive and therapeutic method for various infectious pathogens. In particular, it can strengthen the immunity against viruses.
본 발명의 선천면역 증진 및 약학 조성물은 약학적으로 허용 가능한 담체, 부형제 또는 희석제를 더 포함할 수 있다. 본 발명에 이용될 수 있는 약학적으로 허용 가능한 담체, 부형제 또는 희석제는 본 발명의 효과를 해하지 않는 한 특별히 제한되지 않으며, 예를 들어 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제, 윤활제, 감미제, 방향제, 보존제 등을 포함할 수 있다. 약학적으로 허용 가능한 담체, 부형제 또는 희석제의 대표적인 예로는, 락토즈, 덱스트로스, 슈크로스, 솔비톨, 만니톨, 자일리톨, 말티톨, 전분, 젤라틴, 글리세린, 아카시아 고무, 알지네이트, 칼슘포스페이트, 칼슘카보네이트, 칼슘실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로즈, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트, 광물유, 프로필렌글리콜, 폴리에틸렌글리콜, 식물성 오일, 주사가능한 에스테르, 위텝솔, 마크로골, 트윈 61, 카카오지, 라우리지 등을 들 수 있다. 본 발명의 선천면역 증진 및 항바이러스용 약학 조성물은 정제, 환제, 산제, 과립제, 캡슐제, 현탁액, 에멀젼, 시럽제, 에어로졸, 외용제, 좌제 및 주사제로 이루어진 군으로부터 선택되는 형태일 수 있다. 약학 조성물의 제제화 방법은 기술 분야에 공지된 통상의 방법에 따라 수행될 수 있으며, 특별히 제한되지 않는다. The congenital immunosuppressive and pharmaceutical compositions of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent. The pharmaceutically acceptable carrier, excipient or diluent which can be used in the present invention is not particularly limited so long as the effect of the present invention is not impaired. For example, a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, Flavoring agents, fragrances, preservatives, and the like. Representative examples of pharmaceutically acceptable carriers, excipients or diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, maltitol, starch, gelatin, glycerin, acacia rubber, alginate, calcium phosphate, calcium carbonate, calcium Methylcellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, propylene glycol, polyethylene glycol, vegetable oil, injectable Ester, witepsol, macrogol, tween 61, cacao paper, and laurie paper. The pharmaceutical composition for congenital immunity enhancement and antiviral of the present invention may be in the form of a tablet, a pill, a powder, a granule, a capsule, a suspension, an emulsion, a syrup, an aerosol, a external preparation, a suppository and an injection. The method of preparing the pharmaceutical composition may be performed according to a conventional method known in the art, and is not particularly limited.
본 발명의 선천면역 증진 및 약학 조성물은 경구 또는 비경구 투여될 수 있으며, 투여량은 투여 대상의 연령, 성별, 체중, 상태, 질병의 정도, 약물의 형태, 투여 경로 및 기간에 따라 적절히 선택될 수 있으나, 일반적으로 약 5~500㎎/㎏, 바람직하게는 약 100~250㎎/㎏을 1일 1~3회 투여할 수 있다.The concomitant immunoconjugation and pharmaceutical composition of the present invention may be administered orally or parenterally. The dose may be appropriately selected according to the age, sex, weight, condition, degree of disease, drug form, However, in general, about 5 to 500 mg / kg, preferably about 100 to 250 mg / kg, can be administered one to three times a day.
본 발명의 선천면역 증진 및 약학 조성물의 제제화 방법, 투여량, 투여 경로, 구성성분 등은 기술분야에 공지된 통상의 기술로부터 적절히 선택될 수 있음이 통상의 기술자에게 명백하다. It is apparent to those skilled in the art that the method of enhancing congenital immunity and formulation of a pharmaceutical composition of the present invention, the dosage, route of administration, constituents, etc., can be appropriately selected from conventional techniques known in the art.
본 발명의 선천면역 증진 및 약학 조성물은 박테리아 감염성 질병 또는 바이러스 감염성 질병의 예방 및 치료에 이용될 수 있다. 본 발명의 선천면역 증진 및 항바이러스용 약학 조성물은 유효 성분으로 구맥 추출물 외에 다른 약학적 활성 성분을 함께 포함하거나, 또는 다른 유효 성분을 포함하는 약학 조성물과 혼합되어 이용될 수 있다. The congenital immunity enhancing and pharmaceutical composition of the present invention can be used for the prevention and treatment of bacterial infectious diseases or viral infectious diseases. The pharmaceutical composition for congenital immunity enhancement and antiviral use of the present invention may be used as an active ingredient in combination with a pharmacologically active ingredient in addition to the tofu extract or a pharmaceutical composition containing other effective ingredient.
본 발명의 바람직한 일실시예에 따르면 상기 바이러스는 메르스 코로나 바이러스(MERS-CoV virus)일 수 있다. According to a preferred embodiment of the present invention, the virus may be MERS-CoV virus.
본 발명의 바람직한 일실시예에 따르면 상기 HBD2는 서열번호 1의 아미노산 서열을 포함하는 것을 특징으로 할 수 있다. According to a preferred embodiment of the present invention, the HBD2 comprises the amino acid sequence of SEQ ID NO: 1.
본 발명은 다른 목적을 달성하기 위해, HBD2 (human beta-defensin 2)를 포함하는 선천면역 증진, 또는 바이러스 감염에 대한 예방 또는 개선용 건강기능식품 조성물을 제공한다. The present invention provides a health functional food composition for preventing or improving congenital immune enhancement or viral infection comprising HBD2 (human beta-defensin 2).
발명의 바람직한 일실시예에 따르면 상기 바이러스는 메르스 코로나 바이러스(MERS-CoV virus)일 수 있다. According to a preferred embodiment of the present invention, the virus may be MERS-CoV virus.
본 발명의 바람직한 일실시예에 따르면 상기 HBD2는 서열번호 1의 아미노산 서열을 포함하는 것을 특징으로 할 수 있다. According to a preferred embodiment of the present invention, the HBD2 comprises the amino acid sequence of SEQ ID NO: 1.
본 발명의 선천면역 증진 및 건강기능식품은 식품학적으로 허용가능한 식품 보조 첨가제를 더 포함할 수 있다. 본 발명에 이용될 수 있는 식품학적으로 허용가능한 식품 보조 첨가제는 포도당, 과당, 말토오스, 슈크로스, 덱스트린, 시클로덱스트린과 같은 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당 알코올과 같은 천연 탄수화물, 타우마틴, 스테비아 추출물 등의 천연 향미제, 사카린, 아스파르탐산 등의 합성 향미제, 착색제, 펙트산 또는 그의 염, 알긴산 또는 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산화제 등을 포함하나, 이에 제한되는 것은 아니다. 본 발명의 선천면역 증진 및 항바이러스용 건강기능식품은 분말, 과립, 정제, 캡슐, 캔디, 츄잉검, 젤리 및 음료로 이루어진 군으로부터 선택되는 형태일 수 있다. 선천면역 증진 및 항바이러스용 건강기능식품 중의 구맥 추출물의 함량은 식품의 형태, 풍미, 맛 등을 고려하여 적절하게 선택될 수 있으며, 예를 들어 건강기능식품 전체 중량에 대하여 0.01~30 중량%의 범위일 수 있다. 본 발명의 선천면역 증진 및 항바이러스용 건강기능식품의 형태, 조성 및 제조방법 등은 기술분야에 공지된 통상의 기술로부터 적절히 선택될 수 있음이 통상의 기술자에게 명백하다.The congenital immunosuppressive and health functional food of the present invention may further comprise a pharmaceutically acceptable food-aid additive. Food-acceptable food supplementary additives that may be used in the present invention include sugars such as glucose, fructose, maltose, sucrose, dextrin, cyclodextrins, natural carbohydrates such as sugar alcohols such as xylitol, sorbitol and erythritol, , Natural flavor such as stevia extract, synthetic flavor such as saccharin and aspartame, colorant, pectic acid or its salt, alginic acid or its salt, organic acid, protective colloid thickener, pH adjusting agent, Alcohols, carbonates, and the like. The congenital immunity enhancing and antiviral health functional food of the present invention may be in a form selected from the group consisting of powder, granule, tablet, capsule, candy, chewing gum, jelly and beverage. The content of the tofu extract in the health functional food for congenital immunity enhancement and antiviral treatment can be appropriately selected in consideration of the form, flavor, taste, etc. of the food, and for example, 0.01 to 30% by weight Lt; / RTI > It is apparent to those of ordinary skill in the art that the form, composition and manufacturing method of the health functional food for congenital immunity enhancement and antiviral of the present invention can be appropriately selected from conventional techniques known in the art.
본 발명의 바람직한 일실시예에 따르면 상기 바이러스는 메르스 코로나 바이러스(MERS-CoV virus)일 수 있다. According to a preferred embodiment of the present invention, the virus may be MERS-CoV virus.
본 발명은 다른 목적을 달성하기 위해, 서열번호 2의 아미노산 서열로 구성되는 메르스 코로나 바이러스 에피토프 단백질을 제공한다. In order to achieve another object, the present invention provides a mammalian coronavirus epitope protein consisting of the amino acid sequence of SEQ ID NO: 2.
본 발명에서 용어, 메르스 코로나 바이러스(MERS-CoV)는 베타코로나바이러스의 하나로서, MERS-CoV 게놈은 계통 발생적으로 clade A, clade B, 두 clades로 분류되는데, 초기 MERS 사례들은 clade A 였고(EMC/2012 and Jordan-N3/2012), 새로 보고된 사례들은 유전적으로 별개인 clade B이다. 유전자 길이는 다양하지만 약 30 kb에 해당 하며, 11개의 ORF(open reading frame)를 지닌다. MERS-CoV의 구조 단백질은 S(spike), E(envelope), M(matrix) 및 NP(nucleocapsid) 단백질이 존재한다. 이 바이러스는 베로 세포(Vero cell)와 히말라야원숭이 신장세포 프로키네티신2수용체(LLC-MK2 cells)에서 쉽게 성장한다.In the present invention, the term Mers-CoV (MERS-CoV) is a beta-coronavirus, and the MERS-CoV genome is phylogenetically classified as clade A, clade B and clades. EMC / 2012 and Jordan-N3 / 2012), the newly reported cases are genetically distinct clades B. Although the gene length varies, it corresponds to about 30 kb and has 11 open reading frames (ORFs). The structural proteins of MERS-CoV are S (spike), E (envelope), M (matrix) and NP (nucleocapsid) proteins. The virus grows easily in Vero cells and in Himalayan monkey
본 발명에서 용어, "에피토프"는 특정 항체에 의해 인식되는 항원결합부위의 아미노산 잔기 세트, 또는 T 세포에서는 T 세포 수용체 단백질 및/또는 주요 조직적합성 복합체 (Major Histocompatibility Complex, MHC)수용체에 의해 인식되는 잔기이다. 에피토프는 항체, T 세포 수용체 또는 HLA에 의해 인식되는 부위를 형성하는 분자로, 일차, 이차 및 삼차 펩티드 구조, 또는 전하를 의미한다.As used herein, the term "epitope" refers to a set of amino acid residues of an antigen binding site recognized by a particular antibody, or a T cell receptor protein and / or major histocompatibility complex (MHC) Lt; / RTI > An epitope is a molecule that forms a site recognized by an antibody, T cell receptor or HLA, and refers to a primary, secondary and tertiary peptide structure, or charge.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 에피토프을 포함하는 메르스 코로나 바이러스의 항원을 제공한다. In order to achieve another object, the present invention provides an antigen of a mars coronavirus comprising the epitope described above.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 에피토프 단백질을 암호화하는 유전자를 포함하는 재조합 벡터를 제공한다. In order to achieve another object, the present invention provides a recombinant vector comprising a gene encoding the epitope protein described above.
본 발명에서 용어, "재조합"은 세포가 이종의 핵산을 복제하거나, 상기 핵산을 발현하거나 또는 펩티드, 이종의 펩티드 또는 이종의 핵산에 의해 암호화된 단백질을 발현하는 세포를 지칭하는 것이다. 재조합 세포는 상기 세포의 천연 형태에서는 발견되지 않는 유전자 또는 유전자 절편을, 센스 또는 안티센스 형태 중 하나로 발현할 수 있다. 또한 재조합 세포는 천연 상태의 세포에서 발견되는 유전자를 발현할 수 있으며, 상기 유전자는 변형된 것으로써 인위적인 수단에 의해 세포 내 재도입된 것이다.As used herein, the term "recombinant" refers to a cell in which a cell replicates a heterologous nucleic acid, expresses the nucleic acid, or expresses a protein encoded by a peptide, heterologous peptide or heterologous nucleic acid. The recombinant cell can express a gene or a gene fragment that is not found in the natural form of the cell in one of the sense or antisense form. In addition, the recombinant cell can express a gene found in a cell in a natural state, and the gene has been re-introduced into the cell by an artificial means as a modification.
본 발명에서 용어, "벡터"는 숙주 세포로 염기의 클로닝 및/또는 전이를 위한 임의의 매개물을 말한다. 벡터는 다른 DNA 단편이 결합하여 결합된 단편의 복제를 가져올 수 있는 복제단위 (replicon)일 수 있다. "복제단위"란 생체 내에서 DNA 복제의 자가 유닛으로서 기능하는, 즉, 스스로의 조절에 의해 복제가능한, 임의의 유전적 단위 (예를 들면, 플라스미드, 파지, 코스미드, 염색체, 바이러스)를 말한다. 용어 "벡터"는 시험관 내, 생체 외 또는 생체 내에서 숙주 세포로 염기를 도입하기 위한 바이러스 및 비 바이러스 매개물을 포함한다.As used herein, the term "vector" refers to any medium for cloning and / or transfer of a base into a host cell. A vector can be a replicon that can bring about the replication of a joined fragment of another DNA fragment. Refers to any genetic unit (e.g., a plasmid, phage, cosmid, chromosome, or virus) that functions in vivo as an autologous unit of DNA replication, that is, . The term "vector" includes viral and non-viral mediators for introducing a base into a host cell in vitro, in vitro or in vivo.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 재조합 벡터로 형질전화된 형질전화체를 제공한다. In order to achieve another object, the present invention provides a transgenic transformed plant transformed with the above-mentioned recombinant vector.
본 발명에서 용어, “형질전환”은 외부로부터 주어진 DNA에 의하여 생물의 유전적인 성질이 변하는 것으로, 즉 생물의 어떤 계통의 세포에서 추출된 핵산의 일종인 DNA를 다른 계통의 살아있는 세포의 주었을 때 DNA가 그 세포에 들어가서 유전형질이 변화하는 현상으로 형질변환 형전환 또는 형변환 등이라고도 한다. 본 발명에서 용어, “형질전환체”는 형질전환으로 인해 생성된 형질전환식물 또는 형질전환동물을 의미하며, 유전자 재조합 기술을 이용하여 특정 유전자의 변형 또는 변이가 유발되어 생성된 유전자재조합체를 포함한다.The term " transformed " in the present invention means that the genetic properties of an organism are changed by exogenously given DNA, that is, DNA, which is a kind of nucleic acid extracted from a cell of a certain line of an organism, Is introduced into the cell and the genetic trait is changed, which is also referred to as transformation or transformation. In the present invention, the term " transformant " refers to a transgenic plant or a transgenic animal produced by transformation, and includes a gene recombinant produced by inducing transformation or mutation of a specific gene using a gene recombination technique do.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 형질전환체의 단백질 추출물 또는 상기 형질전화체로 부터 분리된 재조합 메르스 코로나 바이러스 에피토프 단백질을 포함하는 메르스 코로나 바이러스 감염에 대한 예방 또는 치료용 약학적 조성물을 제공한다. In order to accomplish another object of the present invention, there is provided a pharmaceutical composition for preventing or treating a corn virus infection comprising a protein extract of the above-mentioned transformant or a recombinant mars coronavirus epitope protein isolated from the transformant Lt; / RTI >
본 발명의 용어, "감염의 예방 또는 치료용 조성물"은 생체에 면역을 주는 항원을 함유한 생물학적인 제제로서, 감염증의 예방을 위하여 사람이나 동물에 주사하거나 경구 투여함으로써 생체에 면역이 생기게 하는 면역원 또는 항원성 물질인 백신 조성물 또는 약학적 조성물이 포함 될 수 있다. The term "composition for the prevention or treatment of infection" of the present invention is a biological agent containing an antigen that immunizes a living body. In order to prevent infection, an immunogen Or a vaccine composition or a pharmaceutical composition which is an antigenic substance.
본 발명에서 용어, “예방”은 본 발명의 메르스 코로나 바에러스의 에피토프 단백질을 발현하는 형질전환체 또는 상기 형질전환체를 유효성분으로 하는 조성물의 투여로 상기 메르스 코로나 바이러스 감염을 억제 또는 지연시키는 모든 행위를 말한다.The term " prophylactic " in the present invention refers to the administration of a transformant expressing the epitope protein of Mers coronavirus of the present invention, or a composition comprising the transformant as an active ingredient, It refers to all the acts that you do.
본 발명에서 용어, “치료”는 본 발명의 메르스 코로나바이러스 에피토프 단백질을 발현하는 형질전환체 또는 상기 형질전환체를 유효성분으로 하는 조성물의 투여로 상기 메르스 코로나바이러스의 감염 증상이 호전되거나 이롭게 되는 모든 행위를 말한다.In the present invention, the term " treatment " refers to the administration of a transformant expressing the mers coronavirus epitope protein of the present invention or a composition comprising the transformant as an active ingredient to ameliorate or prevent the infection symptoms of the corn virus All activities that
“면역원” 또는 “항원성 물질”은 펩티드, 폴리펩티드, 상기 폴리펩티드를 발현하는 유산균, 단백질, 상기 단백질을 발현하는 유산균, 올리고뉴클레오티드, 폴리뉴클레오티드, 재조합 박테리아 및 재조합 바이러스로 구성된 군에서 선택된 어느 하나인 것을 특징으로 할 수 있다. 구체적인 예를 들면, 상기 항원 물질은 불활성화된전체 또는 부분 세포 제제 형태, 또는 통상적인 단백질 정제, 유전 공학 기법 또는 화학 합성에 의해 수득되는 항원 분자 형태일 수 있다.An "immunogen" or "antigenic substance" is any one selected from the group consisting of a peptide, a polypeptide, a lactic acid bacterium expressing the polypeptide, a protein, a lactic acid bacterium expressing the protein, an oligonucleotide, a polynucleotide, a recombinant bacterium and a recombinant virus . As a specific example, the antigenic substance may be in the form of an inactivated whole or partial cytostatic form, or an antigenic molecule obtained by conventional protein purification, genetic engineering techniques or chemical synthesis.
본 발명의 서술한 형질전환체의 단백질 추출물 또는 상기 형질전화체로 부터 분리된 재조합 메르스 코로나 바이러스 에피토프 단백질을 포함하는 메르스 코로나 바이러스 감염에 대한 예방 또는 치료용 약학적 조성물은 각각의 사용 목적에 맞게 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁제, 에멀젼, 시럽, 에어로졸 등의 경구 제형, 멸균 주사용액의 주사제 등 다양한 형태로 제형화하여 사용할 수 있으며, 경구 투여하거나 정맥 내, 복강 내, 피하, 직장, 국소 투여 등을 포함한 다양한 경로를 통해 투여될 수 있다.The pharmaceutical composition for preventing or treating a mers coronavirus infection comprising the protein extract of the transformant described in the present invention or the recombinant mars coronavirus epitope protein isolated from the transformant may be used for each purpose The composition can be formulated into various forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and the like, injections of sterilized injection solutions according to a conventional method, and they can be administered orally, intravenously, Intravenous, intramuscular, subcutaneous, intramuscular, subcutaneous, rectal, topical, and the like.
이러한 약학적 조성물에는 추가적으로 담체, 부형제 또는 희석제 등이 더 포함될 수 있으며, 포함될 수 있는 적합한 담체, 부형제 또는 희석제의 예로는 락토오스, 덱스트로오스, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리쓰리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로스, 메틸 셀룰로스, 비정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 들 수 있다. 또한, 본 발명의 약학적 조성물은 충전제, 항응집제, 윤활제, 습윤제, 향료, 유화제, 방부제 등을 추가로 더 포함할 수도 있다.Such pharmaceutical compositions may further comprise carriers, excipients or diluents, and examples of suitable carriers, excipients or diluents that may be included include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, But are not limited to, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, amorphous cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, And the like. In addition, the pharmaceutical composition of the present invention may further include a filler, an anti-coagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent, an antiseptic, and the like.
본 발명의 유효 성분은 약제학적으로 유효한 양으로 투여한다. 본 발명에서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료 기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 약학적 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고, 종래의 치료제와 순차적으로 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The active ingredient of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, The sensitivity to the drug, the time of administration, the route of administration and the rate of release, the duration of the treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 약학적 조성물에서 유효성분의 유효량은 환자의 나이, 성별, 체중에 따라 달라질 수 있으며, 일반적으로는 체중 ㎏ 당 1 내지 5,000mg, 바람직하게는 100 내지 3,000mg을 매일 또는 격일 투여하거나 1일 1 내지 3회로 나누어 투여할 수 있다. 그러나, 투여 경로, 질병의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.The effective amount of the active ingredient in the pharmaceutical composition of the present invention may vary depending on the age, sex, and body weight of the patient. Generally, 1 to 5,000 mg, preferably 100 to 3,000 mg per kg of body weight is administered daily or every other day or 1 It may be administered one to three times a day. However, the dosage may not be limited in any way because it may be increased or decreased depending on route of administration, severity of disease, sex, weight, age, and the like.
본 발명의 약학적 조성물은 다양한 경로를 통하여 대상에 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관 내(intracerebroventricular) 주사에 의해 투여될 수 있다.The pharmaceutical composition of the present invention can be administered to a subject through various routes. All modes of administration may be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intra-uterine or intracerebroventricular injections.
본 발명에서 "투여"는 임의의 적절한 방법으로 환자에게 소정의 물질을 제공하는 것을 의미하며, 본 발명의 약학적 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 일반적인 모든 경로를 통하여 경구 또는 비경구 투여될 수 있다. 또한, 본 발명의 조성물은 유효성분을 표적 세포로 전달할 수 있는 임의의 장치를 이용해 투여될 수도 있다.In the present invention, "administration" means providing a predetermined substance to a patient by any suitable method, and the administration route of the pharmaceutical composition of the present invention is either oral or non-oral May be administered orally. The composition of the present invention may also be administered using any device capable of delivering an effective ingredient to a target cell.
본 발명에서 "대상"은, 특별히 한정되는 것은 아니지만, 예를 들어, 인간, 원숭이, 소, 말, 양, 돼지, 닭, 칠면조, 메추라기, 고양이, 개, 마우스, 쥐, 토끼 또는 기니아 피그를 포함하고, 바람직하게는 포유류, 보다 바람직하게는 인간을 의미한다.In the present invention, the term "object" includes, but is not limited to, human, monkey, cow, horse, sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig , Preferably a mammal, more preferably a human.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 형질전환체의 단백질 추출물 또는 상기 형질전화체로 부터 분리된 재조합 메르스 코로나 바이러스 에피토프 단백질을 포함하는 메르스 코로나 바이러스 감염에 대한 예방 또는 개선용 건강기능식품조성물을 제공한다.In order to accomplish another object of the present invention, there is provided a pharmaceutical composition comprising the protein extract of the above-mentioned transformant or a health function for prevention or improvement against a mars coronavirus infection comprising a recombinant mars coronavirus epitope protein isolated from the transformant To provide a food composition.
본 발명의 유효성분을 포함하는 식품으로는, 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강보조, 식품류 등이 있고, 분말, 과립, 정제, 캡슐 또는 음료인 형태로 사용할 수 있다.Examples of foods containing the active ingredient of the present invention include various foods, beverages, gums, tea, vitamin complexes, health supplements and foods, and they can be used in powder, granule, tablet, have.
본 발명의 유효성분은 일반적으로 전체 식품 중량의 0.01 내지 15중량%로 가할 수 있으며, 건강 음료 조성물은 100ml를 기준으로 0.02 내지 10g, 바람직하게는 0.3 내지 1g의 비율로 가할 수 있다.The active ingredient of the present invention may generally be added in an amount of 0.01 to 15% by weight of the total food, and the health beverage composition may be added in a proportion of 0.02 to 10 g, preferably 0.3 to 1 g, based on 100 ml.
본 발명의 건강 기능 식품은 지시된 비율로 필수 성분으로서 상기 유효성분을 함유하는 것 외에 식품학적으로 허용 가능한 식품보조 첨가제, 예컨대, 천연 탄수화물 및 다양한 향미제 등을 추가 성분으로서 함유할 수 있다.The health functional food of the present invention may contain, as an essential ingredient, the above-mentioned active ingredient in a prescribed ratio, as well as a food-acceptable food supplementary additive such as natural carbohydrate and various flavoring agents as an additional ingredient.
상기 천연 탄수화물의 예로는 포도당, 과당 등의 단당류, 말토오스, 수크로오스 등의 이당류 및 덱스트린, 시클로덱스트린 등의 다당류와 같은 통상적인 당 및 자일리톨, 소르비톨, 에리쓰리톨 등의 당알코올이 있다.Examples of the natural carbohydrate include sugar sugars such as glucose, monosaccharides such as fructose, disaccharides such as maltose and sucrose, polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol.
상기 향미제로는 타우마틴, 레바우디오시드 A 또는 글리시르히진과 같은 스테비아 등의 천연 향미제 및 사카린, 아스파르탐 등의 합성 향미제를 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강 기능 식품 100ml 당 일반적으로 약 1 내지 20g, 바람직하게는 약 5 내지 12g을 사용한다. 상기 외에 본 발명의 건강 기능 식품은 여러 가지 영양제, 비타민, 광물, 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 그 밖에 본 발명의 건강 기능 식품은 천연 과일 주스 및 과일 주스 음료 및 야채 음료 등의 제조를 위한 과육을 함유할 수도 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 본 발명의 유효성분 100중량부 당 0.01 내지 약 20중량부의 범위에서 선택되는 것이 일반적이다.Examples of the flavoring agents include natural flavoring agents such as tautatin, rebaudioside A and stiglycerin such as glycyrrhizin, and synthetic flavoring agents such as saccharin and aspartame. The ratio of the natural carbohydrate is generally about 1 to 20 g, preferably about 5 to 12 g per 100 ml of the health functional food of the present invention. In addition to the above, the health functional food of the present invention may contain various kinds of nutrients, vitamins, minerals, flavors such as synthetic flavors and natural flavors, colorants and heavy stabilizers, pectic acid and its salts, alginic acid and its salts, Thickening agents, pH adjusting agents, stabilizers, preservatives, glycerin, alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the health functional food of the present invention may contain flesh for producing natural fruit juice, fruit juice drink, vegetable drink and the like. These components may be used independently or in combination. The ratio of such additives is generally selected in the range of 0.01 to about 20 parts by weight per 100 parts by weight of the active ingredient of the present invention.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 형질전환체의 단백질 추출물 또는 상기 형질전화체로 부터 분리된 재조합 메르스 코로나 바이러스 에피토프 단백질을 포함하는 메르스 코로나 바이러스 감염에 대한 예방 또는 개선용 화장료 조성물을 제공한다. In order to accomplish another object of the present invention, there is provided a cosmetic composition for preventing or improving a mors coronavirus infection comprising the protein extract of the above-mentioned transformant or the recombinant mars coronavirus epitope protein isolated from the transformant .
본 발명에 따른 화장료 조성물은 첨가제를 추가로 포함할 수 있다. 첨가제의 종류는 특별히 제한되는 것은 아니나, 예를 들면, 유분, 물, 계면활성제, 보습제, 저급알코올, 살균제, 산화방지제, 증점제, 킬레이트제, 색소, 방부제 및 향료 중 어느 하나 이상일 수 있다. 이러한 첨가제들은 필요에 따라 적절한 함량으로 배합하여 사용할 수 있다. The cosmetic composition according to the present invention may further comprise an additive. The kind of the additive is not particularly limited, but may be at least one of, for example, oil, water, a surfactant, a moisturizer, a lower alcohol, a bactericide, an antioxidant, a thickener, a chelating agent, a pigment, a preservative and a perfume. These additives may be used in an appropriate amount as required.
본 발명은 다른 목적을 달성하기 위해, 상기 서술한 형질전환체의 단백질 추출물 또는 상기 형질전화체로 부터 분리된 재조합 메르스 코로나 바이러스 에피토프 단백질을 포함하는 메르스 코로나 감염에 대한 예방 또는 치료용 의약외품 조성물 제공한다. In order to accomplish another object of the present invention, there is provided a quasi-drug composition for preventing or treating a cornea infection comprising a protein extract of the above-mentioned transformant or a recombinant maize coronavirus epitope protein isolated from the transformant do.
이하에서는 실시예를 통하여 본 발명을 더욱 상세하게 설명한다. 하기 실시예는 본 발명의 바람직한 일 구체예일 뿐이며, 본 발명의 권리범위가 하기 실시예의 범위로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail by way of examples. The following examples are only exemplary embodiments of the present invention, and the scope of the present invention is not limited to the scope of the following examples.
실험예 1 : HBD2에 의한 항원(MERS-CoV S-RBD) 특이적인 면역반응 증가 EXPERIMENTAL EXAMPLE 1: Antigen (MERS-CoV S-RBD) -specific Immune Response Increase by HBD2
재조합 항원 단백질을 확보하기 위하여 메르스 바이러스의 spike protein(GenBank: AKL59401.1)의 RBD(residues 291-725) 부위의 c-terminal에 HBD2(서열번호 1 : N- GIGDPVTCLK SGAICHPVFC PRRYKQIGTC GLPGTKCCKK P -C )가 융합된 gene construct (서열번호 2 : N- KYYSIIPHSI RSIQSDRKAW AAFYVYKLQP LTFLLDFSVD GYIRRAIDCG FNDLSQLHCS YESFDVESGV YSVSSFEAKP SGSVVEQAEG VECDFSPLLS GTPPQVYNFK RLVFTNCNYN LTKLLSLFSV NDFTCSQISP AAIASNCYSS LILDYFSYPL SMKSDLSVSS AGPISQFNYK QSFSNPTCLI LATVPHNLTT ITKPLKYSYI NKCSRLLSDD RTEVPQLVNA NQYSPCVSIL PSTVWEDGDY YRKQLSPLEG GGWLVASGST VAMTEQLQMG FGITVQYGTD TNSVCPKLEF ANDTKIASQL GNCVEYSLYG VSGRGVFQNC TAVGVRQQRF VYDAYQNLVG YYSDDGNYYC LRACVSVPVS VIYDKETKTH ATLFGSVACE HISSTMSQYS RSTRSMLKRR DSTYGPLQTP VGCVLGLVNS SLFVE -C)을 제작하여 pCold II bactrial expression system에서 발현시킨 다음, N-terminal의 His tag을 기반으로 Ni-NTA Superflow (Qiagen, Valencia, CA)를 사용하여 재조합 항원 단백질을 확보하였다 (도 1). HBD2에 의한 항원(MERS-CoV S-RBD) 특이적인 면역반응 증가를 확인하기 위하여 Freund's complete adjuvant와 함께 각 항원 단백질 10ug씩을 6주-8주령의 암컷 C57BL/6 마우스의 꼬리와 뒷다리에 피하와 근육 주사 10일 후, Freund's incomplete adjuvant와 섞은 각 항원 단백질로 boost한 다음 3일 후 각 마우스로부터 serum sample을 확보하여 항원 특이적인 면역반응과 neutralizing 항체 반응을 확인하였다 (도 2). ELISA를 기반으로 antigen-specific antibody binding assay를 수행하여 MERS-CoV S-RBD-specific antibody responses를 확인하였다. 96-well ELISA plate를 S-RBD 단백질(2 μg/ml)로 4 °C에서 overnight으로 coating한 다음, 5% non-fat milk로 37 °C에서 2시간 동안 blocking한 후 각 serum을 희석하여 37 °C에서 1시간 동안 처리하고 PBST로 세척하고 AP-conjugated anti-mouse IgG(1:7,000, Sigma-Aldrich)를 37 °C에서 1시간 동안 처리 후 pNPP substrate를 처리하여 405nm (A405)에서 absorbance를 측정하였다. 그 결과 S-RBD(단독 항원)만 접종했을 때 보다 HBD-2 conjugated S-RBD(항원 단백질(S-RBD)의 C-terminal에 HDB2가 융합된 제조합 단백질)의 경우 항원 특이적 면역 반응 유도능이 높은 것을 확인 하였다 (도 2). (SEQ ID NO: 1: N-GIGDPVTCLK SGAICHPVFC PRRYKQIGTC GLPGTKCCKKP-C) at the c-terminal of the RBD (residues 291-725) region of the spike protein of Mers virus (GenBank: AKL59401.1) the fused gene construct (SEQ ID NO: 2: N- KYYSIIPHSI RSIQSDRKAW AAFYVYKLQP LTFLLDFSVD GYIRRAIDCG FNDLSQLHCS YESFDVESGV YSVSSFEAKP SGSVVEQAEG VECDFSPLLS GTPPQVYNFK RLVFTNCNYN LTKLLSLFSV NDFTCSQISP AAIASNCYSS LILDYFSYPL SMKSDLSVSS AGPISQFNYK QSFSNPTCLI LATVPHNLTT ITKPLKYSYI NKCSRLLSDD RTEVPQLVNA NQYSPCVSIL PSTVWEDGDY YRKQLSPLEG GGWLVASGST VAMTEQLQMG FGITVQYGTD TNSVCPKLEF ANDTKIASQL GNCVEYSLYG VSGRGVFQNC TAVGVRQQRF VYDAYQNLVG YYSDDGNYYC LRACVSVPVS VIYDKETKTH ATLFGSVACE HISSTMSQYS RSTRSMLKRR DSTYGPLQTP VGCVLGLVNS SLFVE-C) was constructed and expressed in the pCold II bactrial expression system, and then the recombinant antigen protein was obtained using Ni-NTA Superflow (Qiagen, Valencia, CA) based on the His tag of N-terminal And (Fig. 1). In order to confirm the increase of HBsAg-specific antigen (MERS-CoV S-RBD) specific immune response, 10 ug of each antigen protein with Freund's complete adjuvant was subcutaneously injected into the tail and hind legs of female C57BL / After 10 days of injection, each antigen protein mixed with Freund's incomplete adjuvant was boosted. After 3 days, a serum sample was obtained from each mouse to confirm antigen-specific immune response and neutralizing antibody response (FIG. 2). MERS-CoV S-RBD-specific antibody responses were confirmed by ELISA-based antigen-specific antibody binding assay. The 96-well ELISA plate was coated overnight at 4 ° C with S-RBD protein (2 μg / ml), blocked with 5% non-fat milk at 37 ° C for 2 hours, (1: 7,000, Sigma-Aldrich) at 37 ° C for 1 h and then treated with pNPP substrate for absorbance at 405 nm (A405). Respectively. As a result, in case of HBD-2 conjugated S-RBD (combination protein in which HDB2 is fused to the C-terminal of antigen protein (S-RBD)) than when S-RBD (single antigen) was inoculated alone, antigen-specific immune response induction (Fig. 2).
실험예 2 : HBD2에 의하여 유도된 중화항체 반응 및 메르스 바이러스 방어능 확인Experimental Example 2: Neutralizing antibody reaction induced by HBD2 and confirmation of mers virus defense ability
HBD2에 의하여 유도된 면역반응의 메르스 바이러스에 대한 방어능을 확인하기 위하여 MERS-CoV(KCDC,1-001-MER-IS-2015001)의 propagation에 사용된 Vero E6 세포와 메르스 바이러스의 host cell receptor인 hDPP4를 발현하는 Huh-7, (KCLB No. 60104)을 기반으로 in vitro에서 neutralization assay를 수행하였다. receptor binding-inhibition assay를 위하여 각 serum을 1:50으로 희석하여 1 μg의 S-RBD protein과 pre-incubation한 후 4% paraformaldehyde로 고정한 Huh-7 cells에 처리한 다음 Penta-His antibody-Alexa Fluor 488(1:100, Qiagen)을 사용하여 기관내 CURF의 CLSM(LSM 510, Carl Zeiss, Thornwood, NY, USA)로 receptor에 binding한 항원 단백질을 비교 분석 수행하였다. 그 결과 HBD-2 conjugated S-RBD의 접종 후 확보한 serum을 처리한 세료에서 MERS-CoV의 S-RBD protein의 DPP4 특이적인 결합이 현저하게 억제되는 것을 확인하였다 (도 3A). 각각 serum의 중화능을 확인하기 위하여 Vero E6 세포에 메르스 바이러스를 감염 시킨 후 세포에 감염된 viral RNA의 양을 upstream E gene을 target으로 하여 qRT-PCR을 통하여 분석하였다. 먼저 각 serum을 1:100으로 희석하여 103 PFU의 메르스 바이러스와 pre-incubation한 후 Vero E6 cells(1×106 cells)에 처리한 다음, 24시간 후 Tri REAGENT (Sigma, Saint Quentin Fallavier, France)을 사용하여 total RNA를 추출하였다. 각 1 μg의 total RNA를 기반으로 M-MLV Reverse Transcriptase(Promega, Charbonnieres, France)를 사용하여 cDNA를 합성하고, power SYBR Green PCR mastermix(Applied Biosystems, Woolston, Warrington, UK)과 ABI 7500 real-time PCR system을 사용하여 qRT-PCR을 수행하였다. Target인 upstream E gene과 함께 endogenous control로 Vero E6 β-actin gene을 사용하였다. 본 실험에 사용한 upstream E gene의 primer 염기서열은 F: 5'-GCCTCTACACGGGACCCATA-3'과 R: 5'-GCAACGCGCGATTCAGTT-3'이고 Vero E6 β-actin gene의 primer 염기서열은 F: 5'-ATCGTGCGTGACATTAAGGAG-3'과 R: 5'-AGGAAGGAAGGCTGGAAGAG-3'이다. Amplification condition은 95 ℃에서 10 min activation 후 95 ℃에서 15s, 55 ℃에서 30s, 72 ℃에서 30s씩 40 amplification cycles 수행 후 7500 software(v2.3)을 사용하여 Real-time data 분석하였다. HBD-2 conjugated S-RBD에 의하여 유도된 항원 특이적인 항체에 의하여 MERS-CoV의 infection이 저해되는 것을 확인하였다 (도 3B). Vero E6 cells used for propagation of MERS-CoV (KCDC, 1-001-MER-IS-2015001) and host cells of Mers virus were used to confirm the ability of HBD2-induced immune response against Mers virus neutralization assay was performed in vitro based on Huh-7 (KCLB No. 60104) expressing the receptor hDPP4. For the receptor binding-inhibition assay, each serum was diluted 1:50, pre-incubated with 1 μg of S-RBD protein, and then treated with Huh-7 cells fixed with 4% paraformaldehyde. Penta-His antibody-Alexa Fluor 488 (LSM 510, Carl Zeiss, Thornwood, NY, USA) in the intracorporeal CURF using 1: 100, Qiagen. As a result, it was confirmed that DPP4-specific binding of S-RBD protein of MERS-CoV was remarkably inhibited in the serum treated with serum obtained after inoculation with HBD-2 conjugated S-RBD (FIG. 3A). Vero E6 cells were transfected with mers virus and analyzed by qRT-PCR using the amount of infected viral RNA as an upstream E gene as a target. First, each serum was diluted 1: 100, pre-incubated with 103 PFU of Mervis virus, and then treated with Vero E6 cells (1 × 10 6 cells). After 24 hours, Tri REAGENT (Sigma, Saint Quentin Fallavier, France) Were used to extract total RNA. CDNA was synthesized using M-MLV Reverse Transcriptase (Promega, Charbonnieres, France) based on 1 μg of total RNA, and hybridized with a SYBR Green PCR mastermix (Applied Biosystems, Woolston, Warrington, UK) PCR system was used to perform qRT-PCR. The Vero E6 β-actin gene was used as an endogenous control with the upstream E gene as the target. The primer sequence of the upstream E gene used in this experiment is F: 5'-GCCTCTACACGGGACCCATA-3 'and R: 5'-GCAACGCGCGATTCAGTT-3', and the primer sequence of Vero E6 β-actin gene is F: 5'-ATCGTGCGTGACATTAAGGAG- 3 'and R: 5'-AGGAAGGAAGGCTGGAAGAG-3'. Amplification conditions were amplification cycles at 95 ° C for 15 s, 95 ° C for 30 s, 55 ° C for 30 s, and 72 ° C for 30 s. Real-time data were analyzed using 7500 software (v2.3). It was confirmed that the infection of MERS-CoV was inhibited by an antibody-specific antibody induced by HBD-2 conjugated S-RBD (FIG. 3B).
실험예 3 : 항바이러스 면역반응과 연계된 선천면역반응에 미치는 HBD2의 효과Experimental Example 3: Effect of HBD2 on innate immune response associated with antiviral immune response
HBD2에 의하여 조절되는 선천면역반응을 확인하기 위하여 PMA-differentiated THP-1 세포(1×106 cells)에 HBD2 포함 각 재조합 단백질을 1μg/mL씩 처리 후 6시간과 24시간에 Tri REAGENT (Sigma, Saint Quentin Fallavier, France)을 사용하여 total RNA를 추출하였다. 각 1 μg의 total RNA를 기반으로 M-MLV Reverse Transcriptase(Promega, Charbonnieres, France)를 사용하여 cDNA를 합성하고, power SYBR Green PCR mastermix (Applied Biosystems, Woolston, Warrington, UK)과 ABI 7500 real-time PCR system을 사용하여 qRT-PCR을 수행하여 항바이러스 활성을 지닌 주요 선천면역 molecule들을 확인하였다. Beta-actin gene(hACTB)을 Endogenous control로 사용하였고 본 실험에 사용한 primer들의 염기서열은 하기 표 1과 같다. Amplification condition은 95 ℃에서 10 min activation 후 95 ℃에서 15s, 55 ℃에서 30s, 72 ℃에서 30s씩 40 amplification cycles 수행 후 7500 software(v2.3)을 사용하여 Real-time data 분석하였다. 먼저 바이러스 감염 예방 및 치료에 주요한 IFN들과 이의 조절 인자로 알려진 MxA, 그리고 적응 면역에 필요한 pro-inflammatory cytokine의 발현을 유도하고 Host defense에 중요한 viral PRR(pattern recognition receptor)로 생각되고 있는 Nod2를 확인한 결과, HBD-2 conjugated S-RBD 처리시 현저하게 증가되는 것을 확인하였다 (도 4). 아울러 IFN은 antiviral activity를 지닌 다양한 유전자들의 발현을 유도하는데, MxA와 함께 대표적인 antiviral molecule로 바이러스 증식 억제에 관여한다고 알려진 PKR과 RNase L 모두 HBD-2 conjugated S-RBD 처리 시간에 비례하여 발현이 증가되는 것을 확인하였다. IL-1β, TNF-α 및 PAMP(pathogen-associated moleuclar pattern)에 특이적으로 반응하는 IL-6 모두 HBD-2 conjugated S-RBD 처리시 증가되는 것을 확인하였고, IFN-γ에 의하여 유도되는 CXCL-10을 포함하여 CXCL-1, RANTES, MCP-1 및 세균 감염시 대식세포에서 발현되는 대표적인 물질인 MIP-1α 같은 chemokine들 또한 HBD-2 conjugated S-RBD 처리시 유의하미하게 발현이 증가되는 것을 확인 하였다 (도 4). To confirm the innate immune response regulated by HBD2, 1 μg / mL of each recombinant protein containing HBD2 was treated with PMA-differentiated THP-1 cells (1 × 10 6 cells) Total RNA was extracted using Quentin Fallavier, France. CDNA was synthesized using M-MLV Reverse Transcriptase (Promega, Charbonnieres, France) based on 1 μg of total RNA, and hybridized with a SYBR Green PCR mastermix (Applied Biosystems, Woolston, Warrington, UK) QRT-PCR was performed using the PCR system to identify the major innate immune molecules with antiviral activity. The beta-actin gene (hACTB) was used as an endogenous control and the nucleotide sequences of the primers used in this experiment are shown in Table 1 below. Amplification conditions were amplification cycles at 95 ° C for 15 s, 95 ° C for 30 s, 55 ° C for 30 s, and 72 ° C for 30 s. Real-time data were analyzed using 7500 software (v2.3). First, we identified the major IFNs, MxA, which is a major regulator of viral infection, and Nod2, which is thought to be an important viral PRR (pattern recognition receptor) in host defense, and induces the expression of pro-inflammatory cytokines required for adaptive immunity As a result, it was confirmed that HBD-2 conjugated S-RBD treatment significantly increased (FIG. 4). In addition, IFN induces the expression of various genes with antiviral activity. Both PKR and RNase L, which are known to be involved in the inhibition of virus proliferation, are a typical antiviral molecule together with MxA. Expression increases in proportion to the time of HBD-2 conjugated S-RBD treatment Respectively. IL-6, which specifically reacts with IL-1β, TNF-α and PAMP (pathogen-associated molecule pattern), was increased during treatment with HBD-2 conjugated S-RBD. CXCL- The expression of CXCL-1, RANTES, MCP-1, and chemokines such as MIP-1α, which are expressed in macrophages during bacterial infection, is also significantly increased in HBD-2 conjugated S-RBD treatment (Fig. 4).
<110> INDUSTRIAL COOPERATION FOUNDATION CHONBUK NATIONAL UNIVERSITY <120> A composition for preventing or treating MERS-CoV virus comprising HBD2 (human beta-defensin 2) or an fusion protein comprising epitope protein of MERS-CoV virus and the HBD2 <130> 1063238 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> gene of HDB2 <400> 1 Gly Ile Gly Asp Pro Val Thr Cys Leu Lys Ser Gly Ala Ile Cys His 1 5 10 15 Pro Val Phe Cys Pro Arg Arg Tyr Lys Gln Ile Gly Thr Cys Gly Leu 20 25 30 Pro Gly Thr Lys Cys Cys Lys Lys Pro 35 40 <210> 2 <211> 435 <212> PRT <213> Artificial Sequence <220> <223> MERS-CoV S-RBD <400> 2 Lys Tyr Tyr Ser Ile Ile Pro His Ser Ile Arg Ser Ile Gln Ser Asp 1 5 10 15 Arg Lys Ala Trp Ala Ala Phe Tyr Val Tyr Lys Leu Gln Pro Leu Thr 20 25 30 Phe Leu Leu Asp Phe Ser Val Asp Gly Tyr Ile Arg Arg Ala Ile Asp 35 40 45 Cys Gly Phe Asn Asp Leu Ser Gln Leu His Cys Ser Tyr Glu Ser Phe 50 55 60 Asp Val Glu Ser Gly Val Tyr Ser Val Ser Ser Phe Glu Ala Lys Pro 65 70 75 80 Ser Gly Ser Val Val Glu Gln Ala Glu Gly Val Glu Cys Asp Phe Ser 85 90 95 Pro Leu Leu Ser Gly Thr Pro Pro Gln Val Tyr Asn Phe Lys Arg Leu 100 105 110 Val Phe Thr Asn Cys Asn Tyr Asn Leu Thr Lys Leu Leu Ser Leu Phe 115 120 125 Ser Val Asn Asp Phe Thr Cys Ser Gln Ile Ser Pro Ala Ala Ile Ala 130 135 140 Ser Asn Cys Tyr Ser Ser Leu Ile Leu Asp Tyr Phe Ser Tyr Pro Leu 145 150 155 160 Ser Met Lys Ser Asp Leu Ser Val Ser Ser Ala Gly Pro Ile Ser Gln 165 170 175 Phe Asn Tyr Lys Gln Ser Phe Ser Asn Pro Thr Cys Leu Ile Leu Ala 180 185 190 Thr Val Pro His Asn Leu Thr Thr Ile Thr Lys Pro Leu Lys Tyr Ser 195 200 205 Tyr Ile Asn Lys Cys Ser Arg Leu Leu Ser Asp Asp Arg Thr Glu Val 210 215 220 Pro Gln Leu Val Asn Ala Asn Gln Tyr Ser Pro Cys Val Ser Ile Leu 225 230 235 240 Pro Ser Thr Val Trp Glu Asp Gly Asp Tyr Tyr Arg Lys Gln Leu Ser 245 250 255 Pro Leu Glu Gly Gly Gly Trp Leu Val Ala Ser Gly Ser Thr Val Ala 260 265 270 Met Thr Glu Gln Leu Gln Met Gly Phe Gly Ile Thr Val Gln Tyr Gly 275 280 285 Thr Asp Thr Asn Ser Val Cys Pro Lys Leu Glu Phe Ala Asn Asp Thr 290 295 300 Lys Ile Ala Ser Gln Leu Gly Asn Cys Val Glu Tyr Ser Leu Tyr Gly 305 310 315 320 Val Ser Gly Arg Gly Val Phe Gln Asn Cys Thr Ala Val Gly Val Arg 325 330 335 Gln Gln Arg Phe Val Tyr Asp Ala Tyr Gln Asn Leu Val Gly Tyr Tyr 340 345 350 Ser Asp Asp Gly Asn Tyr Tyr Cys Leu Arg Ala Cys Val Ser Val Pro 355 360 365 Val Ser Val Ile Tyr Asp Lys Glu Thr Lys Thr His Ala Thr Leu Phe 370 375 380 Gly Ser Val Ala Cys Glu His Ile Ser Ser Thr Met Ser Gln Tyr Ser 385 390 395 400 Arg Ser Thr Arg Ser Met Leu Lys Arg Arg Asp Ser Thr Tyr Gly Pro 405 410 415 Leu Gln Thr Pro Val Gly Cys Val Leu Gly Leu Val Asn Ser Ser Leu 420 425 430 Phe Val Glu 435 <110> INDUSTRIAL COOPERATION FOUNDATION CHONBUK NATIONAL UNIVERSITY <120> A composition for preventing or treating MERS-CoV virus comprising HBD2 (human beta-defensin 2) or an fusion protein comprising epitope protein of MERS-CoV virus and the HBD2 <130> 1063238 <160> 2 <170> KoPatentin 3.0 <210> 1 <211> 41 <212> PRT <213> Artificial Sequence <220> <223> gene of HDB2 <400> 1 Gly Ile Gly Asp Pro Val Thr Cys Leu Lys Ser Gly Ala Ile Cys His 1 5 10 15 Pro Val Phe Cys Pro Arg Arg Tyr Lys Gln Ile Gly Thr Cys Gly Leu 20 25 30 Pro Gly Thr Lys Cys Cys Lys Lys Pro 35 40 <210> 2 <211> 435 <212> PRT <213> Artificial Sequence <220> <223> MERS-CoV S-RBD <400> 2 Lys Tyr Tyr Ser Ile Ile Pro His Ser Ile Arg Ser Ile Gln Ser Asp 1 5 10 15 Arg Lys Ala Trp Ala Ala Phe Tyr Val Tyr Lys Leu Gln Pro Leu Thr 20 25 30 Phe Leu Leu Asp Phe Ser Val Asp Gly Tyr Ile Arg Arg Ala Ile Asp 35 40 45 Cys Gly Phe Asn Asp Leu Ser Gln Leu His Cys Ser Tyr Glu Ser Phe 50 55 60 Asp Val Glu Ser Gly Val Ser Ser Val Ser Ser Phe Glu Ala Lys Pro 65 70 75 80 Ser Gly Ser Val Val Glu Gln Ala Glu Gly Val Glu Cys Asp Phe Ser 85 90 95 Pro Leu Leu Ser Gly Thr Pro Pro Gln Val Tyr Asn Phe Lys Arg Leu 100 105 110 Val Phe Thr Asn Cys Asn Tyr Asn Leu Thr Lys Leu Leu Ser Leu Phe 115 120 125 Ser Val Asn Asp Phe Thr Cys Ser Gln Ile Ser Pro Ala Ala Ile Ala 130 135 140 Ser Asn Cys Tyr Ser Ser Leu Ile Leu Asp Tyr Phe Ser Tyr Pro Leu 145 150 155 160 Ser Met Lys Ser Asp Leu Ser Val Ser Ser Ala Gly Pro Ile Ser Gln 165 170 175 Phe Asn Tyr Lys Gln Ser Phe Ser Asn Pro Thr Cys Leu Ile Leu Ala 180 185 190 Thr Val Pro His Asn Leu Thr Thr Ile Thr Lys Pro Leu Lys Tyr Ser 195 200 205 Tyr Ile Asn Lys Cys Ser Arg Leu Leu Ser Asp Asp Arg Thr Glu Val 210 215 220 Pro Gln Leu Val Asn Ala Asn Gln Tyr Ser Pro Cys Val Ser Ile Leu 225 230 235 240 Pro Ser Thr Val Trp Glu Asp Gly Asp Tyr Tyr Arg Lys Gln Leu Ser 245 250 255 Pro Leu Glu Gly Gly Gly Trp Leu Val Ala Ser Gly Ser Thr Val Ala 260 265 270 Met Thr Glu Gln Leu Gln Met Gly Phe Gly Ile Thr Val Gln Tyr Gly 275 280 285 Thr Asp Thr Asn Ser Val Cys Pro Lys Leu Glu Phe Ala Asn Asp Thr 290 295 300 Lys Ile Ala Ser Gln Leu Gly Asn Cys Val Glu Tyr Ser Leu Tyr Gly 305 310 315 320 Val Ser Gly Arg Gly Val Phe Gln Asn Cys Thr Ala Val Gly Val Arg 325 330 335 Gln Gln Arg Phe Val Tyr Asp Ala Tyr Gln Asn Leu Val Gly Tyr Tyr 340 345 350 Ser Asp Asp Gly Asn Tyr Tyr Cys Leu Arg Ala Cys Val Ser Val Pro 355 360 365 Val Ser Val Ile Tyr Asp Lys Glu Thr Lys Thr His Ala Thr Leu Phe 370 375 380 Gly Ser Val Ala Cys Glu His Ile Ser Ser Thr Met Ser Gln Tyr Ser 385 390 395 400 Arg Ser Thr Arg Ser Met Leu Lys Arg Arg Asp Ser Thr Tyr Gly Pro 405 410 415 Leu Gln Thr Pro Val Gly Cys Val Leu Gly Leu Val Asn Ser Ser Leu 420 425 430 Phe Val Glu 435
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WO2023125432A1 (en) * | 2021-12-27 | 2023-07-06 | Versitech Limited | Antiviral peptides and methods of use thereof |
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WO2021256795A1 (en) * | 2020-06-15 | 2021-12-23 | 한국과학기술원 | Epitope of new coronavirus and use thereof |
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