KR20220002156A - Kit for screening for therapeutic agent for preventing or treating Corona-virus infection by using of esterase activity of Corona-19 virus spike protein and pharmaceutical composition comprising material selected therefrom - Google Patents
Kit for screening for therapeutic agent for preventing or treating Corona-virus infection by using of esterase activity of Corona-19 virus spike protein and pharmaceutical composition comprising material selected therefrom Download PDFInfo
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Abstract
Description
본 발명은 코로나-19 바이러스(COVID-19, Coronavirus Disease 2019)의 재조합 스파이크 단백질의 에스터가수분해효소의 활성의 발견 및 이를 이용한 코로나-19 바이러스의 치료법 개발에 관한 것이다. 자세하게는 본 발명자들은 코로나-19 바이러스의 스파이크 단백질(Spike protein)이 높은 에스터가수분해효소의 활성을 나타내는 것을 최초로 확인하였고, 이를 이용하여 코로나-19 바이러스의 스파이크 단백질의 에스터가수분해효소의 활성을 이용하여 코로나-19 바이러스의 치료제를 스크리닝하는 방법을 개발하였다. 스크리닝 통해 선별된 에스터가부수분해효소를 저해하는 물질은 코로나-19 바이러스 스파이크 단백질의 에스터가수분해효소의 활성을 저해함으로써 바이러스의 세포 감염(cell infection) 또는 세포로부터의 방출(release) 과정을 저해하고 이를 통해서 바이러스의 체내 증식을 억제하여 코로나-19 바이러스의 감염증을 치료할 수 있는 효과가 있다. 이에 본원발명은 코로나-19 바이러스의 스파이크 단백질의 에스터가수분해효소 활성을 이용한 코로나 바이러스 치료제를 스크리닝 하는 방법 및 이를 통해 스크리닝된 물질을 이용한 코로나-19 바이러스의 예방 또는 치료용 약학적 조성물을 제공한다.The present invention relates to the discovery of the activity of an esterase of a recombinant spike protein of the Corona-19 virus (COVID-19, Coronavirus Disease 2019) and the development of a treatment for the Corona-19 virus using the same. In detail, the present inventors first confirmed that the spike protein of the Corona-19 virus exhibited high esterase activity, and using this, the activity of the esterase protein of the spike protein of the Corona-19 virus was used. Thus, a method for screening a therapeutic agent for the COVID-19 virus was developed. Substances that inhibit esterases selected through screening inhibit the activity of esterases of the COVID-19 virus spike protein, thereby inhibiting the cell infection or release process of the virus. Through this, it has the effect of suppressing the proliferation of the virus in the body and treating the infection of the Corona 19 virus. Accordingly, the present invention provides a method for screening a coronavirus therapeutic agent using the esterase activity of the spike protein of the Corona-19 virus, and a pharmaceutical composition for preventing or treating the Corona-19 virus using the screened material.
코로나 바이러스는 아데노바이러스, 리노바이러스와 함께 사람에게 감기를 일으키는 3대 바이러스 중 하나로, 사람과 다양한 동물에 감염될 수 있는 유전자 크기 27~32kb의 RNA 바이러스이다. 전자 현미경으로 봤을 때, 바이러스 입자 표면이 돌기처럼 튀어나와 있는데 이 모양이 마치 왕관처럼 생겼다고 해서 라틴어로 왕관을 뜻하는 "corona"에서 파생돼 명명됐다. 주로 추운 겨울철에 발생하는 성인 감기의 10~30%를 차지하며, 두통이나 인후통, 기침을 동반한 코감기를 주 증상으로 한다. 코로나 바이러스는 1930년대 닭에서 처음으로 발견된 이후 개, 돼지, 조류 등의 동물에서 발견되었고, 1960년대에는 사람에서도 발견되어 동물과 사람 모두에게 발견되는 것으로 확인된다.Corona virus is one of the three major viruses that cause colds in humans along with adenovirus and rhinovirus, and is an RNA virus with a gene size of 27 to 32 kb that can infect humans and various animals. When viewed under an electron microscope, the surface of the virus particle protrudes like a protrusion. It accounts for 10 to 30% of adult colds that occur mainly in the cold winter, and the main symptom is a nasal cold accompanied by a headache, sore throat, or cough. Since the coronavirus was first discovered in chickens in the 1930s, it was discovered in animals such as dogs, pigs, and birds, and in the 1960s, it was also found in humans, confirming that it is found in both animals and humans.
인간 활동 영역이 광범위해지면서 동물 사이에서만 유행하던 바이러스가 생존을 위해 유전자 변이를 일으켜 사람에게로 넘어오기도 하는데, 예컨대 사스(박쥐와 사향 고양이), 메르스(박쥐와 낙타), 코로나바이러스감염증-19(박쥐로 추정)가 이에 해당된다. 지금까지 발견된 코로나 바이러스는 알파(Alpha)·베타(Beta)·감마(Gamma)·델타(Delta) 등 4속(屬)으로 분류된다. 여기서 알파는 다시 1a형과 1b형으로 나뉘고, 베타는 2a, 2b, 2c, 2d형으로 나뉜다. 이 중 알파와 베타는 사람과 동물에게 감염되며, 감마와 델타는 동물에게 감염된다. 현재까지 확인된 인체 전염 코로나 바이러스는 총 7종으로, HCoV 229E·HCoV NL63·HCoV OC43·HCoV HKU1·SARS-CoV·MERS-CoV·SARS-CoV-2가 이에 해당한다. 이 가운데 4종(229E, OC43, NL63, HKU1)은 감기와 비슷한 가벼운 증상만 일으킨다. 하지만 사스(SARS-CoV·중증급성호흡기증후군), 메르스(MERS-CoV·중동호흡기증후군), 코로나바이러스감염증-19(SARS-CoV-2, severe acute respiratory syndrome coronavirus 2)는 중증 폐렴 등 심각한 호흡기 질환을 일으킬 수 있으며, 많은 사망자를 발생시킨다.As the field of human activity expands, viruses that only spread among animals cause genetic mutations for survival and are passed on to humans, for example, SARS (bats and civets), MERS (bats and camels), Coronavirus Infectious Disease-19 (presumed to be a bat) is one such case. The coronaviruses discovered so far are classified into four genera: Alpha, Beta, Gamma, and Delta. Here, alpha is further divided into types 1a and 1b, and beta is divided into types 2a, 2b, 2c, and 2d. Of these, alpha and beta infect humans and animals, and gamma and delta infect animals. There are a total of 7 types of coronaviruses that have been identified so far, including HCoV 229E · HCoV NL63 · HCoV OC43 · HCoV HKU1 · SARS-CoV · MERS-CoV · SARS-CoV-2. Of these, four (229E, OC43, NL63, and HKU1) caused only mild symptoms similar to colds. However, SARS (Severe Acute Respiratory Syndrome), MERS (MERS-CoV), and Coronavirus Infectious Disease-19 (SARS-CoV-2, severe acute respiratory syndrome coronavirus 2) It can cause disease and cause many deaths.
코로나-19 바이러스(COVID-19)는 2019년 12월 중국 우한에서 처음 발생한 이후 중국 전역과 전 세계로 확산된, 새로운 유형의 코로나바이러스(SARS-CoV-2)이다. 코로나-19 바이러스는 대단히 높은 전파율을 보여서 전염성이 특히 높다. 코로나-19 바이러스에 감염되면 약 2~14일(추정)의 잠복기를 거친 뒤 발열(37.5도) 및 기침이나 호흡곤란 등 호흡기 증상, 폐렴이 주 증상으로 나타나지만 무증상 감염 사례도 드물지 않게 나오고 있다. 코로나-19 바이러스(COVID-19)의 스파이크 단백질은 대단히 커다란 엑토 도메인(ecto-domain) 영역, 단일 막 관통 도메인(transmembrane domain; TMD) 및 짧은 세포질 꼬리를 포함하는 타입 1의 막 당단백질(glycoprotein)이다. 상기 스파이크 단백질은 다른 코로나 바이러스의 스파이크(spike; S) 단백질과 마찬가지로 바이러스의 표면에 삼량체로 존재하고, 바이러스의 숙주세포 침입에 필요한 수용체 결합 영역(receptor binding domain) 및 세포 침입 시 바이러스 막과 세포 소기관막 사이의 융합을 유도하는 융합 펩타이드(fusion peptide)를 가지고 있으며, 자연 숙주에서 상기 스파이크 단백질에 대한 중화된 항체를 유도하는 등의 역할을 하는 것으로 알려져 있다. 상기 코로나 스파이크 단백질은 바이러스막의 표면에 삼량체로 존재한다.Coronavirus (COVID-19) is a new type of coronavirus (SARS-CoV-2) that first emerged in Wuhan, China in December 2019 and has spread throughout China and around the world. The COVID-19 virus has a very high transmission rate, making it particularly contagious. After being infected with the COVID-19 virus, after an incubation period of about 2 to 14 days (estimated), the main symptoms include fever (37.5 degrees), respiratory symptoms such as cough or shortness of breath, and pneumonia, but asymptomatic infections are not uncommon. The spike protein of the COVID-19 virus (COVID-19) is a type 1 membrane glycoprotein comprising a very large ecto-domain region, a single transmembrane domain (TMD) and a short cytoplasmic tail. to be. The spike protein, like the spike (S) protein of other coronaviruses, exists as a trimer on the surface of the virus, and has a receptor binding domain necessary for the virus to invade the host cell and the virus membrane and organelles during cell invasion. It has a fusion peptide that induces fusion between membranes, and is known to play a role, such as inducing neutralized antibodies against the spike protein in a natural host. The corona spike protein exists as a trimer on the surface of the virus membrane.
바이러스는 세포에 침입할 때 세포의 표면에 결합해야 하는데, 이를 위해서 다양한 수용체를 사용한다. 코로나-19는, 인간세포 표면에 존재하는 ACE라는 단백질을 바이러스의 표면에 존재하는 스파이크 단백질이 인식하여 결합하고, 이를 통해서 표적세표를 인식하는 것으로 알려져 있다. 코로나 바이러스는 수용체 결합에 있어서 세 종류로 구별되고 있다. 한 종류는 특정 단백질에 결합하고, 두 번째 종류는 당에 결합하고, 또 다른 종류는 단백질과 당 둘 다에 결합한다. 구체적으로 설명하자면, 코로나 바이러스의 α-속(α-genus)의 NL63과 PRCV는 ACE2와 아미노펩티다아제 N(aminopeptidase N, APN)이라는 각각의 단백질 수용체에 결합하고, 같은 α-속(α-genus)의 TGEV는 APN과 당 둘 다 결합한다. 코로나 바이러스 β-속(β-genus) 중의 MHV와 BCoV는 각각 암배항원관련 세포접착분자(carcinoembryonic antigen-related cell adhesion molecule 1, CEACAM1)와 당 둘 다에 결합하는 반면, MERS-CoV와 SARS는 단백질인 디펩티딜 펩티다아제 4(dipeptidyl peptidase 4, DPP4)와 안지오텐신 전환효소 2(angiotensin-converting enzyme 2, ACE2)에 결합한다(Garcia-Sastre, A.(2010) Influenza Virus Receptor Specificity. Disease and Transmission. Am J Pathol. 176: 1584-1585). 하지만 MERS는 DPP4에 덧붙여 시알산(sialic acid)에도 결합한다고 알려져 있다(Li et al.,(2017) Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein.Proc Natl Acad Sci U S A. 114:E8508-E8517). 시알산이 제거된 세포에는 MERS-CoV의 전염이 저해되므로, 이를 통해 시알산과의 결합이 바이러스의 감염에 대단히 중요하다고 제안되었다. γ-속(γ-genus)인 IBV는 당에 결합한다고 알려져 있다. When a virus invades a cell, it must bind to the cell's surface, and for this, it uses a variety of receptors. Corona-19 is known to recognize and bind to a protein called ACE present on the surface of human cells by a spike protein present on the surface of the virus, thereby recognizing target cells. Coronaviruses are classified into three types in terms of receptor binding. One type binds to a specific protein, a second type binds to a sugar, and another type binds to both a protein and a sugar. Specifically, NL63 and PRCV of the α-genus of the corona virus bind to respective protein receptors called ACE2 and aminopeptidase N (APN), and are of the same α-genus. TGEV binds both APN and sugar. MHV and BCoV of the corona virus β-genus bind to both carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) and sugar, respectively, whereas MERS-CoV and SARS are proteins Binds to dipeptidyl peptidase 4 (DPP4) and angiotensin-converting enzyme 2 (ACE2) (Garcia-Sastre, A. (2010) Influenza Virus Receptor Specificity. Disease and Transmission. Am J Pathol. 176: 1584-1585). However, MERS is known to bind to sialic acid in addition to DPP4 (Li et al., (2017) Identification of sialic acid-binding function for the Middle East respiratory syndrome coronavirus spike glycoprotein. Proc Natl Acad Sci US A. 114:E8508-E8517). Since MERS-CoV transmission is inhibited in cells from which sialic acid has been removed, it has been suggested that binding to sialic acid is very important for virus infection. IBV, a γ-genus, is known to bind to sugars.
바이러스의 표면 단백질이 동물 세포 표면에 존재하는 시알산과 같은 당 잔기에 결합을 하는 바이러스의 경우에는, 이들이 세포에 침입할 때나 세포로부터 방출(release)될 때 바이러스 표면 단백질과 동물세포 표면의 당 잔기 사이의 결합이 제거되어야 한다. 이 시알산과의 결합을 제거하는 방법 중의 하나는 시알산 잔기를 당쇄로부터 자르는 것이다. 이러한 활성을 갖는 단백질을 수용체 파괴 효소(receptor destroying enzymes, RDEs)라 하며, 코로나 바이러스의 일부 속(genus)인, 인플루엔자 C(influenza C) 등은 혈구응집소 에스터가수분해효소(hemagglutinin-esterase, HE)라는 단백질이 이러한 활성을 갖는 것으로 알려져 있다. 특히, 인체 감염 코로나 바이러스 OC43(HCoV-OC43)와 소의 코로나 바이러스(BCoV)의 경우에는 혈구응집소 에스터가수분해효소(hemagglutinin-esterase, HE)를 가지고 있다고 알려져 있다. HCoV-OC43의 경우, 중화 항체를 이용하거나 변형을 이용하여 활성을 저해하였을 때, 바이러스의 증식이 현저하게 줄어들었으며, 이의 활성을 보강하여 주었을 때는 다시 바이러스의 증식이 증가된다는 것이 보고되었다(Desforges et al.,(2013) The acetyl-esterase activity of the hemagglutinin-esterase protein of human coronavirus OC43 strongly enhances the production of infectious virus. J Virol). 이 바이러스의 HE는 아세틸 에스터가수분해효소(acetyl esterase)의 활성을 가지며, O-아세틸화 시알산(O-acetylated sialic acid)으로부터 아세틸기(acetyl group)를 제거하는 활성을 나타낸다. 그리고 다른 종류의 바이러스인 인플루엔자 바이러스(influenza virus) 경우에는 바이러스 유형에 따라서 다른 종류의 당 가수분해 효소(sugar hydrolysing enzyme)를 가지고 있다. A형과 B형은 뉴라미니다아제(neuraminidase, NA)를 가지고 있으며, C형의 경우에는 HEF를 가지고 있다. 따라서, 이들 인플루엔자 바이러스들은 상기 단백질들의 활성을 이용하여 시알산 잔기를 자른다. 인플루엔자 바이러스의 NA 활성은 특히 인플루엔자 바이러스가 세포로부터 방출될 때 중요하다는 것이 보고되었다. SARS-CoV와 SARS-CoV-2(COVID-19)는 독립적인 HE 유전자를 갖지 않는 것으로 알려져 있다. 따라서, 이들 바이러스가 에스터가수분해효소와 같은 효소 활성이 필요한지에 대해서는 알려져 있지 않다. 본 발명에서는 SARS-CoV-2 바이러스의 S 단백질이 p-니트로페놀 아세테이트(p-nitrophenol acetate)를 가수분해하는 에스터가수분해효소의 활성을 가지고 있음을 최초로 밝혔으며, 특히 S1과 S2 서브유닛 둘 다 이러한 에스터가수분해효소의 활성이 있음을 밝히고, 이 스파이크 단백질의 에스터가수분해효소 활성을 방해함으로써 바이러스의 세포 감염 및 증식을 방해할 수 있는 저해제를 개발하고자 한다.In the case of viruses in which the surface protein of a virus binds to sugar residues such as sialic acid present on the surface of animal cells, when they enter the cell or when released from the cell, between the surface protein of the virus and the sugar residue on the surface of the animal cell binding should be removed. One of the methods for removing the bond with sialic acid is to cut the sialic acid residue from the sugar chain. Proteins having this activity are called receptor destroying enzymes (RDEs), and some genus of coronavirus, such as influenza C, are hemagglutinin-esterase (HE). is known to have such an activity. In particular, human coronavirus OC43 (HCoV-OC43) and bovine coronavirus (BCoV) are known to have hemagglutinin-esterase (HE). In the case of HCoV-OC43, it was reported that when the activity was inhibited using a neutralizing antibody or modification, the proliferation of the virus was significantly reduced, and when the activity was reinforced, the proliferation of the virus was increased again (Desforges et al.) al., (2013) The acetyl-esterase activity of the hemagglutinin-esterase protein of human coronavirus OC43 strongly enhances the production of infectious virus. J Virol). HE of this virus has the activity of acetyl esterase, and shows the activity of removing an acetyl group from O-acetylated sialic acid. And in the case of influenza virus, which is a different kind of virus, it has different kinds of sugar hydrolysing enzymes depending on the virus type. Types A and B have neuraminidase (NA), and type C has HEF. Thus, these influenza viruses use the activity of these proteins to cut sialic acid residues. It has been reported that the NA activity of influenza virus is important, especially when influenza virus is released from cells. It is known that SARS-CoV and SARS-CoV-2 (COVID-19) do not have independent HE genes. Therefore, it is not known whether these viruses require enzymatic activity such as esterases. In the present invention, it was revealed for the first time that the S protein of SARS-CoV-2 virus has an esterase activity that hydrolyzes p-nitrophenol acetate, and in particular, both S1 and S2 subunits The purpose of this study is to reveal the esterase activity, and to develop an inhibitor that can interfere with virus cell infection and proliferation by interfering with the esterase activity of the spike protein.
바이러스가 인체에 침입을 할 때, 바이러스의 표면에 있는 단백질들은 표적세포의 표면에 있는 단백질의 당쇄를 인식하여 수용체로 활용하거나, 표적세포의 표면에 있는 단백질의 당쇄를 일차적으로 인식하여 표적세포에 부착된 후 이어서 주 수용체와의 결합을 통해 바이러스가 감염될 수 있도록 한다. 또한, 바이러스가 표적세포에서 증식한 후 이 세포로부터 방출될 때에도 바이러스 표면의 단백질이 표적세포의 표면 단백질의 당쇄와 결합을 하기도 한다. 따라서, 바이러스의 표적세포 감염과 방출에 있어서 이러한 단백질과 당쇄의 결합을 해소하는 것이 중요하다. 이러한 과정에 에스터가수분해효소가 중요한 역할을 한다. 따라서, 이러한 에스터가수분해효소가 항바이러스제 개발의 중요한 표적이 되고 있다. 특히, 신종플루의 치료제인 타미플루가 이러한 과정에 관여하는 뉴라미니다아제의 활성 저해제로 개발되었다. When a virus invades the human body, the proteins on the surface of the virus recognize the sugar chain of the protein on the surface of the target cell and use it as a receptor, or first recognize the sugar chain of the protein on the surface of the target cell and enter the target cell. After attachment, it subsequently binds to its main receptor, allowing the virus to infect. In addition, when the virus is released from the target cell after it has proliferated, the protein on the virus surface also binds to the sugar chain of the target cell's surface protein. Therefore, it is important to break the binding of these proteins to sugar chains in the virus target cell infection and release. Esterases play an important role in this process. Therefore, these esterases are becoming important targets for the development of antiviral agents. In particular, Tamiflu, a treatment for swine flu, has been developed as an activity inhibitor of neuraminidase involved in this process.
본 발명에서는 코로나 바이러스의 스파이크 단백질이 강력한 에스터가수분해효소 활성을 갖는 것을 확인하였으며, 특히, S1과 S2 서브유닛으로 나누었을 때에도 각 서브유닛이 에스터가수분해효소의 활성을 나타냄을 확인하였다. 에스터가수분해효소는 파라-니트로페닐 아세테이트(para-nitrophenyl acetate, p-NPA)와 같은 표준 기질뿐만 아니라, 다양한 형태의 시알산을 포함하는 다양한 화합물의 에스터 결합을 분해할 수 있다.In the present invention, it was confirmed that the spike protein of corona virus has a strong esterase activity. In particular, it was confirmed that each subunit exhibited esterase activity even when divided into S1 and S2 subunits. Esterases are capable of cleaving ester bonds in various compounds, including various forms of sialic acid, as well as standard substrates such as para-nitrophenyl acetate (p-NPA).
본 발명에서는 스파이크 단백질의 전장(full length), S1 및 S2 서브유닛의 삼량체 형태를 생산 및 분리 정제한 후 이들 세 종류의 S 단백질(전장, S1 및 S2)들이 p-NPA를 가수분해하는 에스터가수분해효소의 활성을 가짐을 확인하고, 이 활성을 저해하는 화합물을 스크리닝하였다. 다양한 화합물이 에스터가수분해효소의 활성을 저해하는 것으로 보고되었다. 특히, 일부 에스터가수분해효소의 활성을 저해하는 물질은 항암제, 항생제 등의 의약품으로 활용되기도 한다. 우선적으로 이들을 이용하여 스파이크 단백질의 활성 저해 여부를 확인하였다. 그리고 이들 에스터가수분해효소 활성 저해제를 이용하여 항바이러스제로 활용하고자 한다. 인플루엔자 바이러스의 경우에는 NA 억제제인 타미플루가 신종 플루의 증식을 억제하는 것으로 잘 알려져 있다. 이는 타미플루가 NA의 활성을 억제하여 바이러스 입자가 표적세포로부터 방출되지 않도록 함으로써 바이러스의 증식이 일어나지 못하도록 한다고 알려져 있다. HCoV-OC43의 경우에도, HE의 활성을 억제함으로써 표적세포에 감염 및 표적세포로부터 바이러스의 방출이 억제되어 전반적으로 바이러스의 증식이 억제되었다. 이러한 결과들은 본 발명에서 확인한 스파이크 단백질의 에스터가수분해효소의 활성을 억제하면 코로나바이러스의 증식을 억제할 수 있을 것이라는 주장을 뒷받침한다. 따라서, 본 발명에서는 스파이크 단백질의 에스터가수분해효소 활성을 억제하는 화합물을 찾고, 이를 바이러스의 증식을 억제하는 의약품으로 개발하고자 한다. In the present invention, the three types of S proteins (full length, S1 and S2) hydrolyze p-NPA after production and separation and purification of the trimer form of the full-length, S1 and S2 subunits of the spike protein. It was confirmed that it has the activity of a hydrolase, and a compound that inhibits this activity was screened. Various compounds have been reported to inhibit the activity of esterases. In particular, substances that inhibit the activity of some esterases are used as medicines such as anticancer drugs and antibiotics. First, it was confirmed whether the activity of the spike protein was inhibited using these. And it is intended to utilize these esterase activity inhibitors as antiviral agents. In the case of influenza virus, it is well known that Tamiflu, an NA inhibitor, inhibits the proliferation of H1N1 influenza. It is known that Tamiflu inhibits the activity of NA so that the virus particles are not released from the target cells, thereby preventing the proliferation of the virus. In the case of HCoV-OC43, by inhibiting HE activity, infection into target cells and release of virus from target cells were inhibited, thereby inhibiting virus proliferation overall. These results support the claim that by inhibiting the activity of the esterase of the spike protein identified in the present invention, the proliferation of the coronavirus can be inhibited. Therefore, in the present invention, it is intended to find a compound that inhibits the esterase activity of the spike protein, and to develop it as a drug that inhibits the proliferation of viruses.
이에 따라, 본 발명의 목적은 에스터가수분해효소 활성을 갖는, 코로나 바이러스의 스파이크 단백질(Spike protein) 유래 재조합 단백질을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a recombinant protein derived from the spike protein of coronavirus, which has esterase activity.
본 발명의 다른 목적은 코로나 바이러스의 스파이크 단백질의 에스터가수분해효소 활성에 대한 억제 여부 확인을 통해 코로나 바이러스 감염증을 예방 또는 치료할 수 있는 물질을 스크리닝할 수 있는 키트 및 이를 이용한 코로나 바이러스 감염증의 예방 또는 치료용 물질의 스크리닝 방법을 제공하는 것이다.Another object of the present invention is a kit capable of screening a substance capable of preventing or treating a corona virus infection by checking whether the esterase activity of the spike protein of the corona virus is inhibited, and prevention or treatment of a corona virus infection using the same It is to provide a method for screening a substance for use.
나아가, 본 발명의 다른 목적은 코로나 바이러스의 스파이크 단백질의 에스터가수분해효소 활성 저해제를 유효성분으로 포함하는 코로나 바이러스 감염증 예방 또는 치료용 약학 조성물 및/또는 동일 구성을 유효성분으로 포함하는 코로나 바이러스 감염증 예방 또는 개선용 건강기능식품을 제공하는 것이다.Further, another object of the present invention is a pharmaceutical composition for preventing or treating coronavirus infection comprising an esterase activity inhibitor of the spike protein of coronavirus as an active ingredient and/or corona virus infection prevention comprising the same composition as an active ingredient Or to provide health functional food for improvement.
상술한 과제를 해결하기 위해, 본 발명은 에스터가수분해효소 활성을 갖는, 코로나 바이러스의 스파이크 단백질(Spike protein)의 상기 S1 서브유닛 또는 S2 서브유닛을 포함하는 재조합 단백질 또는 상기 S1 서브유닛과 S2 서브유닛을 포함하는 재조합 단백질을 제공한다.In order to solve the above problems, the present invention provides a recombinant protein comprising the S1 subunit or S2 subunit of the coronavirus spike protein, or the S1 subunit and the S2 subunit having esterase activity. Provided is a recombinant protein comprising a unit.
본 발명의 바람직한 일실시예에 따르면, 상기 코로나 바이러스가 코로나-19 바이러스(SARS-Corona Virus-2)인 경우, 상기 S1 서브유닛은 서열번호 4의 아미노산을 포함하고, 상기 S2 서브유닛은 서열번호 6의 아미노산 서열을 포함하며, 상기 S1 서브유닛과 S2 서브유닛을 포함하는 재조합 단백질은 서열번호 2의 아미노산 서열을 포함할 수 있다.According to a preferred embodiment of the present invention, when the corona virus is SARS-Corona Virus-2, the S1 subunit comprises the amino acid of SEQ ID NO: 4, and the S2 subunit is SEQ ID NO: The recombinant protein comprising the amino acid sequence of 6, the recombinant protein comprising the S1 subunit and the S2 subunit may include the amino acid sequence of SEQ ID NO: 2.
본 발명의 바람직한 다른 일실시예에 따르면, 상기 재조합 단백질은 삼량체 형태일 수 있다.According to another preferred embodiment of the present invention, the recombinant protein may be in a trimeric form.
본 발명의 바람직한 다른 일실시예에 따르면, 상기 재조합 단백질은 도 1의 (a), (b) 또는 (c)의 유전자 컨스트럭트를 포함하는 재조합 벡터를 이용하여 생산될 수 있다.According to another preferred embodiment of the present invention, the recombinant protein can be produced using a recombinant vector containing the gene construct of Figure 1 (a), (b) or (c).
또한, 본 발명은 다음을 포함하는 코로나 바이러스 감염증의 예방 또는 치료용 후보 물질의 스크리닝 키트를 제공한다:In addition, the present invention provides a screening kit for a candidate substance for the prevention or treatment of a coronavirus infection, comprising:
코로나 바이러스의 스파이크 단백질(Spike protein) 유래 재조합 단백질; 및Recombinant protein derived from the spike protein of coronavirus; and
상기 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성을 측정할 수 있는 물질.A substance capable of measuring the esterase activity of the recombinant protein derived from the spike protein of the corona virus.
본 발명의 바람직한 일실시예에 따르면, 상기 코로나 바이러스는 사스 바이러스(SARS-Corona Virus), 메르스 바이러스(MERS-Corona Virus) 및 코로나-19 바이러스(SARS-Corona Virus-2)로 이루어진 군으로부터 선택되는 어느 하나일 수 있다.According to a preferred embodiment of the present invention, the corona virus is selected from the group consisting of SARS-Corona Virus, MERS-Corona Virus, and SARS-Corona Virus-2 may be any one of
본 발명의 바람직한 다른 일실시예에 따르면, 상기 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질은 코로나-19 바이러스의 스파이크 단백질의 S1 서브유닛, S2 서브유닛, 상기 S1 서브유닛 또는 S2 서브유닛을 포함하는 재조합 단백질, 및 상기 S1 서브유닛과 S2 서브유닛을 포함하는 재조합 단백질일 수 있다.According to another preferred embodiment of the present invention, the recombinant protein derived from the spike protein of the coronavirus is a recombinant protein comprising the S1 subunit, the S2 subunit, the S1 subunit or the S2 subunit of the spike protein of the Corona-19 virus. , and may be a recombinant protein comprising the S1 subunit and the S2 subunit.
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 코로나 바이러스가 코로나-19 바이러스(SARS-Corona Virus-2)인 경우, 상기 S1 서브유닛은 서열번호 4의 아미노산을 포함하고, 상기 S2 서브유닛은 서열번호 6의 아미노산 서열을 포함하며, 상기 S1 서브유닛과 S2 서브유닛을 포함하는 재조합 단백질은 서열번호 2의 아미노산 서열을 포함할 수 있다.According to another preferred embodiment of the present invention, when the corona virus is SARS-Corona Virus-2, the S1 subunit comprises the amino acid of SEQ ID NO: 4, and the S2 subunit is The recombinant protein comprising the amino acid sequence of SEQ ID NO: 6, the recombinant protein comprising the S1 subunit and the S2 subunit may include the amino acid sequence of SEQ ID NO: 2.
본 발명의 바람직한 다른 일실시예에 따르면, 상기 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질은 삼량체 형태일 수 있다.According to another preferred embodiment of the present invention, the recombinant protein derived from the spike protein of the corona virus may be in the form of a trimer.
본 발명의 바람직한 또 다른 일실시예에 따르면, 상기 에스터가수분해효소 활성을 측정할 수 있는 물질은 일반적인 에스터가수분해효소의 기질; 시알산을 포함하는 화합물; BCECF, AM(2',7'-Bis-(2-카르복시에틸)-5-(앤드-6)-카르복시플루오레세인, 아세톡시메틸 에스테르)(BCECF, AM(2',7'-Bis-(2-Carboxyethyl)-5-(and-6)-Carboxyfluorescein, Acetoxymethyl Ester)); 칼세인 AM(Calcein AM); 카르복시에오신 디아세테이트, 숙신이미딜 에스테르(Carboxyeosin diacetate, succinimidyl ester); 카르복시플루오레세인 디아세테이트, 아세톡시메틸 에스테르(Carboxyfluorescein diacetate, acetoxymethyl ester); 또는 카르복시플루오레세인 디아세테이트, 숙신이미딜 에스테르(Carboxyfluorescein diacetate, succinimidyl ester)일 수 있다.According to another preferred embodiment of the present invention, the substance capable of measuring the esterase activity is a substrate of a general esterase; compounds comprising sialic acid; BCECF, AM(2',7'-Bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester) (BCECF, AM(2',7'-Bis- (2-Carboxyethyl)-5-(and-6)-Carboxyfluorescein, Acetoxymethyl Ester)); Calcein AM; Carboxyeosin diacetate, succinimidyl ester; Carboxyfluorescein diacetate, acetoxymethyl ester; Or it may be carboxyfluorescein diacetate, succinimidyl ester (Carboxyfluorescein diacetate, succinimidyl ester).
본 발명의 바람직한 다른 일실시예에 따르면, 상기 에스터가수분해효소의 기질은 파라 나이트로 페닐 아세테이트(para nitropheny acetate, p-NPA)이고, 상기 시알산을 포함하는 화합물은 Neu5,9Ac2, 4-메틸움벨리페릴 아세테이트(4-methylumbelliferyl acetate) 또는 9Ac2-락토오스(9Ac2-lactose)일 수 있다.According to another preferred embodiment of the present invention, the substrate of the esterase is para nitropheny acetate (p-NPA), and the compound containing sialic acid is Neu5,9Ac2, 4-methyl It may be umbelliferyl acetate (4-methylumbelliferyl acetate) or 9Ac2-lactose (9Ac2-lactose).
추가로, 본 발명은 전술한 키트를 이용하여, 코로나 바이러스 감염증의 예방 또는 치료용 후보 물질을 스크리닝 하는 방법을 제공한다.In addition, the present invention provides a method for screening a candidate substance for the prevention or treatment of a coronavirus infection using the above-described kit.
본 발명의 바람직한 일실시예에 따르면, 상기 코로나 바이러스 감염증의 예방 또는 치료용 후보 물질을 스크리닝 하는 방법은 다음의 단계를 포함할 수 있다:According to a preferred embodiment of the present invention, the method for screening a candidate substance for the prevention or treatment of coronavirus infection may include the following steps:
(i) 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질에 후보 물질을 처리하는 단계;(i) treating a candidate material with a recombinant protein derived from the spike protein of coronavirus;
(ii) 상기 후보 물질을 처리한 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성(esterase activity)을 측정하는 단계; 및 (ii) measuring the esterase activity of the recombinant protein derived from the spike protein of the corona virus treated with the candidate substance; and
(iii) 상기 후보 물질이 에스터가수분해효소 활성을 30% 이상 억제하는 경우, 상기 후보 물질을 코로나 바이러스의 예방 또는 치료용 후보 물질로 선별하는 단계.(iii) when the candidate material inhibits esterase activity by 30% or more, selecting the candidate material as a candidate material for prevention or treatment of coronavirus.
본 발명의 바람직한 다른 일실시예에 따르면, 상기 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질은 코로나 바이러스의 스파이크 단백질의 S1 서브유닛, S2 서브유닛, 상기 S1 서브유닛 또는 S2 서브유닛을 포함하는 재조합 단백질, 및 상기 S1 서브유닛과 S2 서브유닛을 포함하는 재조합 단백질일 수 있다.According to another preferred embodiment of the present invention, the recombinant protein derived from the spike protein of the coronavirus is a recombinant protein comprising the S1 subunit, the S2 subunit, the S1 subunit or the S2 subunit of the spike protein of the coronavirus, and It may be a recombinant protein comprising the S1 subunit and the S2 subunit.
나아가, 본 발명은 전술한 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성 저해제를 포함하는, 코로나 바이러스 감염증의 예방 또는 치료용 약학 조성물을 제공한다.Furthermore, the present invention provides a pharmaceutical composition for the prevention or treatment of corona virus infection, comprising the inhibitor of esterase activity of the recombinant protein derived from the spike protein of the corona virus described above.
본 발명의 바람직한 일실시예에 따르면, 상기 선별된 물질은 에스터가수분해효소의 활성 부위에 결합하여 에스터가수분해효소의 활성을 저해하거나, 에스터가수분해효소의 활성 부위가 아닌 다른 부위에 결합하여 에스터가수분해효소의 구조 변화를 유도하여 에스터가수분해효소의 활성을 저해하는 것일 수 있다.According to a preferred embodiment of the present invention, the selected substance binds to the active site of the esterase and inhibits the activity of the esterase, or binds to a site other than the active site of the esterase and binds to an ester. It may be to inhibit the activity of the esterase by inducing a structural change of the hydrolase.
추가로, 본 발명은 설파메톡사졸(sulfamethoxazole), 이의 유도체, 이성질체 또는 약학적으로 허용 가능한 염을 포함하는, 코로나-19 바이러스 감염증의 예방 또는 치료용 약학적 조성물, 및 설파메톡사졸(sulfamethoxazole), 이의 유도체, 이성질체 또는 식품학적으로 허용 가능한 염을 포함하는, 코로나-19 바이러스 감염증의 예방 또는 개선용 건강기능식품 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating COVID-19 virus infection, comprising sulfamethoxazole, a derivative, isomer, or pharmaceutically acceptable salt thereof, and sulfamethoxazole; It provides a health functional food composition for preventing or improving Corona-19 virus infection, including a derivative, isomer, or food pharmaceutically acceptable salt thereof.
본 발명은 코로나-19 바이러스의 스파이크 단백질의 S1과 S2 서브유닛이 가지고 있는 에스터가수분해효소 활성을 기반으로 이의 활성을 저해하는 저해제를 개발하고, 이를 이용하여 코로나바이러스 치료제를 개발하고자 한다. 에스터가수분해효소의 활성 부위에 결합하여 직접적으로 에스터가수분해효소의 활성을 저해할 수도 있고, 스파이크 단백질의 에스터가수분해효소의 활성부위가 아닌 다른 부위에 결합하여 구조의 변화 등을 유도하여 간접적으로 에스터가수분해효소의 활성을 저해할 수도 있다. 이들 물질은 화학 물질을 포함하는 다양한 화합물일 수도 있으며, 압타머와 같이 핵산에 기반을 둔 물질일 수도 있으며, 아미노산, 또는 변종 아미노산을 포함하는 작은 올리고 펩타이드일 수도 있다. The present invention is based on the esterase activity of the S1 and S2 subunits of the spike protein of the Corona-19 virus to develop an inhibitor that inhibits its activity, and uses this to develop a coronavirus therapeutic agent. It can directly inhibit the activity of esterase by binding to the active site of esterase, or indirectly by inducing a change in structure by binding to a site other than the active site of esterase of the spike protein. It may also inhibit the activity of esterases. These substances may be various compounds including chemical substances, nucleic acid-based substances such as aptamers, or small oligopeptides containing amino acids or mutated amino acids.
도 1은 본 발명에 사용된 코로나-19 바이러스의 스파이크 단백질의 3 종류(Sf, S1 및 S2)의 재조합 단백질 유전자의 모식도이다.
도 2는 도 1의 코로나-19 바이러스의 스파이크 단백질의 3 종류(Sf, S1 및 S2)의 재조합 단백질을 니코티아나 벤타미아나(Nicotaiana benthamiana)에서 생산하고, 이를 단백질 A 친화 컬럼 크로마토그래피(Protein A affinity column chromatography)를 통해서 분리 정제한 것을 확인한 것이다.
도 3은 3 종류의 스파이크 재조합 단백질(전장, S1 및 S2)의 에스터가수분해효소의 활성을 확인한 것이다.
도 4는 3 종류의 스파이크 재조합 단백질(전장, S1 및 S2)에 설파메톡사졸을 처리한 후, 이의 에스터가수분해효소의 활성을 확인한 것이다.1 is a schematic diagram of a recombinant protein gene of three types (Sf, S1 and S2) of the spike protein of the Corona-19 virus used in the present invention.
Figure 2 is a recombinant protein of three types (Sf, S1 and S2) of the spike protein of the corona-19 virus of Figure 1 is produced in Nicotaiana benthamiana , and it is produced by protein A affinity column chromatography (Protein A It was confirmed that they were separated and purified through affinity column chromatography).
3 is a graph showing the activity of esterases of three types of spike recombinant proteins (full length, S1 and S2).
Figure 4 shows the activity of the esterase after treatment with sulfamethoxazole to three types of spike recombinant proteins (full length, S1 and S2).
이하, 본 발명을 자세히 설명한다. Hereinafter, the present invention will be described in detail.
전술한 바와 같이, 에스터가수분해효소는 항바이러스제 개발의 중요한 표적이 되고 있으며, 특히, 신종플루의 치료제인 타미플루가 이러한 과정에 관여하는 뉴라미니다아제의 활성 저해제로 개발된 바 있다. 이러한 배경 하에, 본 발명자들은 SARS-CoV 및 SARS-CoV-2(COVID-19)와 같은 코로나 바이러스의 스파이크 단백질, 특히 상기 스파이크 단백질에서 S1 서브유닛 및/또는 S2 서브유닛을 포함하는 형태의 재조합 단백질이 p-니트로페놀 아세테이트를 가수분해하는 에스터가수분해효소의 활성을 가지고 있음을 최초로 밝히고, 코로나 바이러스의 스파이크 단백질의 에스터가수분해효소 활성을 방해함으로써 바이러스의 세포 감염 및 증식을 방해할 수 있는 저해제를 개발하였다.As described above, ester hydrolase is an important target for the development of antiviral agents, and in particular, Tamiflu, a treatment for H1N1 influenza, has been developed as an activity inhibitor of neuraminidase involved in this process. Under this background, the present inventors have developed a coronavirus spike protein such as SARS-CoV and SARS-CoV-2 (COVID-19), in particular, a recombinant protein in a form comprising the S1 subunit and/or the S2 subunit in the spike protein. It was first revealed that it has an esterase activity that hydrolyzes p-nitrophenol acetate, and an inhibitor that can interfere with virus cell infection and proliferation by interfering with the esterase activity of the spike protein of coronavirus developed.
따라서, 본 발명의 제1 측면은 에스터가수분해효소 활성을 갖는, 코로나 바이러스의 스파이크 단백질(Spike protein)의 상기 S1 서브유닛 또는 S2 서브유닛을 포함하는 재조합 단백질 또는 상기 S1 서브유닛과 S2 서브유닛을 포함하는 재조합 단백질 및 이를 이용한 코로나 바이러스 감염증의 예방 또는 치료용 후보 물질의 스크리닝 키트에 관한 것이다.Accordingly, the first aspect of the present invention is a recombinant protein comprising the S1 subunit or S2 subunit of the coronavirus spike protein, or the S1 subunit and the S2 subunit having esterase activity. It relates to a screening kit for a recombinant protein comprising the same and a candidate material for the prevention or treatment of coronavirus infection using the same.
구체적으로, 본 발명의 키트는 다음을 포함할 수 있다:Specifically, the kit of the present invention may comprise:
코로나 바이러스의 스파이크 단백질(spike protein) 유래 재조합 단백질; 및Recombinant protein derived from the spike protein of coronavirus; and
상기 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성을 측정할 수 있는 물질.A substance capable of measuring the esterase activity of the recombinant protein derived from the spike protein of the corona virus.
본 발명의 키트에 있어서, 상기 코로나 바이러스는 사스 바이러스(SARS-Corona Virus), 메르스 바이러스(MERS-Corona Virus) 및 코로나-19 바이러스(SARS-Corona Virus-2)로 이루어진 군으로부터 선택되는 어느 하나일 수 있다.In the kit of the present invention, the coronavirus is any one selected from the group consisting of SARS-Corona Virus, MERS-Corona Virus, and SARS-Corona Virus-2 can be
본 발명의 용어 "스크리닝 키트"는 다수의 후보 물질 중에서 특정한 효과를 나타내는 물질을 선발하는데 사용되는 키트를 의미한다. 본 발명의 목적상 상기 스크리닝 키트는 코로나 바이러스의 스파이크 단백질 및/또는 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성을 저해하여 바이러스의 세포 감염(cell infection) 또는 세포로부터의 방출(release) 과정을 효과적으로 저해시킬 수 있는 물질을 선별하는데 사용되는 키트가 될 수 있다.As used herein, the term “screening kit” refers to a kit used to select a substance exhibiting a specific effect from among a plurality of candidate substances. For the purpose of the present invention, the screening kit inhibits the esterase activity of the spike protein and/or the spike protein-derived recombinant protein of the coronavirus to effectively inhibit the cell infection or release process of the virus. It can be a kit used to screen for substances capable of inhibiting.
본 발명의 키트에 있어서, 상기 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질은 코로나 바이러스의 스파이크 단백질의 S1 서브유닛, S2 서브유닛, 상기 S1 서브유닛 또는 상기 S2 서브유닛을 포함하는 재조합 단백질, 또는 상기 S1 서브유닛과 상기 S2 서브유닛을 포함하는 재조합 단백질일 수 있다.In the kit of the present invention, the recombinant protein derived from the coronavirus spike protein is a recombinant protein comprising the S1 subunit, the S2 subunit, the S1 subunit or the S2 subunit of the coronavirus spike protein, or the S1 subunit It may be a recombinant protein comprising a unit and the S2 subunit.
코로나-19 바이러스(SARS-Corona Virus-2)에서, 스파이크 단백질은 수용체 인식 및 세포막 융합 과정에서 핵심적인 역할을 하며, 2개의 서브유닛인 S1 서브유닛과 S2 서브유닛으로 구성된다. S1 서브유닛은 숙주 수용체 안지오텐신 전환 효소 2를 인식하고 결합하는 수용체 결합 도메인을 포함하는 반면, S2 서브유닛은 2-헵타드 반복 도메인(two-heptad repeat domain)을 통해 6-나선 다발(six-helical bundle)을 형성하여 바이러스 세포막 융합을 매개한다.In SARS-Corona Virus-2, the spike protein plays a key role in receptor recognition and cell membrane fusion processes, and is composed of two subunits, the S1 subunit and the S2 subunit. The S1 subunit contains a receptor binding domain that recognizes and binds to the host receptor
본 발명의 키트에 있어서, 상기 코로나 바이러스가 코로나-19 바이러스(SARS-Corona Virus-2)인 경우, 상기 S1 서브유닛은 서열번호 4의 아미노산 서열을 포함하고, 상기 S2 서브유닛은 서열번호 6의 아미노산 서열을 포함하며, 상기 S1 서브유닛과 상기 S2 서브유닛을 포함하는 재조합 단백질은 서열번호 2의 아미노산 서열을 포함할 수 있다.In the kit of the present invention, when the corona virus is SARS-Corona Virus-2, the S1 subunit includes the amino acid sequence of SEQ ID NO: 4, and the S2 subunit includes the amino acid sequence of SEQ ID NO: 6 It includes an amino acid sequence, and the recombinant protein including the S1 subunit and the S2 subunit may include the amino acid sequence of SEQ ID NO:2.
상기 S1 서브유닛을 코딩하는 유전자는 서열번호 3의 염기서열, 또는 상기 서열번호 3의 염기서열과 70% 이상, 더욱 바람직하게는 80% 이상, 보다 더 바람직하게는 90% 이상, 가장 바람직하게는 95% 이상의 서열 상동성을 가지는 염기 서열을 포함할 수 있다.The gene encoding the S1 subunit comprises the nucleotide sequence of SEQ ID NO: 3, or the nucleotide sequence of SEQ ID NO: 3 and at least 70%, more preferably at least 80%, even more preferably at least 90%, most preferably It may include a nucleotide sequence having 95% or more sequence homology.
상기 S2 서브유닛을 코딩하는 유전자는 서열번호 5의 염기서열, 또는 상기 서열번호 5의 염기서열과 70% 이상, 더욱 바람직하게는 80% 이상, 보다 더 바람직하게는 90% 이상, 가장 바람직하게는 95% 이상의 서열 상동성을 가지는 염기 서열을 포함할 수 있다.The gene encoding the S2 subunit comprises the nucleotide sequence of SEQ ID NO: 5, or the nucleotide sequence of SEQ ID NO: 5 and at least 70%, more preferably at least 80%, even more preferably at least 90%, most preferably It may include a nucleotide sequence having 95% or more sequence homology.
상기 S1 서브유닛과 S2 서브유닛을 포함하는 재조합 단백질은 서열번호 1의 염기서열, 또는 상기 서열번호 1의 염기서열과 70% 이상, 더욱 바람직하게는 80% 이상, 보다 더 바람직하게는 90% 이상, 가장 바람직하게는 95% 이상의 서열 상동성을 가지는 염기 서열을 포함할 수 있다.The recombinant protein comprising the S1 subunit and the S2 subunit is 70% or more, more preferably 80% or more, even more preferably 90% or more of the nucleotide sequence of SEQ ID NO: 1 or the nucleotide sequence of SEQ ID NO: 1 , most preferably a nucleotide sequence having 95% or more sequence homology.
폴리뉴클레오티드에 대한 "서열 상동성의 %"는 두 개의 최적으로 배열된 서열과 비교 영역을 비교함으로써 확인되며, 비교 영역에서의 폴리뉴클레오티드 서열의 일부는 두 서열의 최적 배열에 대한 참고 서열(추가 또는 삭제를 포함하지 않음)에 비해 추가 또는 삭제(즉, 갭)를 포함할 수 있다.The "% sequence homology" for a polynucleotide is determined by comparing two optimally aligned sequences with a comparison region, wherein a portion of the polynucleotide sequence in the comparison region is a reference sequence (additions or deletions) to the optimal alignment of the two sequences. may include additions or deletions (ie, gaps) compared to (not including).
본 발명의 키트에 있어서, 상기 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질은 삼량체 형태일 수 있다.In the kit of the present invention, the recombinant protein derived from the spike protein of the coronavirus may be in a trimeric form.
전술한 코로나 바이러스의 스파이크 단백질은 바이러스 표면에 삼량체로 존재하므로, 본 발명에서는 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질을 삼량체 형태로 생산하기 위해 Coronin 1의 삼량체 모티프(trimeric motif) 부위의 단백질을 코딩하는 유전자를 활용하였다.Since the above-mentioned spike protein of corona virus exists as a trimer on the surface of the virus, in the present invention, in order to produce a recombinant protein derived from the spike protein of corona virus in a trimeric form, the protein of the trimeric motif region of Coronin 1 is encoded. genes were used.
상기 Coronin 1은 마우스 유래의 Coronin 1(mCor 1)(GenBank: EDL17419.1)일 수 있고, 이의 삼량체 모티프(trimeric motif) 부위의 단백질은 서열번호 8의 아미노산 서열을 포함할 수 있다.The Coronin 1 may be mouse-derived Coronin 1 (mCor 1) (GenBank: EDL17419.1), and the protein of its trimeric motif region may include the amino acid sequence of SEQ ID NO: 8.
상기 Coronin 1(mCor 1)의 삼량체 모티프 부위의 단백질을 코딩하는 유전자는 서열번호 7의 염기서열을 포함할 수 있으며. 구체적으로 상기 유전자는 서열번호 7의 염기서열과 70% 이상, 보다 바람직하게는 80% 이상, 보다 더 바람직하게는 90% 이상, 가장 바람직하게는 95% 이상의 서열 상동성을 가지는 염기 서열을 포함할 수 있다.The gene encoding the protein of the trimeric motif region of Coronin 1 (mCor 1) may include the nucleotide sequence of SEQ ID NO: 7. Specifically, the gene includes a nucleotide sequence having a sequence homology of 70% or more, more preferably 80% or more, even more preferably 90% or more, and most preferably 95% or more to the nucleotide sequence of SEQ ID NO: 7. can
또한, 상기 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질을 ER(소포체)에 고농도로 축적하기 위해, 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질을 코딩하는 유전자의 N- 및 C-말단에 각각 BiP(chaperone binding protein)의 리더 서열(leader sequence)과 소포체 보유 신호(ER retention signal)인 HDEL를 추가할 수 있다. 상기 BiP를 코딩하는 유전자는 서열번호 9의 염기서열을 포함할 수 있고, HDEL(His-Asp-Glu-Leu)는 서열번호 10의 염기서열을 포함할 수 있다.In addition, in order to accumulate the recombinant protein derived from the spike protein of the coronavirus at a high concentration in the ER (endoplasmic reticulum), BiP (chaperone binding protein) at the N- and C-terminus of the gene encoding the recombinant protein derived from the spike protein of the corona virus, respectively of the leader sequence and HDEL, which is an ER retention signal, can be added. The BiP-encoding gene may include the nucleotide sequence of SEQ ID NO: 9, and HDEL (His-Asp-Glu-Leu) may include the nucleotide sequence of SEQ ID NO: 10.
본 발명의 구체적인 일실시예에서는 다음을 포함하는 컨스트럭트를 이용하여, 1) 코로나-19 바이러스의 스파이크 단백질에서 막 관통 도메인(transmembrane domain)부터 C-말단까지 결여된 전장 엑토도메인(full length ectodomain)을 포함하는 재조합 단백질(전장 또는 S-f로 명명함), 2) 코로나-19 바이러스의 스파이크 단백질에서 N-말단부터 서브도메인 2(subdomain 2; SD2)까지 포함하는 재조합 단백질(S1으로 명명함), 및 코로나-19 바이러스의 스파이크 단백질의 S2 서브유닛에서 막관통 도메인부터 C-말단까지 결여된 부위를 포함하는 재조합 단백질(S2로 명명함)을 각각 제조하였다:In a specific embodiment of the present invention, by using a construct comprising the following, 1) a full length ectodomain lacking from the transmembrane domain to the C-terminus in the spike protein of Corona-19 virus (full length ectodomain) ) comprising a recombinant protein (named full-length or Sf), 2) a recombinant protein comprising from the N-terminus to subdomain 2 (SD2) in the spike protein of Corona-19 virus (named S1), and a recombinant protein (designated as S2) comprising a region lacking from the transmembrane domain to the C-terminus in the S2 subunit of the spike protein of Corona-19 virus (named as S2) was prepared, respectively:
(i) 코로나-19 바이러스의 스파이크 단백질에서 막관통 도메인(transmembrane domain)부터 C-말단까지 결여된 전장 엑토 도메인(full length ectodomain)을 포함하는 재조합 단백질(전장 또는 S-f로 명명함), 코로나-19 바이러스의 스파이크 단백질에서 N-말단부터 서브도메인 2(subdomain 2; SD2)까지 포함하는 재조합 단백질(S1으로 명명함), 또는 코로나-19 바이러스의 스파이크 단백질의 S2 서브유닛에서 막관통 도메인부터 C-말단까지 결여된 부위를 포함하는 재조합 단백질(S2로 명명함)을 코딩하는 유전자;(ii) 상기 3종의 재조합 단백질을 소포체에 발현시키기 위해 상기 각각의 재조합 단백질의 N-말단에 융합된 애기장대의 BiP의 리더 서열을 코딩하는 유전자 부위;(iii) 상기 각각의 재조합 단백질의 C-말단에 순차적으로 융합된 Coronin 1(mCor 1)의 삼량체 모티프(trimeric motif) 부위의 단백질을 코딩하는 유전자, 단량체 인간 Fc를 코딩하는 유전자 및 ER 보유 모티프인 HDEL을 코딩하는 유전자.(i) a recombinant protein comprising a full length ectodomain lacking from the transmembrane domain to the C-terminus in the spike protein of the Corona-19 virus (named full-length or Sf), Corona-19 Recombinant protein containing from N-terminus to subdomain 2 (SD2) in the spike protein of the virus (designated as S1), or from the transmembrane domain to the C-terminus in the S2 subunit of the spike protein of the Corona-19 virus A gene encoding a recombinant protein (named S2) containing a region lacking until; (ii) Arabidopsis thaliana fused to the N-terminus of each recombinant protein to express the three recombinant proteins in the endoplasmic reticulum; A gene region encoding the leader sequence of BiP; (iii) a gene encoding a protein of a trimeric motif region of Coronin 1 (mCor 1) sequentially fused to the C-terminus of each recombinant protein, monomer A gene encoding human Fc and a gene encoding HDEL, which is an ER retention motif.
상기와 같이 구성된 3종의 스파이크 단백질 유래 재조합 단백질을 코딩하는 유전자(BiP:S-f:mCor1:mhFC:HDEL, BiP:S1:mCor1:mhFC:HDEL 및 BiP:S2:mCor1:mhFC:HDEL)의 발현을 위해 적절한 프로모터를 선택하여 적용할 수 있다. 예를 들어, 꽃양배추 모자이크 바이러스(cauliflower mosaic virus)에서 유래한 35S 프로모터, 꽃양배추 모자이크 바이러스(cauliflower mosaic virus)에서 유래한 19S RNA 프로모터, Mac 프로모터(Mac promoter), 식물의 액틴 단백질 프로모터 및 유비퀴틴 단백질 프로모터로 이루어진 군으로부터 선택되는 어느 하나의 프로모터를 추가로 포함할 수 있으며, 바람직하게는 Mac 프로모터(Mac promoter)를 포함할 수 있으며, 더 바람직하게는 MacT 프로모터(MacT promoter)를 포함할 수 있으나, 이로 한정되지 않는다.The expression of the genes encoding the three types of spike protein-derived recombinant proteins constructed as described above (BiP:Sf:mCor1:mhFC:HDEL, BiP:S1:mCor1:mhFC:HDEL and BiP:S2:mCor1:mhFC:HDEL) was It can be applied by selecting an appropriate promoter for this purpose. For example, 35S promoter derived from cauliflower mosaic virus, 19S RNA promoter derived from cauliflower mosaic virus, Mac promoter, plant actin protein promoter and ubiquitin protein It may further include any one promoter selected from the group consisting of promoters, preferably it may include a Mac promoter (Mac promoter), more preferably it may include a MacT promoter (MacT promoter), It is not limited to this.
상기 MacT 프로모터는 Mac 프로모터 염기서열의 3'말단 염기인 A를 T로 치환한 프로모터일 수 있고, 상기 MacT 프로모터는 서열번호 16의 염기서열을 포함할 수 있으며, 구체적으로 상기 유전자는 서열번호 16의 염기서열과 70% 이상, 보다 바람직하게는 80% 이상, 보다 더 바람직하게는 90% 이상, 가장 바람직하게는 95% 이상의 서열 상동성을 가지는 염기서열을 포함할 수 있다.The MacT promoter may be a promoter in which A, which is the 3' terminal base of the Mac promoter base sequence, is substituted with T, and the MacT promoter may include the base sequence of SEQ ID NO: 16, and specifically, the gene is of SEQ ID NO: 16 It may include a nucleotide sequence having a sequence homology of 70% or more, more preferably 80% or more, even more preferably 90% or more, and most preferably 95% or more to the nucleotide sequence.
또한, 상기 컨스트럭트는 RD29B-t 종결 부위를 추가로 포함할 수 있고, 상기 RD29B-t 종결 부위 유전자는 서열번호 17의 염기서열을 포함할 수 있으며, 구체적으로 상기 유전자는 서열번호 17의 염기서열과 70% 이상, 보다 바람직하게는 80% 이상, 보다 더 바람직하게는 90% 이상, 가장 바람직하게는 95% 이상의 서열 상동성을 가지는 염기서열을 포함할 수 있다.In addition, the construct may further include an RD29B-t termination site, and the RD29B-t termination site gene may include the nucleotide sequence of SEQ ID NO: 17, and specifically, the gene includes the nucleotide sequence of SEQ ID NO: 17 and 70% or more, more preferably 80% or more, even more preferably 90% or more, and most preferably 95% or more.
본 발명의 바람직한 일실시예에 따르면, 전술한 삼량체를 형성하는 3종의 재조합 스파이크 단백질들은 도 1의 (a), (b) 또는 (c)의 유전자 컨스트럭트를 포함하는 재조합 벡터를 이용하여 생산될 수 있다.According to a preferred embodiment of the present invention, the three types of recombinant spike proteins forming the above-mentioned trimer are obtained by using a recombinant vector containing the gene construct of FIG. 1 (a), (b) or (c). can be produced by
본 발명에서 디자인된 삼량체를 형성하는 3종의 재조합 스파이크 단백질들을 코딩하는 컨스트럭트는 적절한 벡터를 이용하여 숙주에 도입시킬 수 있다.The construct encoding the three recombinant spike proteins forming the trimer designed in the present invention can be introduced into a host using an appropriate vector.
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, 그러나 상기 유전자는 변형된 것으로서 인위적인 수단에 의해 세포 내 재도입된 것이다.As used herein, the term "recombinant" refers to a cell in which the cell replicates a heterologous nucleic acid, expresses the nucleic acid, or expresses a peptide, a heterologous peptide, or a protein encoded by the heterologous nucleic acid. Recombinant cells can express genes or gene segments not found in the native form of the cell in either the sense or antisense form. Recombinant cells can also express genes found in cells in a natural state, but the genes are modified and re-introduced into cells by artificial means.
용어 "재조합 발현 벡터"는 세균 플라스미드, 파아지, 효모 플라스미드, 식물세포 바이러스, 포유동물 세포 바이러스 또는 다른 벡터를 의미한다. 대체로, 임의의 플라스미드 및 벡터는 숙주 내에서 복제 및 안정화시킬 수 있다면 사용 가능하다. 상기 발현 벡터의 중요한 특성은 복제 원점, 프로모터, 마커 유전자 및 번역 조절 요소(translation control element)를 가지는 것이다. 상기 재조합 발현 벡터 및 적당한 전사/번역 조절 신호를 포함하는 발현 벡터는 당업자에 주지된 방법에 의해 구축될 수 있다. 상기 방법은 시험관내 재조합 DNA 기술, DNA 합성 기술 및 생체 내 재조합 기술 등을 포함한다.The term "recombinant expression vector" means a bacterial plasmid, phage, yeast plasmid, plant cell virus, mammalian cell virus or other vector. In general, any plasmid and vector can be used as long as it can be replicated and stabilized in a host. An important characteristic of the expression vector is that it has an origin of replication, a promoter, a marker gene and a translation control element. The recombinant expression vector and the expression vector containing appropriate transcriptional/translational control signals can be constructed by methods well known to those skilled in the art. The method includes in vitro recombinant DNA technology, DNA synthesis technology, and in vivo recombination technology.
본 발명의 재조합 벡터의 바람직한 예는 적당한 숙주에 존재할 때 그 자체의 일부, 소위 T-영역을 식물 세포로 전이시킬 수 있는 Ti-플라스미드 벡터이다. 다른 유형의 Ti-플라스미드 벡터는 현재 식물 세포, 또는 잡종 DNA를 식물의 게놈 내에 적당하게 삽입시키는 새로운 식물이 생산될 수 있는 원형질체로 잡종 DNA 서열을 전이시키는데 이용되고 있다. Ti-플라스미드 벡터의 특히 바람직한 형태는 EP 0 120 516 B1호 및 미국 특허 제4,940,838호에 청구된 바와 같은 소위 바이너리(binary) 벡터이다. 본 발명에서 디자인된 삼량체를 형성하는 코로나 바이러스 유래 재조합 스파이크 단백질들을 코딩하는 컨스트럭트를 식물 숙주에 도입시키는데 이용될 수 있는 다른 적합한 벡터는 이중 가닥 식물 바이러스(예를 들면, CaMV) 및 단일 가닥 바이러스, 게미니 바이러스 등으로부터 유래될 수 있는 것과 같은 바이러스 벡터, 예를 들면 비완전성 식물 바이러스벡터로부터 선택될 수 있다. 그러한 벡터의 사용은 특히 식물 숙주를 적당하게 형질전환하는 것이 어려울 때 유리할 수 있다.A preferred example of the recombinant vector of the present invention is a Ti-plasmid vector capable of transferring a part of itself, the so-called T-region, into a plant cell when present in a suitable host. Another type of Ti-plasmid vector is currently being used to transfer hybrid DNA sequences into plant cells, or protoplasts from which new plants can be produced that properly insert the hybrid DNA into the genome of the plant. A particularly preferred form of the Ti-plasmid vector is the so-called binary vector as claimed in
전술한 재조합 벡터를 숙주 숙주세포 내로 운반하는 방법은, 숙주세포가 원핵세포인 경우, CaCl2 방법, 하나한 방법 및 전기천공 방법 등에 의해 실시될 수 있다. 또한, 숙주세포가 진핵세포인 경우에는, 미세주입법, 칼슘포스페이트 침전법, 전기천공법, 리포좀-매개 형질감염법, DEAE-덱스트란 처리법, 및 유전자 밤바드먼트 등에 의해 벡터를 숙주세포 내로 주입할 수 있다.The method for delivering the above-described recombinant vector into a host cell may be carried out by a CaCl2 method, a Hanhan method, an electroporation method, or the like when the host cell is a prokaryotic cell. In addition, when the host cell is a eukaryotic cell, the vector may be injected into the host cell by microinjection, calcium phosphate precipitation, electroporation, liposome-mediated transfection, DEAE-dextran treatment, and gene bombardment. can
상기 숙주세포는 원핵생물 또는 진핵생물일 수 있으며, 그 예로서, 효모(Saccharomyce cerevisiae), 대장균 등의 곰팡이, 곤충세포, 사람세포(예컨대, CHO 세포주(Chinese hamster ovary), W138, BHK, COS-7, 293, HepG2, 3T3, RIN 및 MDCK 세포주) 및 식물세포 등이 이용될 수 있으며, 바람직하게는 아그로박테리움(Agrobacterium)될 수 있다. 곤충세포, 사람세포 등의 경우에는 삼량체를 형성하는 재조합 HA 단백질을 코딩하는 유전자를 각 종류의 세포 발현에 필요한 발현 벡터를 사용하여 발현할 수 있다.The host cell may be a prokaryote or a eukaryote, for example, yeast (Saccharomyce cerevisiae), fungi such as E. coli, insect cells, human cells (eg, CHO cell line (Chinese hamster ovary), W138, BHK, COS- 7, 293, HepG2, 3T3, RIN and MDCK cell lines) and plant cells may be used, preferably Agrobacterium. In the case of insect cells and human cells, a gene encoding a recombinant HA protein forming a trimer can be expressed using an expression vector required for expression of each type of cell.
본 발명의 구체적인 일실시예에서는 식물의 잎 세포에 아그로박테리움 매개 침윤(Agrobacterium-mediated infiltration)을 이용하여 3종의 재조합 스파이크 단백질들을 코딩하는 컨스트럭트를 포함하는 재조합 벡터를 도입한 후 이들로부터 상기 재조합 유전자로 코딩되는 재조합 단백질을 생산하였다. 이어서, 식물의 잎 추출물에서 3종의 재조합 스파이크 단백질을 단백질 A 친화 컬럼 크로마토그래피를 이용하여 분리 정제하였다.In a specific embodiment of the present invention, a recombinant vector comprising a construct encoding three types of recombinant spike proteins is introduced into leaf cells of a plant using Agrobacterium-mediated infiltration, and then from these A recombinant protein encoded by the recombinant gene was produced. Then, the three recombinant spike proteins from the leaf extract of the plant were separated and purified using protein A affinity column chromatography.
본 발명의 구체적인 일실시예에서는, 상기 분리 정제된 3종의 삼량체 스파이크 재조합 단백질이 에스터가수분해효소의 활성을 갖는지를 확인하기 위해, 이들 3종의 삼량체 스파이크 재조합 단백질을 p-NPA라는 에스터가수분해효소의 일반적인 기질(general substrate)과 함께 시험관 내(in vitro) 배양하였다. 그 결과, 도 3에서 확인되는 바와 같이, 상기 3 종의 재조합 스파이크 단백질(BiP:S-f:mCor1:mhFC:HDEL, BiP:S1:mCor1:mhFC:HDEL, BiP:S2:mCor1:mhFC:HDEL)은 모두 에스터가수분해효소의 활성을 갖는 것으로 나타났다. 따라서, S1 및 S2가 각각 독립적인 에스터가수분해효소의 활성을 갖는 것으로 확인하였다.In a specific embodiment of the present invention, in order to confirm whether the separated and purified three kinds of trimer spike recombinant proteins have esterase activity, these three kinds of trimer spike recombinant proteins are esters called p-NPA. It was cultured in vitro with a general substrate of the hydrolase. As a result, as shown in FIG. 3 , the three recombinant spike proteins (BiP:Sf:mCor1:mhFC:HDEL, BiP:S1:mCor1:mhFC:HDEL, BiP:S2:mCor1:mhFC:HDEL) were All were shown to have esterase activity. Therefore, it was confirmed that S1 and S2 each have independent esterase activity.
일부 코로나 바이러스의 경우, HE라는 다른 단백질이 에스터가수분해효소의 활성을 보이는 것으로 알려졌지만, 지금까지 SARS-CoV나 COVID-19 코로나바이러스는 에스터가수분해효소의 활성이 존재하는지 여부에 대해서는 확인된 바가 없다. 본 발명에서 확인된 에스터가수분해효소는 활성의 정확한 역할은 알려져 있지 않지만, 바이러스의 에스터가수분해효소들은 바이러스 단백질이 동물 세포 표면에 존재하는 시알산과 같은 당 잔기에 결합되어 있는 것을 제거하는데 역할을 하는 것으로 알려져 있다. 따라서, 코로나 바이러스의 스파이크 단백질의 에스터가수분해효소 활성도 유사한 역할을 할 것으로 생각된다. 이에 따라, 에스터가수분해효소의 활성을 방해하면 바이러스의 감염과 세포로부터의 방출(release)에 중요한 역할을 할 것으로 예상되며, 바이러스 생성에 저해를 초래할 것으로 예상된다. In the case of some coronaviruses, another protein called HE is known to show esterase activity, but so far, it has not been confirmed whether SARS-CoV or COVID-19 coronaviruses have esterase activity. none. Although the exact role of the activity of the esterases identified in the present invention is not known, viral esterases play a role in removing the binding of viral proteins to sugar residues such as sialic acid present on the surface of animal cells. it is known Therefore, the esterase activity of the spike protein of coronavirus is thought to play a similar role. Accordingly, interfering with the activity of esterases is expected to play an important role in virus infection and release from cells, and is expected to result in inhibition of virus production.
이에 따라, 본 발명의 키트에는 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성을 측정할 수 있는 물질이 포함되며, 이러한 물질의 예로는 에스터가수분해효소의 기질; 시알산을 포함하는 화합물; BCECF, AM(2',7'-Bis-(2-카르복시에틸)-5-(앤드-6)-카르복시플루오레세인, 아세톡시메틸 에스테르)(BCECF, AM(2',7'-Bis-(2-Carboxyethyl)-5-(and-6)-Carboxyfluorescein, Acetoxymethyl Ester)); 칼세인 AM(Calcein AM); 카르복시에오신 디아세테이트, 숙신이미딜 에스테르(Carboxyeosin diacetate, succinimidyl ester); 카르복시플루오레세인 디아세테이트, 아세톡시메틸 에스테르(Carboxyfluorescein diacetate, acetoxymethyl ester); 또는 카르복시플루오레세인 디아세테이트, 숙신이미딜 에스테르(Carboxyfluorescein diacetate, succinimidyl ester)가 있으나, 이로 한정되는 것은 아니다.Accordingly, the kit of the present invention includes a material capable of measuring the esterase activity of a recombinant protein derived from the spike protein of coronavirus, and examples of such material include an esterase substrate; compounds comprising sialic acid; BCECF, AM(2',7'-Bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester) (BCECF, AM(2',7'-Bis- (2-Carboxyethyl)-5-(and-6)-Carboxyfluorescein, Acetoxymethyl Ester)); Calcein AM; Carboxyeosin diacetate, succinimidyl ester; Carboxyfluorescein diacetate, acetoxymethyl ester; Or carboxyfluorescein diacetate, succinimidyl ester (Carboxyfluorescein diacetate, succinimidyl ester), but is not limited thereto.
본 발명의 바람직한 다른 일실시예에 따르면, 상기 에스터가수분해효소의 기질은 파라 나이트로 페닐 아세테이트(para nitropheny acetate, p-NPA)와 같은 표준 기질일 수 있고, 상기 시알산을 포함하는 화합물은 Neu5,9Ac2, 4-메틸움벨리페릴 아세테이트(4-methylumbelliferyl acetate) 또는 9Ac2-락토오스(9Ac2-lactose)일 수 있으나, 이로 한정되는 것은 아니다.According to another preferred embodiment of the present invention, the substrate of the esterase may be a standard substrate such as para nitropheny acetate (p-NPA), and the compound containing sialic acid is Neu5 , 9Ac2, 4-methylumbelliferyl acetate (4-methylumbelliferyl acetate) or 9Ac2-lactose (9Ac2-lactose), but is not limited thereto.
본 발명의 제2 측면은 전술한 스크리닝 키트를 이용한 코로나 바이러스 감염증의 예방 또는 치료용 후보 물질을 스크리닝하는 방법에 관한 것이다.A second aspect of the present invention relates to a method of screening a candidate for preventing or treating a coronavirus infection using the above-described screening kit.
구체적으로, 본 발명의 스크리닝 방법은 하기의 단계를 포함할 수 있다:Specifically, the screening method of the present invention may include the following steps:
(i) 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질에 후보 물질을 처리하는 단계;(i) treating a candidate material with a recombinant protein derived from the spike protein of coronavirus;
(ii) 상기 후보 물질을 처리한 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성(esterase activity)을 측정하는 단계; 및 (ii) measuring the esterase activity of the recombinant protein derived from the spike protein of the corona virus treated with the candidate substance; and
(iii) 상기 후보 물질이 에스터가수분해효소 활성을 30% 이상 억제하는 경우, 상기 후보 물질을 코로나 바이러스의 예방 또는 치료용 후보 물질로 선별하는 단계.(iii) when the candidate material inhibits esterase activity by 30% or more, selecting the candidate material as a candidate material for prevention or treatment of coronavirus.
본 발명의 스크리닝 방법에 있어서, 상기(i) 단계의 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질은 스파이크 단백질의 S1 서브유닛 또는 S2 서브유닛을 포함하거나, 상기 S1 서브유닛과 상기 S2 서브유닛을 모두 포함하는, 삼량체 형태의 재조합 스파이크 단백질일 수 있다.In the screening method of the present invention, the recombinant protein derived from the spike protein of the corona virus in step (i) includes the S1 subunit or the S2 subunit of the spike protein, or includes both the S1 subunit and the S2 subunit , it may be a trimeric form of recombinant spike protein.
전술한 바와 같이, 본 발명에서는 분리 정제된 재조합 단백질 S1 및 S2가 각각 독립적으로 에스터가수분해효소 활성을 나타내는 것으로 확인되었으므로, 상기 S1 및/또는 S2를 포함하는 다양한 형태의 재조합 단백질을 사용하여 이의 에스터가수분해효소 활성을 확인함으로써, 코로나 바이러스 감염증의 예방 또는 치료용 후보 물질을 스크리닝할 수 있다.As described above, in the present invention, since it was confirmed that the separated and purified recombinant proteins S1 and S2 each independently exhibit esterase activity, various types of recombinant proteins including the S1 and/or S2 were used to ester their esters. By confirming the hydrolase activity, it is possible to screen candidate substances for the prevention or treatment of coronavirus infection.
본 발명의 스크리닝 방법에 있어서, 상기 후보 물질은 에스터가수분해효소를 저해하는 물질을 제한 없이 포함하며, 예를 들어, 화합물, 미생물 배양액, 미생물 추출물, 핵산, 항체, 단백질, 펩타이드, 압타머 및 천연 추출물로 이루어진 군으로부터 선택되는 어느 하나일 수 있으나, 이로 한정되지 않는다.In the screening method of the present invention, the candidate substances include, without limitation, substances that inhibit esterases, for example, compounds, microbial cultures, microbial extracts, nucleic acids, antibodies, proteins, peptides, aptamers and natural substances. It may be any one selected from the group consisting of extracts, but is not limited thereto.
상기 핵산은 microRNA, siRNA, shRNA, 안티센스 RNA, 압타머(aptamer), LNA(locked nucleic acid), PNA(peptide nucleic acid), 및 모폴리노(morpholino)로 이루어진 군으로부터 선택되는 것일 수 있으나, 이에 한정되는 것은 아니다.The nucleic acid may be selected from the group consisting of microRNA, siRNA, shRNA, antisense RNA, aptamer, LNA (locked nucleic acid), PNA (peptide nucleic acid), and morpholino (morpholino), but It is not limited.
본 발명에서 사용되는 용어, "micro RNA"란 약 22개의 염기서열로 이루어진 짧은 비코딩(non-coding) RNA를 의미한다. 유전자의 발현 과정에서 전사 후 조절인자(post-transcriptional regulator)로서 기능을 한다고 알려져 있다. 상보적인 염기 서열을 가진 표적(target) mRNA에 상보적으로 결합함으로써 표적 mRNA들을 분해시키거나 단백질로 번역되는 것을 억제한다.As used herein, the term "micro RNA" refers to a short non-coding RNA consisting of about 22 nucleotide sequences. It is known to function as a post-transcriptional regulator in the process of gene expression. By complementary binding to a target mRNA having a complementary base sequence, degradation of the target mRNA or translation into a protein is inhibited.
본 발명에서 사용되는 용어, "siRNA(small interfering RNA)"란 특정 mRNA의 절단(cleavage)을 통하여 RNA간섭(RNA interference; RNAi) 현상을 유도할 수 있는 짧은 이중사슬 RNA를 의미한다. 타겟 유전자의 mRNA와 상동인 서열을 가지는 센스 RNA 가닥과 이와 상보적인 서열을 가지는 안티센스 RNA 가닥으로 구성된다. siRNA는 타겟 유전자의 발현을 억제할 수 있기 때문에 효율적인 유전자 넉다운(knock-down) 방법으로서 또는, 유전자치료(gene therapy)의 방법으로 제공된다.As used herein, the term “small interfering RNA (siRNA)” refers to a short double-stranded RNA capable of inducing an RNA interference (RNAi) phenomenon through cleavage of a specific mRNA. It is composed of a sense RNA strand having a sequence homologous to the mRNA of a target gene and an antisense RNA strand having a sequence complementary thereto. Since siRNA can inhibit the expression of a target gene, it is provided as an efficient gene knock-down method or as a gene therapy method.
본 발명에서 사용되는 용어 "shRNA(small hairpin RNA)"란 단일 가닥으로 50-60개로 구성된 뉴클레오타이드를 의미하며, in vivo상에서 스템-루프(stem-loop) 구조를 이루고 있다. 즉, shRNA는 RNA 간섭을 통해 유전자 발현을 억제하기 위한 타이트한 헤어핀 구조를 만드는 RNA 서열이다. 5-10개의 뉴클레오타이드의 루프 부위 양쪽으로 상보적으로 15-30개의 뉴클레오타이드의 긴 RNA가 염기쌍을 이루어 이중가닥의 스템을 형성한다. shRNA는 언제나 발현되도록 하기 위하여 U6 프로모터를 포함하는 벡터를 통해 세포 내로 형질주입되며 대개 딸세포로 전달되어 유전자 발현 억제가 유전되도록 한다. shRNA 헤어핀 구조는 세포 내 기작에 의하여 절단되어 siRNA가 된 후 RISC(RNA-induced silencing complex)에 결합한다. 이들 RISC는 mRNA에 결합하여 이를 절단한다. shRNA는 RNA 폴리머레이즈(polymerase)에 의해 전사된다.As used herein, the term “shRNA (small hairpin RNA)” refers to a single strand consisting of 50 to 60 nucleotides, and forms a stem-loop structure in vivo. That is, shRNA is an RNA sequence that creates a tight hairpin structure for suppressing gene expression through RNA interference. A long RNA of 15-30 nucleotides is complementary to both sides of a loop of 5-10 nucleotides to form a double-stranded stem. In order to always be expressed, shRNA is transfected into cells through a vector containing a U6 promoter, and is usually transferred to daughter cells so that gene expression suppression is inherited. The shRNA hairpin structure is cleaved by an intracellular mechanism to become siRNA and then binds to RISC (RNA-induced silencing complex). These RISCs bind to and cleave mRNA. shRNA is transcribed by RNA polymerase.
본 발명에서, 용어 “압타머”란 특정 물질에 대해 높은 특이성과 친화도를 가지는 단일가닥 DNA(ssDNA) 또는 RNA 를 말한다. 앱타머는 특정 물질에 대한 친화도가 매우 높고 안정하고, 비교적 단순한 방법으로 합성할 수 있으며, 결합력을 높이기 위해 다양한 변형이 가능하고, 세포, 단백질, 및 작은 유기물질까지도 표적물질이 될 수 있기 때문에, 그 특이성 및 안정성이 이미 개발되어 있는 항체에 비해 매우 높은 특징이 있다.In the present invention, the term “aptamer” refers to single-stranded DNA (ssDNA) or RNA having high specificity and affinity for a specific substance. Aptamers have very high affinity for specific substances and are stable, can be synthesized by a relatively simple method, can be modified in various ways to increase binding strength, and can be targeted to cells, proteins, and even small organic substances. Its specificity and stability are very high compared to antibodies that have already been developed.
본 발명의 스크리닝 방법에 있어서, 상기(ii) 단계의 에스터가수분해효소 활성(esterase activity)은 에스터가수분해효소 기질 또는 시알산을 포함하는 화합물을 이용하여 측정할 수 있다. 예를 들어, 에스터가수분해효소의 표준 기질인 pNPA를 후보 물질이 처리된 재조합 스파이크 단백질과 배양하고, 이로부터 방출되는 파라니트로페놀의 양을 측정함으로써 후보 물질의 에스터가수분해효소 저해 활성을 평가할 수 있다. 다르게는, 시알산을 포함하는 화합물을 후보 물질이 처리된 재조합 스파이크 단백질과 배양하고, 이로부터 방출되는 시알산의 양을 측정함으로써 후보 물질의 에스터가수분해효소 저해 활성을 평가할 수 있다.In the screening method of the present invention, the esterase activity in step (ii) can be measured using an esterase substrate or a compound containing sialic acid. For example, the esterase inhibitory activity of a candidate substance can be evaluated by incubating pNPA, a standard substrate for an esterase, with a recombinant spike protein treated with a candidate substance, and measuring the amount of paranitrophenol released therefrom. have. Alternatively, the esterase inhibitory activity of the candidate substance may be evaluated by incubating a compound containing sialic acid with a recombinant spike protein treated with a candidate substance, and measuring the amount of sialic acid released therefrom.
본 발명의 스크리닝 방법에 있어서, 상기(iii) 단계에서 선별된 후보 물질은 적어도 30% 이상, 바람직하게는 50% 이상의 에스터가수분해효소 저해 활성을 나타내므로, 코로나 바이러스 감염증의 치료제로 개발하기 위한 유효성분으로 활용될 수 있다. In the screening method of the present invention, since the candidate material selected in step (iii) exhibits esterase inhibitory activity of at least 30% or more, preferably 50% or more, effective for development as a therapeutic agent for coronavirus infection It can be used as an ingredient.
본 발명의 구체적인 일실시예에서는, 식물 잎으로부터 분리 정제된 3종의 스파이크 재조합 단백질을 이용하여, 스파이크 단백질의 S1과 S2에 존재하는 에스터가수분해효소의 활성을 저해하는 물질을 스크리닝 하고자 하였다. 이를 위해, 에스터가수분해효소의 저해제로 알려진 여러 종류의 화합물들 중에서 먼저 아세타졸아미드(acetazoleamide), 설파닐아미드(sulfanilaminde), 설파피리딘(sulfapyridin) 및 설파메톡사졸(sulfamethoxazole)이라는 4종의 화합물을 선택하여 이들 화합물이 스파이크 단백질의 에스터가수분해효소 활성을 저해하는지 여부를 확인하였다. 에스터가수분해효소의 기질로는 pNPA를 사용하였고, 0.2 μg의 순수 분리된 스파이크 단백질에 상기 4종의 화합물을 0.5 mM, 1.0 mM, 또는 2.0mM의 농도로 각각 처리하여 배양한 후 37℃에서 효소 활성을 측정하였다. 그 결과, 도 4에 나타난 바와 같이 상기 4종의 화합물 중에서 설파메톡사졸(sulfamethoxazole)이 1.0 mM의 농도에서 스파이크 단백질의 에스터가수분해효소의 활성을 약 50% 정도 저해하는 것을 확인하였다.In a specific embodiment of the present invention, it was attempted to screen for substances that inhibit the activity of esterases present in S1 and S2 of the spike protein using three kinds of recombinant spike proteins isolated and purified from plant leaves. For this purpose, among the various types of compounds known as inhibitors of esterases, first four types of compounds, namely acetazoleamide, sulfanilaminde, sulfapyridin, and sulfamethoxazole, were prepared. By selection, it was determined whether these compounds inhibit the esterase activity of the spike protein. pNPA was used as a substrate for esterase, and 0.2 μg of pure isolated spike protein was treated with the above four compounds at a concentration of 0.5 mM, 1.0 mM, or 2.0 mM, respectively, and incubated at 37 ° C. Activity was measured. As a result, as shown in FIG. 4 , it was confirmed that among the four compounds, sulfamethoxazole inhibited the activity of the spike protein esterase by about 50% at a concentration of 1.0 mM.
본 발명에서 확인한 스파이크 단백질의 에스터가수분해효소 활성 저해제인 설파메톡사졸을 기반으로 추가적인 변형을 통해서 더 나은 저해 활성을 갖는 물질을 합성할 수 있을 것이다. 또한, 스파이크 단백질과 에스터가수분해효소 기질인 p-NPA가 결합한 복합체의 구조를 규명하고, 이를 이용하여 에스터가수분해효소의 활성 부위를 확인한 후, 이를 기반으로 더 나은 에스터가수분해효소 활성 저해제를 개발하는 것이 가능하다.It will be possible to synthesize a substance having better inhibitory activity through additional modification based on sulfamethoxazole, which is an esterase activity inhibitor of the spike protein identified in the present invention. In addition, the structure of the complex in which the spike protein and p-NPA, which is an esterase substrate, is combined, and the active site of the esterase by using it, is identified, and based on this, a better inhibitor of esterase activity is developed. it is possible to do
따라서, 본 발명의 제3 측면은 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성 저해제를 유효성분으로 포함하는, 코로나 바이러스 감염증의 예방 또는 치료용 약학 조성물에 관한 것이다.Accordingly, a third aspect of the present invention relates to a pharmaceutical composition for preventing or treating coronavirus infection, comprising an inhibitor of esterase activity of a recombinant protein derived from a spike protein of coronavirus as an active ingredient.
본 발명의 약학 조성물에 있어서, 상기 선별된 에스터가수분해효소 활성 저해제는 에스터가수분해효소의 활성 부위에 결합하여 에스터가수분해효소의 활성을 저해하거나, 에스터가수분해효소의 활성 부위가 아닌 다른 부위에 결합하여 에스터가수분해효소의 구조 변화를 유도하여 에스터가수분해효소의 활성을 저해하는 것일 수 있다.In the pharmaceutical composition of the present invention, the selected esterase activity inhibitor binds to the active site of the esterase to inhibit the activity of the esterase, or to a site other than the active site of the esterase. It may be to inhibit the activity of the esterase by inducing a structural change of the esterase by binding.
전술한 바와 같이, 본 발명의 구체적인 일실시예에서는 설파메톡사졸(sulfamethoxazole)이 코로나-19 바이러스의 스파이크 단백질의 에스터가수분해효소 활성을 약 50% 정도 저해하는 것을 확인하였다. 이에 따라, 본 발명은 설파메톡사졸(sulfamethoxazole), 이의 유도체, 이성질체 또는 약학적으로 허용 가능한 염을 유효성분으로 포함하는, 코로나-19 바이러스 감염증의 예방 또는 치료용 약학적 조성물을 제공한다.As described above, in a specific embodiment of the present invention, it was confirmed that sulfamethoxazole inhibited the esterase activity of the spike protein of Corona-19 virus by about 50%. Accordingly, the present invention provides a pharmaceutical composition for preventing or treating COVID-19 virus infection, comprising sulfamethoxazole, a derivative, isomer, or pharmaceutically acceptable salt thereof as an active ingredient.
본 발명에서, 용어 "유도체"는 설파메톡사졸의 구조 일부를 다른 원자나 원자단으로 치환하여 얻어지는 화합물을 의미한다. 상기 "약학적으로 허용 가능한 염"은 유기산 또는 무기산을 이용하여 형성된 산 부가염일 수 있으며, 상기 유기산은 예를 들면 포름산, 아세트산, 프로피온산, 락트산, 부티르산, 이소부티르산, 트리플루오로아세트산, 말산, 말레산, 말론산, 푸마르산, 숙신산, 숙신산 모노아미드, 글루탐산, 타르타르산, 옥살산, 시트르산, 글리콜산, 글루쿠론산, 아스코르브산, 벤조산, 프탈산, 살리실산, 안트라닐산, 디클로로아세트산, 아미노옥시 아세트산, 벤젠술폰산, p-톨루엔술폰산 또는 메탄술폰산을 포함한다. 무기산은 예를 들면 염산, 브롬산, 황산, 인산, 질산, 탄산 또는 붕산을 포함한다. 산 부가염은 바람직하게는 염산염 또는 아세트산염 형태일 수 있으며, 보다 바람직하게는 염산염 형태일 수 있다.In the present invention, the term "derivative" refers to a compound obtained by substituting a part of the structure of sulfamethoxazole with another atom or group of atoms. The "pharmaceutically acceptable salt" may be an acid addition salt formed using an organic acid or an inorganic acid, and the organic acid is, for example, formic acid, acetic acid, propionic acid, lactic acid, butyric acid, isobutyric acid, trifluoroacetic acid, malic acid, maleic acid Acid, malonic acid, fumaric acid, succinic acid, succinic acid monoamide, glutamic acid, tartaric acid, oxalic acid, citric acid, glycolic acid, glucuronic acid, ascorbic acid, benzoic acid, phthalic acid, salicylic acid, anthranilic acid, dichloroacetic acid, aminooxyacetic acid, benzenesulfonic acid, p-toluenesulfonic acid or methanesulfonic acid. Inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid or boric acid. The acid addition salt may preferably be in the form of hydrochloride or acetate, and more preferably in the form of hydrochloride.
이외에도 추가적으로 염이 가능한 형태는 가바염, 가바펜틴염, 프레가발린염, 니코틴산염, 아디페이트염, 헤미말론산염, 시스테인염, 아세틸시스테인염, 메티오닌염, 아르기닌염, 라이신염, 오르니틴염 또는 아스파르트산염 등이 있다.In addition, additional salts available include gaba salt, gabapentin salt, pregabalin salt, nicotinate salt, adipate salt, hemimalonate, cysteine salt, acetylcysteine salt, methionine salt, arginine salt, lysine salt, ornithine salt or aspartate salt etc.
또한, 본 발명의 약학적 조성물은 약학적으로 허용가능한 담체를 더 포함할 수 있다. 약학적으로 허용되는 담체로는 예컨대, 경구 투여용 담체 또는 비경구 투여용 담체를 추가로 포함할 수 있다. 경구 투여용 담체는 락토스, 전분, 셀룰로스 유도체, 마그네슘 스테아레이트, 스테아르산 등을 포함할 수 있다. 비경구 투여용 담체는 물, 적합한 오일, 식염수, 수성 글루코스 및 글리콜 등을 포함할 수 있다. 또한, 안정화제 및 보존제를 추가로 포함할 수 있다. 적합한 안정화제로는 아황산수소나트륨, 아황산나트륨 또는 아스코르브산과 같은 항산화제가 있다. 적합한 보존제로는 벤즈알코늄 클로라이드, 메틸- 또는 프로필-파라벤 및 클로로부탄올이 있다. 그 밖의 약학적으로 허용되는 담체로는 다음의 문헌에 기재되어 있는 것을 참고로 할 수 있다(Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).In addition, the pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may further include, for example, a carrier for oral administration or a carrier for parenteral administration. Carriers for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Carriers for parenteral administration may include water, suitable oils, saline, aqueous glucose and glycols, and the like. In addition, it may further include a stabilizer and a preservative. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives are benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. As other pharmaceutically acceptable carriers, reference may be made to those described in the following literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, PA, 1995).
본 발명에서, 용어 "이성질체"란 화학식은 같으나 동일하지는 않은 화합물의 관계를 의미하며, 이러한 이성질체의 종류에는 구조 이성질체, 기하 이성질체, 광학 이성질체 및 기하 이성질체가 있다. 입체이성질체란, 동일한 화학적 구성을 갖지만, 공간 중에서 원자 또는 기의 배열의 측면에서 상이한 화합물 의미하고, 광학 이성질체(거울상 이성질체)는 서로 겹치지 않는 거울상을 갖는 한 화합물의 두 입체이성질체를 의미하며, 부분입체이성질체는 둘 이상의 비대칭 중심을 가지고 그것의 분자들이 서로 거울상이 아닌 입체이성질체를 의미한다.In the present invention, the term "isomer" means a relationship between compounds having the same chemical formula but not identical, and the types of such isomers include structural isomers, geometric isomers, optical isomers and geometric isomers. By stereoisomer is meant a compound that has the same chemical constitution but differs in the arrangement of atoms or groups in space, and optical isomer (enantiomer) means two stereoisomers of a compound that have non-superimposable mirror images of each other, diastereomers An isomer means a stereoisomer that has two or more asymmetric centers and whose molecules are not mirror images of each other.
본 발명의 약학 조성물은 상기 성분에 추가로 동일 또는 유사한 기능을 나타내는 유효성분을 1종 이상 포함할 수 있다. 본 발명의 약학적 조성물은 약제학적으로 허용 가능한 첨가제를 더 포함할 수 있으며, 이때 약제학적으로 허용 가능한 첨가제로는 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바 납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 사용될 수 있다. 본발명에 따른 약제학적으로 허용 가능한 첨가제는 상기 조성물에 대해 0.1 ~ 90 중량부 포함될 수 있으나, 이에 한정되는 것은 아니다.The pharmaceutical composition of the present invention may include one or more active ingredients exhibiting the same or similar function in addition to the above ingredients. The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive includes starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicon dioxide, calcium hydrogen phosphate. , lactose, mannitol, syrup, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, lead carnauba, synthetic aluminum silicate, stearic acid, magnesium stearate, aluminum stearate, Calcium stearate, sucrose, dextrose, sorbitol and talc and the like may be used. The pharmaceutically acceptable additive according to the present invention may be included in an amount of 0.1 to 90 parts by weight based on the composition, but is not limited thereto.
본 발명의 약학적 조성물은 실제 임상 투여 시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있는데, 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 본 발명의 추출물에 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(Calcium carbonate), 수크로스(Sucrose), 락토오스(Lactose) 또는 젤라틴 등을 섞어 조제될 수 있다. 또한, 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용될 수 있다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데 흔히 사용되는 단순희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제, 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제, 좌제가 포함될 수 있다. 비수성용제, 현탁용제로는 프로필렌 글리콜(Propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세로제라틴 등이 사용될 수 있다.The pharmaceutical composition of the present invention may be administered in various oral and parenteral formulations during actual clinical administration, and when formulated, commonly used fillers, extenders, binders, wetting agents, disintegrants, diluents or excipients such as surfactants It can be prepared using Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations include at least one excipient in the extract of the present invention, for example, starch, calcium carbonate, sucrose (Sucrose), may be prepared by mixing lactose (Lactose) or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc may also be used. Liquid formulations for oral use include suspensions, solutions, emulsions, and syrups, and various excipients such as wetting agents, sweetening agents, fragrances, and preservatives in addition to commonly used simple diluents such as water and liquid paraffin may be included. . Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Non-aqueous solvents and suspensions may include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin, glycerogelatin, and the like can be used.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구 투여할 수 있으며, 비경구 투여시 피부 외용 또는 복강 내 주사, 직장 내 주사, 피하주사, 정맥주사, 근육 내 주사 또는 흉부 내 주사 주입방식을 선택할 수 있다. 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따라 그 범위가 다양할 수 있다.The pharmaceutical composition of the present invention may be administered orally or administered parenterally according to a desired method, and when administered parenterally, external skin or intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection You can choose the injection method. The dosage may vary depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate, and severity of disease.
본 발명의 약학적 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도에 따라 그 범위가 다양하며, 일일 투여량은 본 발명의 추출물의 양을 기준으로 0.0001 mg/kg 내지 100 mg/kg일 수 있으며, 구체적으로 0.001 mg/kg 내지 10 mg/kg일 수 있으나, 이에 제한되지 않는다.The dosage of the pharmaceutical composition of the present invention varies depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate and severity of disease, and the daily dosage is the dosage of the present invention. It may be 0.0001 mg/kg to 100 mg/kg based on the amount of the extract, and specifically 0.001 mg/kg to 10 mg/kg, but is not limited thereto.
본 발명에서, 용어 "예방", "개선" 및/또는 "치료"는 질병 또는 병증의 발병을 억제하거나 지연시키는 모든 행위, 질병 또는 병증 상태를 호전 또는 이롭게 변경하는 모든 행위, 및 질병 또는 병증의 진행을 지연, 중단 또는 역전시키는 모든 행위를 의미한다.In the present invention, the terms “prevention”, “amelioration” and/or “treatment” refer to any action that inhibits or delays the onset of a disease or condition, any action that ameliorates or beneficially alters the disease or condition state, and the treatment of the disease or condition. means any action that delays, stops or reverses progress.
본 발명에 따른 약학 조성물은 기존의 코로나 바이러스 감염증 치료제와 병용 투여될 수 있다. 용어 "병용 투여(administered in combination)"는 본 발명의 약학 조성물이 기존의 코로나 바이러스 감염증 치료제와 함께 이를 필요로 하는 개체에게 투여되는 것을 의미한다. 각각의 성분이 함께 투여된다는 것은 원하는 효과를 얻기 위해서, 각 성분을 동시에(simultaneous), 별도로(separate) 또는 순차적(sequential)으로 투여될 수 있음을 의미한다.The pharmaceutical composition according to the present invention may be administered in combination with an existing therapeutic agent for coronavirus infection. The term "administered in combination" means that the pharmaceutical composition of the present invention is administered to a subject in need thereof together with an existing therapeutic agent for coronavirus infection. Administering each component together means that each component may be administered simultaneously, separately, or sequentially to obtain a desired effect.
나아가, 본 발명의 제4 측면은 설파메톡사졸(sulfamethoxazole), 이의 유도체, 이성질체 또는 식품학적으로 허용 가능한 염을 유효성분으로 포함하는, 코로나-19 바이러스 감염증의 예방 또는 개선용 건강기능식품 조성물에 관한 것이다. Furthermore, a fourth aspect of the present invention relates to a health functional food composition for preventing or improving Corona-19 virus infection, comprising sulfamethoxazole, a derivative, isomer, or pharmaceutically acceptable salt thereof as an active ingredient. will be.
본 발명에서 용어, "식품"은 예를 들어, 각종 식품류, 음료, 껌, 차, 비타민 복합제, 건강 기능성 식품류 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다. 상기 식품은 공지의 제조방법에 따라 정제, 과립, 분말, 캅셀, 액상의 용액 및 환 등의 제형으로 제조할 수 있으며, 본 발명에 따른 추출물의 함량은 제형에 따라 식품 조성물 총 중량을 기준으로 0.0001중량% 내지 100중량%로 조절할 수 있다. 본 발명의 화합물을 포함하는 외에는 다른 성분에는 특별한 제한이 없으며, 통상의 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 포함할 수 있다.As used herein, the term "food" includes, for example, various foods, beverages, gum, tea, vitamin complexes, health functional foods, and the like, and includes all foods in a conventional sense. The food can be prepared in dosage forms such as tablets, granules, powders, capsules, liquid solutions and pills according to a known manufacturing method, and the content of the extract according to the present invention is 0.0001 based on the total weight of the food composition depending on the dosage form. It can be adjusted to 100% by weight to 100% by weight. There is no particular limitation on other ingredients other than including the compound of the present invention, and various conventional flavoring agents or natural carbohydrates may be included as additional ingredients.
상기 천연 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스 등; 및 폴리사카라이드, 예를 들어 덱스트린, 시클로덱스트린 등과 같은 통상적인 당, 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 상술한 것 이외의 향미제로서 천연 향미제(타우마틴, 스테비아 추출물(예를 들어, 레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 유리하게 사용할 수 있다. Examples of the natural carbohydrate include monosaccharides such as glucose, fructose and the like; disaccharides such as maltose, sucrose and the like; and polysaccharides such as conventional sugars such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatine, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. have.
본 발명에서 용어, "건강기능(성) 식품"은 특정보건용 식품(food for special health use, FoSHU)와 동일한 용어로, 영양 공급 외에도 생체조절기능이 효율적으로 나타나도록 가공된 의학, 의료효과가 높은 식품을 의미한다. 여기서 "기능(성)"이라 함은 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건용도에 유용한 효과를 얻는 것을 의미한다. 본 발명의 식품은 당 업계에서 통상적으로 사용되는 방법에 의하여 제조가능하며, 상기 제조 시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할수 있다. 또한 상기 식품의 제형 또한 식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없으며, 휴대성이 뛰어난 장점이 있다.In the present invention, the term "health functional (sex) food" is the same term as food for special health use (FoSHU), and in addition to nutritional supply, it has medical and medical effects processed to efficiently exhibit bioregulatory functions. It means high food. Here, "function (sex)" means to obtain a useful effect for health purposes such as regulating nutrients or physiological action with respect to the structure and function of the human body. The food of the present invention can be prepared by a method commonly used in the art, and during the manufacture, it can be prepared by adding raw materials and components commonly added in the art. In addition, the formulation of the food may be prepared without limitation as long as it is a formulation recognized as a food. The food composition of the present invention can be prepared in various types of dosage forms, and unlike general drugs, there is no side effect that may occur during long-term administration of the drug using food as a raw material, and has excellent portability.
구체적으로, 상기 건강 기능 식품은 본 발명의 조성물을 음료, 차류, 향신료, 껌, 과자류 등의 식품 소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과가 있는 것을 의미하나, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용이 없는 장점이 있다.Specifically, the health functional food is a food prepared by adding the composition of the present invention to food materials such as beverages, teas, spices, gum, and confectionery, or encapsulating, powdering, suspension, etc., and when ingested, It means that it is effective, but unlike general drugs, it has the advantage that there are no side effects that may occur when taking the drug for a long time using food as a raw material.
상기 식품 조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지는 않는다.The food composition may further include a physiologically acceptable carrier, the type of carrier is not particularly limited.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예를 제시한다. 그러나 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 하기 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are only provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.
코로나-19 바이러스의 재조합 스파이크 단백질을 코딩하는 유전자의 설계 Design of the gene encoding the recombinant spike protein of the COVID-19 virus
코로나-19 바이러스 표면 단백질 유래 스파이크(spike, S)를 ER 내강(lumen)에 가용성 형태(soluble form)로 발현하도록 유도하기 위해 스파이크 단백질(GenBank No. MZ433938.1)의 막관통 도메인(TMD)에서 C-말단까지를 없앤 스파이크 단백질의 엑토-도메인(ecto-domain; 16 번째 아미노산에서 1213번째 아미노산까지, 총 1198 개의 잔기; S-f), N-말단에서부터 SD2 도메인까지를 포함하는 부위(16번째 아미노산부터 681번째 아미노산 까지, 총 666 개의 잔기; S1), 및 S2 서브유닛에서 막관통 도메인(TMD)부터 C-말단까지를 없앤 단백질 부위(682번째 아미노산에서 1213번째 까지, 총 532 개의 잔기; S2)를 확보하였다. 상기 코로나-19 바이러스의 스파이크 유전자의 5'-말단에 애기장대 단백질인 BiP로부터 확보한 ER 표적화 신호를 융합하여 ER 타겟팅 되도록 하였다. 추가적으로 마우스 mCoronin1이라는 단백질로부터 동종 삼량체의 형성을 유도하는 모티프를 스파이크에 첨가하여 컨스트럭트를 구축 하였다. 그리고 이들 재조합 단백질을 분리 및 정제하기 위한 태그(tag)로 단량체 형태(monomeric form)의 인간 FC를 포함시켰으며, 이어서 HDEL을 포함시켜 ER에 재조합 단백질이 축적되도록 하였다. 이들 유전자의 발현을 위해서 macT를 사용하였으며 Rd29b의 말단을 전사종결자로 사용하였다(도 1). 상기 전사 종결자는 이전 연구결과 높은 전사효율을 보이는 것으로 확인되었다. 실험에 사용되는 염기 서열은 하기 표 1과 같다. In the transmembrane domain (TMD) of the spike protein (GenBank No. MZ433938.1) to induce the expression of a spike (S) derived from the corona-19 virus surface protein in the ER lumen in a soluble form Spike protein ecto-domain (from the 16th amino acid to the 1213th amino acid, a total of 1198 residues; Sf), from the N-terminus to the SD2 domain (from the 16th amino acid) Up to amino acid 681, a total of 666 residues; S1), and a protein region from the transmembrane domain (TMD) to the C-terminus in the S2 subunit (from amino acid 682 to 1213, a total of 532 residues; S2) secured. The ER targeting signal obtained from BiP, an Arabidopsis protein, was fused to the 5'-end of the spike gene of the Corona-19 virus to enable ER targeting. Additionally, a motif inducing the formation of a homotrimer from a protein called mouse mCoronin1 was added to the spike to construct a construct. And human FC in a monomeric form was included as a tag for isolating and purifying these recombinant proteins, and then HDEL was included to allow the recombinant protein to accumulate in the ER. For the expression of these genes, macT was used, and the end of Rd29b was used as a transcription terminator (FIG. 1). The transcription terminator was confirmed to show high transcription efficiency as a result of previous studies. The nucleotide sequences used in the experiment are shown in Table 1 below.
염기서열Sf
base sequence
아미노산 서열Sf
amino acid
염기서열S1
base sequence
아미노산 서열S1
amino acid sequence
염기서열S2
base sequence
아미노산 서열S2
amino acid sequence
염기서열mCOr1
base sequence
아미노산 서열mCor1
amino acid sequence
염기서열BiP
base sequence
염기서열HDEL
base sequence
아미노산서열 HDEL
amino acid sequence
염기서열linker
base sequence
아미노산 서열linker
amino acid sequence
인간 FC
염기서열monomer
human FC
base sequence
인간 FC
아미노산
서열monomer
human FC
amino acid
order
염기서열MacT
base sequence
전사
종결자
염기서열RD29B
Warrior
terminator
base sequence
코로나-19 바이러스의 재조합 스파이크 단백질의 단백질 A 친화 컬럼 크로마토그래피를 이용한 분리 정제Separation and purification of recombinant spike protein of COVID-19 virus using protein A affinity column chromatography
코로나-19 바이러스의 재조합 스파이크 단백질을 진공 침윤(vacuum infiltration) 방법을 사용하여 4-5주령 니코티아나 벤타미아나(Nicotiana benthamiana) 식물 잎에서 일과성 발현을 통하여 발현을 유도하였다. 침윤된 잎을 침윤 후 5 일(dpi)에 수확하고, 삼량체 S 단백질을 발현하는 니코티아나 벤타미아나 잎 조직을 액체 질소에 넣고 갈아서 분말로 만들고, 여기에 잎의 생중량(fresh weight)의 5배에 해당하는 버퍼 용액을 넣고, 총 가용성 단백질(total souble protein)을 추출하였다. 그리고 이것을 단백질 A 친화 컬럼 크로마토그래피를 이용하여 분리 정제하였다. 1 g의 잎 신선 조직(leaf fresh tissue)에 해당하는 총 단백질 추출물(total protein extract)에 1 mg의 단백질 A 친화 수지 컬럼을 이용하였다. 컬럼에 총 수용성 추출물을 통과 시킨 후, 10 부피(volume)의 세척 버퍼(washing buffer)로 컬럼을 세척하고, 컬럼으로부터 단백질 A 수지를 회수한 다음 500 μml의 200 mM 글리신 용액을 이용하여 단백질 친화 수지에 결합된 단백질을 용리하였다. 이어서 바로 0.1 M NaOH를 이용하여 pH를 중성으로 중화하였다. 분리 정제된 단백질을 SDS/PAGE를 이용하여 쿠마시 브릴리언트 블루(Coommassie brilliant blue)와 항-인간 IgG 항체를 이용하여 검증하였다(도 2).Expression of the recombinant spike protein of the Corona-19 virus was induced through transient expression in 4-5 week-old Nicotiana benthamiana plant leaves using a vacuum infiltration method. The infiltrated leaves are harvested 5 days (dpi) after infiltration, and Nicotiana benthamiana leaf tissue expressing the trimeric S protein is placed in liquid nitrogen and ground to a powder, where the fresh weight of the leaf is obtained. A buffer solution corresponding to 5 times was added, and total soluble protein was extracted. And this was separated and purified using protein A affinity column chromatography. A 1 mg protein A affinity resin column was used for a total protein extract corresponding to 1 g of leaf fresh tissue. After the total aqueous extract was passed through the column, the column was washed with 10 volumes of washing buffer, the protein A resin was recovered from the column, and then the protein affinity resin using 500 μml of 200 mM glycine solution. The protein bound to was eluted. The pH was then immediately neutralized with 0.1 M NaOH. The separated and purified protein was verified using Coommassie brilliant blue and anti-human IgG antibody using SDS/PAGE (FIG. 2).
삼량체를 형성하는 코로나-19 바이러스의 재조합 스파이크 단백질들의 에스터가수분해효소 활성Esterase Activity of Recombinant Spike Proteins of Corona-19 Virus Forming Trimers
삼량체를 형성하는 코로나-19 바이러스 S 단백질의 3 종의 재조합 단백질(S-f, S1 및 S2)의 에스터가수분해효소 활성은 파라나이트로페닐 아세테이트(para-nitrophenyl acetate, pNPA)에서의 파라니트로페놀(paranitrophenol, pNP) 방출량을 측정하여 결정하였다. 활성을 측정하기 위해서 0.5 ml의 50 mM 소듐 포스페이트 버퍼(pNPA는 pH 7.0)에 기질(p-NPA)을 1 mM 되게 하고 여기에 200 ng의 분리 정제된 S 단백질의 재조합 단백질을 함유 하도록 혼합물을 만든 후 37℃에서 10분간 배양하였다. 이어서 1M 소듐 카르보네이트 1ml를 첨가하여 반응을 종결시켰다. 흡광도는 405 nm에서 측정하였다. 정상상태(Steady-state) 역학 측정은 기질의 농도(0.5 내지 2 mM)를 바꿔가며 pNPA의 최적 온도 및 pH에서 실시하였다. Km 및 Vmax 값은 최초 pNP 유리 비율로부터 계산하였다. 삼량체를 형성하는 코로나-19 바이러스의 재조합 스파이크 단백질의 에스터가수분해효소 활성은 환원당(reducing sugars)의 양을 측정함으로써 결정하였다. 1 유닛 효소 활성은 분당 1 μmol의 pNP 또는 환원당을 생산한 효소의 양으로 정의하였다. S 단백질의 농도가 증가할수록, 그리고 시간이 지날수록 에스터가수분해효소 활성이 증가하는 것을 확인하였다(도 3).The esterase activity of the three recombinant proteins (Sf, S1 and S2) of the Corona 19 virus S protein to form a trimer was determined by para-nitrophenyl acetate (pNPA) paranitrophenol, pNP) was determined by measuring the release amount. To measure the activity, the substrate (p-NPA) was made to 1 mM in 0.5 ml of 50 mM sodium phosphate buffer (pNPA is pH 7.0), and the mixture was prepared to contain 200 ng of the isolated and purified S protein recombinant protein. Then, it was incubated at 37°C for 10 minutes. The reaction was then quenched by the addition of 1 ml of 1M sodium carbonate. Absorbance was measured at 405 nm. Steady-state kinetics measurements were performed at the optimum temperature and pH of pNPA while changing the substrate concentration (0.5 to 2 mM). Km and Vmax values were calculated from the original pNP free ratio. The esterase activity of the recombinant spike protein of Corona-19 virus to form a trimer was determined by measuring the amount of reducing sugars. One unit enzyme activity was defined as the amount of enzyme that produced 1 μmol of pNP or reducing sugar per minute. As the concentration of the S protein increased, it was confirmed that the esterase activity increased with time (FIG. 3).
삼량체를 형성하는 코로나-19 바이러스의 재조합 스파이크 단백질들의 에스터가수분해효소 활성 저해제 스크리닝Esterase activity inhibitor screening of recombinant spike proteins of Corona-19 virus that form trimers
삼량체를 형성하는 코로나-19 바이러스의 재조합 스파이크 단백질에 설파메톡사졸(sulfamethoxazole)을 각각 0.5 mM, 1.0 mM, 및 2 mM로 처리하여 에스터가수분해효소 활성을 확인하였다. 에스터가수분해효소 활성은 파라 나이트로페닐 아세테이트(pNPA)에서의 파라니트로페놀(pNP) 방출량을 측정하여 결정하였다. 활성을 측정하기 위해서 0.5 ml의 50 mM 소듐 포스페이트 버퍼(pH 7.0)에 기질(p-NPA)을 6 mM 되게 하고 여기에 200 ng의 분리 정제된 S 단백질의 재조합 단백질을 함유 하도록 혼합물을 만든 후 37℃에서 10분간 배양하였다. 반응은 1M 소듐 카르보네이트 1ml를 첨가하여 종결시켰다. 흡광도는 405 nm에서 측정하였다. 1 유닛 효소 활성은 분당 1 μmol의 pNP 또는 환원당을 생산한 효소의 양으로 정의하였다. 그 결과 설파메톡사졸의 농도가 증가할 수록 S-F, S1 및 S2의 에스터가수분해효소 활성이 감소하는 것을 확인할 수 있었다(도 4). 설파메톡사졸이 코로나-19 바이러스의 스파이크 단백질의 에스터가수분해효소의 활성을 저해함으로써, 바이러스의 세포 감염 또는 세포로부터의 방출 과정을 저해하고, 이를 통해서 바이러스의 체내 증식을 억제하여 코로나-19 바이러스의 감염증을 치료할 수 있다.Esterase activity was confirmed by treatment with sulfamethoxazole at 0.5 mM, 1.0 mM, and 2 mM, respectively, to the recombinant spike protein of Corona-19 virus forming a trimer. Esterase activity was determined by measuring the release amount of para-nitrophenol (pNP) in para-nitrophenyl acetate (pNPA). To measure the activity, the substrate (p-NPA) was made to 6 mM in 0.5 ml of 50 mM sodium phosphate buffer (pH 7.0), and a mixture was prepared to contain 200 ng of the isolated and purified S protein recombinant protein. Incubated at ℃ for 10 minutes. The reaction was quenched by the addition of 1 ml of 1M sodium carbonate. Absorbance was measured at 405 nm. One unit enzyme activity was defined as the amount of enzyme that produced 1 μmol of pNP or reducing sugar per minute. As a result, it was confirmed that the esterase activity of S-F, S1 and S2 decreased as the concentration of sulfamethoxazole increased (FIG. 4). Sulfamethoxazole inhibits the activity of the esterase of the spike protein of the Corona-19 virus, thereby inhibiting the cell infection or release process of the virus, thereby inhibiting the proliferation of the virus in the body Infection can be treated.
SEQUENCE LISTING <110> POSTECH ACADEMY-INDUSTRY FOUNDATION <120> Kit for screening for therapeutic agent for preventing or treating Corona-virus infection by using of esterase activity of Corona-19 virus spike protein and pharmaceutical composition comprising material selected therefrom <130> 1069405 <150> KR 10-2020-0080622 <151> 2020-06-30 <160> 17 <170> PatentIn version 3.2 <210> 1 <211> 3594 <212> DNA <213> Artificial <220> <223> Sf <400> 1 gttaacctta ccaccagaac tcagttaccc ccagcataca ctaattcttt cacacgtggt 60 gtttactacc ctgacaaagt tttcagaagc agcgttttac acagcactca ggatttattc 120 ctacctttct tttccaacgt gacctggttc catgctatac atgtatctgg gaccaatggt 180 accaagaggt ttgataaccc ggtcctacca tttaatgatg gagtctattt tgcctccact 240 gagaagtcta atataataag aggctggatt tttggaacta ctcttgattc gaagacccag 300 agtctactta ttgttaataa cgctacaaat gttgttatca aagtatgtga atttcaattc 360 tgtaatgatc cattcttggg tgtttactac cacaaaaaca acaaaagttg gatggaaagt 420 gagtttcggg tttatagcag tgcgaataat tgcacttttg agtacgtctc ccaacctttt 480 cttatggacc ttgaaggaaa gcagggaaat ttcaagaatc ttcgcgaatt tgtgtttaag 540 aatatcgatg gttatttcaa gatatattct aagcacacgc ctattaattt agtgcgagat 600 ctccctcagg gtttttcggc gctggaacca ttggtagatt tgccgatagg aatcaatatc 660 actaggttcc agactttact tgctctgcat agaagttact tgacccctgg agatagctca 720 tcaggttgga cagctggtgc ggcagcttat tacgtggggt atcttcagcc taggacgttc 780 ctattaaaat ataatgaaaa tggaaccatt acagatgctg tagactgtgc acttgaccct 840 ctctcagaaa caaagtgtac gttgaaatcc ttcacggtag aaaaagggat ctaccaaacg 900 tctaacttca gagtccagcc aacagaatct attgtgagat ttcccaatat tacaaacttg 960 tgccctttcg gagaagtttt taacgccacc aggtttgcat cggtttatgc ttggaacagg 1020 aaaagaatca gcaactgtgt tgctgattat agtgtcctat ataactccgc atccttttcc 1080 actttcaagt gttacggagt ttctcctact aaattaaatg atctctgctt tactaatgtc 1140 tatgcagatt catttgtaat cagaggtgat gaggtcagac aaatcgctcc agggcagact 1200 ggaaagattg ctgattataa ttataagctt cctgatgatt ttacaggctg cgttatagca 1260 tggaattcta ataatcttga ctctaaggtg gggggaaatt ataattacct gtatagactg 1320 tttaggaaga gcaatctcaa gcctttcgag agagacattt caactgagat ctaccaggcg 1380 ggaagcactc cgtgtaatgg tgttgagggt tttaattgtt actttccttt acagtcatac 1440 ggtttccaac ccacgaatgg ggttggttac caaccgtacc gagtagtagt actttctttc 1500 gagcttctac atgccccagc aactgtttgt ggacctaaga agtctactaa tttggttaaa 1560 aataagtgtg tcaattttaa tttcaatgga cttacgggca caggagttct tactgagtct 1620 aacaagaagt ttctgccttt ccagcagttc ggcagagata ttgctgacac tactgatgct 1680 gtgcgtgatc cacagacact tgaaattctt gacattacac catgttcttt tggtggcgtg 1740 agtgttataa ctcccggaac aaatacctcc aaccaggtgg ctgttctgta tcaggacgtg 1800 aactgtacag aagtccctgt tgcaattcat gcagatcagc ttactcctac ctggcgtgtt 1860 tattctacgg gttccaatgt ttttcaaaca cgtgcaggct gcttgatagg ggctgaacat 1920 gtcaacaact catatgaatg cgacataccc ataggtgcag gtatatgcgc tagttatcag 1980 actcagacca attctccgcg gcgggcacga agtgtagcta gtcaatccat cattgcctac 2040 actatgtcac ttggtgcaga aaattcagtt gcttactcta ataactctat tgccataccc 2100 acaaatttta ctattagtgt taccacagaa attctaccag tgtctatgac caagacatca 2160 gttgactgta caatgtatat ttgcggggat tcaactgagt gctcgaatct gttgttgcaa 2220 tacggcagtt tttgtaccca attgaaccgg gctctgactg gaatagctgt ggaacaagat 2280 aaaaacaccc aagaagtttt tgcacaagtc aaacaaattt ataaaacacc accaattaaa 2340 gatttcggtg gtttcaactt ctcacaaata ctgccagatc cgagcaaacc aagcaagagg 2400 tcattcattg aagacctact tttcaacaaa gtgacacttg cagatgctgg cttcattaaa 2460 cagtatggtg attgcttggg ggatattgct gctagagacc tcatttgtgc acaaaagttt 2520 aacgggctga cagtgttgcc acctttgttg acagatgaga tgattgctca gtacacttct 2580 gcactgctcg ctggtacaat cacatctggg tggacctttg gtgcaggtgc tgccttacaa 2640 ataccatttg ctatgcagat ggcttatagg ttcaatggta tcggagttac acagaacgtt 2700 ctctatgaga accaaaaatt gattgccaac caattcaata gtgccattgg caagattcag 2760 gactcacttt caagcacagc gagtgcactt ggaaagttgc aagatgtggt caaccagaat 2820 gcacaagctt taaacacgct tgtgaaacaa ctcagctcca actttggggc aatttcaagt 2880 gttttgaatg atatcctttc acgtcttgat aaagtggaag ccgaggtgca aattgacagg 2940 ttgatcacag gccgacttca aagtttgcag acttatgtga ctcaacaatt aattagggca 3000 gcagaaatcc gcgcttcggc taatctggcg gctactaaaa tgtcagagtg tgtacttgga 3060 caatctaaac gagttgattt ttgcggaaag ggctatcatc tcatgtcctt ccctcagtca 3120 gcgcctcacg gtgtagtgtt cttgcacgtg acttacgttc ctgcacaaga aaagaatttc 3180 acaactgctc cggccatttg tcatgatgga aaagcccact ttccgcgtga aggtgtcttt 3240 gtttcgaatg gcacacactg gtttgtaacc caaaggaatt tttatgagcc acaaatcatt 3300 acgacggaca acacttttgt gtctggtaat tgtgatgttg taatcggaat cgtcaacaac 3360 accgtttacg atcctttgca gcctgagtta gattctttca aagaggagct ggataagtat 3420 ttcaagaatc atacatcacc cgatgttgat ctcggtgata tctctggaat taatgcttca 3480 gttgtgaaca ttcaaaagga gattgaccgc ctcaatgagg ttgccaagaa tttgaatgaa 3540 tcgctcatcg atctccaaga acttggaaag tatgagcagt atatcaagtg gcca 3594 <210> 2 <211> 1198 <212> PRT <213> Artificial <220> <223> Sf <400> 2 Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser 1 5 10 15 Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val 20 25 30 Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr 35 40 45 Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe 50 55 60 Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr 65 70 75 80 Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp 85 90 95 Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val 100 105 110 Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val 115 120 125 Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val 130 135 140 Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe 145 150 155 160 Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu 165 170 175 Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His 180 185 190 Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu 195 200 205 Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln 210 215 220 Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser 225 230 235 240 Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln 245 250 255 Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp 260 265 270 Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu 275 280 285 Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg 290 295 300 Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu 305 310 315 320 Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr 325 330 335 Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val 340 345 350 Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser 355 360 365 Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser 370 375 380 Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr 385 390 395 400 Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly 405 410 415 Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly 420 425 430 Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro 435 440 445 Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro 450 455 460 Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr 465 470 475 480 Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val 485 490 495 Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro 500 505 510 Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe 515 520 525 Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe 530 535 540 Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala 545 550 555 560 Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser 565 570 575 Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln 580 585 590 Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala 595 600 605 Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly 610 615 620 Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His 625 630 635 640 Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys 645 650 655 Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val 660 665 670 Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn 675 680 685 Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr 690 695 700 Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser 705 710 715 720 Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn 725 730 735 Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu 740 745 750 Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala 755 760 765 Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly 770 775 780 Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg 785 790 795 800 Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala 805 810 815 Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg 820 825 830 Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro 835 840 845 Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala 850 855 860 Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln 865 870 875 880 Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val 885 890 895 Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe 900 905 910 Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser 915 920 925 Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu 930 935 940 Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser 945 950 955 960 Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val 965 970 975 Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr 980 985 990 Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn 995 1000 1005 Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys 1010 1015 1020 Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro 1025 1030 1035 Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val 1040 1045 1050 Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His 1055 1060 1065 Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn 1070 1075 1080 Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln 1085 1090 1095 Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val 1100 1105 1110 Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro 1115 1120 1125 Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn 1130 1135 1140 His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn 1145 1150 1155 Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu 1160 1165 1170 Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu 1175 1180 1185 Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro 1190 1195 <210> 3 <211> 1998 <212> DNA <213> Artificial <220> <223> S1 <400> 3 gttaacctta ccaccagaac tcagttaccc ccagcataca ctaattcttt cacacgtggt 60 gtttactacc ctgacaaagt tttcagaagc agcgttttac acagcactca ggatttattc 120 ctacctttct tttccaacgt gacctggttc catgctatac atgtatctgg gaccaatggt 180 accaagaggt ttgataaccc ggtcctacca tttaatgatg gagtctattt tgcctccact 240 gagaagtcta atataataag aggctggatt tttggaacta ctcttgattc gaagacccag 300 agtctactta ttgttaataa cgctacaaat gttgttatca aagtatgtga atttcaattc 360 tgtaatgatc cattcttggg tgtttactac cacaaaaaca acaaaagttg gatggaaagt 420 gagtttcggg tttatagcag tgcgaataat tgcacttttg agtacgtctc ccaacctttt 480 cttatggacc ttgaaggaaa gcagggaaat ttcaagaatc ttcgcgaatt tgtgtttaag 540 aatatcgatg gttatttcaa gatatattct aagcacacgc ctattaattt agtgcgagat 600 ctccctcagg gtttttcggc gctggaacca ttggtagatt tgccgatagg aatcaatatc 660 actaggttcc agactttact tgctctgcat agaagttact tgacccctgg agatagctca 720 tcaggttgga cagctggtgc ggcagcttat tacgtggggt atcttcagcc taggacgttc 780 ctattaaaat ataatgaaaa tggaaccatt acagatgctg tagactgtgc acttgaccct 840 ctctcagaaa caaagtgtac gttgaaatcc ttcacggtag aaaaagggat ctaccaaacg 900 tctaacttca gagtccagcc aacagaatct attgtgagat ttcccaatat tacaaacttg 960 tgccctttcg gagaagtttt taacgccacc aggtttgcat cggtttatgc ttggaacagg 1020 aaaagaatca gcaactgtgt tgctgattat agtgtcctat ataactccgc atccttttcc 1080 actttcaagt gttacggagt ttctcctact aaattaaatg atctctgctt tactaatgtc 1140 tatgcagatt catttgtaat cagaggtgat gaggtcagac aaatcgctcc agggcagact 1200 ggaaagattg ctgattataa ttataagctt cctgatgatt ttacaggctg cgttatagca 1260 tggaattcta ataatcttga ctctaaggtg gggggaaatt ataattacct gtatagactg 1320 tttaggaaga gcaatctcaa gcctttcgag agagacattt caactgagat ctaccaggcg 1380 ggaagcactc cgtgtaatgg tgttgagggt tttaattgtt actttccttt acagtcatac 1440 ggtttccaac ccacgaatgg ggttggttac caaccgtacc gagtagtagt actttctttc 1500 gagcttctac atgccccagc aactgtttgt ggacctaaga agtctactaa tttggttaaa 1560 aataagtgtg tcaattttaa tttcaatgga cttacgggca caggagttct tactgagtct 1620 aacaagaagt ttctgccttt ccagcagttc ggcagagata ttgctgacac tactgatgct 1680 gtgcgtgatc cacagacact tgaaattctt gacattacac catgttcttt tggtggcgtg 1740 agtgttataa ctcccggaac aaatacctcc aaccaggtgg ctgttctgta tcaggacgtg 1800 aactgtacag aagtccctgt tgcaattcat gcagatcagc ttactcctac ctggcgtgtt 1860 tattctacgg gttccaatgt ttttcaaaca cgtgcaggct gcttgatagg ggctgaacat 1920 gtcaacaact catatgaatg cgacataccc ataggtgcag gtatatgcgc tagttatcag 1980 actcagacca attctccg 1998 <210> 4 <211> 666 <212> PRT <213> Artificial <220> <223> S1 <400> 4 Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser 1 5 10 15 Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val 20 25 30 Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr 35 40 45 Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe 50 55 60 Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr 65 70 75 80 Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp 85 90 95 Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val 100 105 110 Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val 115 120 125 Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val 130 135 140 Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe 145 150 155 160 Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu 165 170 175 Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His 180 185 190 Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu 195 200 205 Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln 210 215 220 Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser 225 230 235 240 Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln 245 250 255 Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp 260 265 270 Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu 275 280 285 Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg 290 295 300 Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu 305 310 315 320 Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr 325 330 335 Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val 340 345 350 Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser 355 360 365 Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser 370 375 380 Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr 385 390 395 400 Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly 405 410 415 Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly 420 425 430 Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro 435 440 445 Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro 450 455 460 Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr 465 470 475 480 Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val 485 490 495 Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro 500 505 510 Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe 515 520 525 Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe 530 535 540 Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala 545 550 555 560 Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser 565 570 575 Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln 580 585 590 Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala 595 600 605 Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly 610 615 620 Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His 625 630 635 640 Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys 645 650 655 Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro 660 665 <210> 5 <211> 1596 <212> DNA <213> Artificial <220> <223> S2 <400> 5 cggcgggcac gaagtgtagc tagtcaatcc atcattgcct acactatgtc acttggtgca 60 gaaaattcag ttgcttactc taataactct attgccatac ccacaaattt tactattagt 120 gttaccacag aaattctacc agtgtctatg accaagacat cagttgactg tacaatgtat 180 atttgcgggg attcaactga gtgctcgaat ctgttgttgc aatacggcag tttttgtacc 240 caattgaacc gggctctgac tggaatagct gtggaacaag ataaaaacac ccaagaagtt 300 tttgcacaag tcaaacaaat ttataaaaca ccaccaatta aagatttcgg tggtttcaac 360 ttctcacaaa tactgccaga tccgagcaaa ccaagcaaga ggtcattcat tgaagaccta 420 cttttcaaca aagtgacact tgcagatgct ggcttcatta aacagtatgg tgattgcttg 480 ggggatattg ctgctagaga cctcatttgt gcacaaaagt ttaacgggct gacagtgttg 540 ccacctttgt tgacagatga gatgattgct cagtacactt ctgcactgct cgctggtaca 600 atcacatctg ggtggacctt tggtgcaggt gctgccttac aaataccatt tgctatgcag 660 atggcttata ggttcaatgg tatcggagtt acacagaacg ttctctatga gaaccaaaaa 720 ttgattgcca accaattcaa tagtgccatt ggcaagattc aggactcact ttcaagcaca 780 gcgagtgcac ttggaaagtt gcaagatgtg gtcaaccaga atgcacaagc tttaaacacg 840 cttgtgaaac aactcagctc caactttggg gcaatttcaa gtgttttgaa tgatatcctt 900 tcacgtcttg ataaagtgga agccgaggtg caaattgaca ggttgatcac aggccgactt 960 caaagtttgc agacttatgt gactcaacaa ttaattaggg cagcagaaat ccgcgcttcg 1020 gctaatctgg cggctactaa aatgtcagag tgtgtacttg gacaatctaa acgagttgat 1080 ttttgcggaa agggctatca tctcatgtcc ttccctcagt cagcgcctca cggtgtagtg 1140 ttcttgcacg tgacttacgt tcctgcacaa gaaaagaatt tcacaactgc tccggccatt 1200 tgtcatgatg gaaaagccca ctttccgcgt gaaggtgtct ttgtttcgaa tggcacacac 1260 tggtttgtaa cccaaaggaa tttttatgag ccacaaatca ttacgacgga caacactttt 1320 gtgtctggta attgtgatgt tgtaatcgga atcgtcaaca acaccgttta cgatcctttg 1380 cagcctgagt tagattcttt caaagaggag ctggataagt atttcaagaa tcatacatca 1440 cccgatgttg atctcggtga tatctctgga attaatgctt cagttgtgaa cattcaaaag 1500 gagattgacc gcctcaatga ggttgccaag aatttgaatg aatcgctcat cgatctccaa 1560 gaacttggaa agtatgagca gtatatcaag tggcca 1596 <210> 6 <211> 532 <212> PRT <213> Artificial <220> <223> S2 <400> 6 Arg Arg Ala Arg Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met 1 5 10 15 Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala 20 25 30 Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val 35 40 45 Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp 50 55 60 Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr 65 70 75 80 Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn 85 90 95 Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro 100 105 110 Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro 115 120 125 Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys 130 135 140 Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu 145 150 155 160 Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly 165 170 175 Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr 180 185 190 Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly 195 200 205 Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg 210 215 220 Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys 225 230 235 240 Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser 245 250 255 Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn 260 265 270 Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn 275 280 285 Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp 290 295 300 Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu 305 310 315 320 Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu 325 330 335 Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val 340 345 350 Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu 355 360 365 Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val 370 375 380 Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile 385 390 395 400 Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser 405 410 415 Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln 420 425 430 Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val 435 440 445 Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu 450 455 460 Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser 465 470 475 480 Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val 485 490 495 Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu 500 505 510 Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr 515 520 525 Ile Lys Trp Pro 530 <210> 7 <211> 96 <212> DNA <213> Artificial <220> <223> mCOr1 <400> 7 gtgtctaggc ttgaggaaga tgttagaaat ctcaacgcaa ttgtccagaa acttcaggaa 60 aggttggata ggctggagga aactgttcaa gctaag 96 <210> 8 <211> 32 <212> PRT <213> Artificial <220> <223> mCor1 <400> 8 Val Ser Arg Leu Glu Glu Asp Val Arg Asn Leu Asn Ala Ile Val Gln 1 5 10 15 Lys Leu Gln Glu Arg Leu Asp Arg Leu Glu Glu Thr Val Gln Ala Lys 20 25 30 <210> 9 <211> 272 <212> DNA <213> Artificial <220> <223> BiP <400> 9 atggctcgct cgtttggagc taacagtacc gttgtgttgg cgatcatctt cttcggtgag 60 tgattttccg atcttcttct ccgatttaga tctcctctac attgttgctt aatctcagaa 120 ccttttttcg ttgttcctgg atctgaatgt gtttgtttgc aatttcacga tcttaaaagg 180 ttagatctcg attggtattg acgattggaa tctttacgat ttcaggatgt ttatttgcgt 240 tgtcctctgc aatagaagag gctacgaagt ta 272 <210> 10 <211> 12 <212> DNA <213> Artificial <220> <223> HDEL <400> 10 cacgatgagc tc 12 <210> 11 <211> 4 <212> PRT <213> Artificial <220> <223> HDEL <400> 11 His Asp Glu Leu 1 <210> 12 <211> 42 <212> DNA <213> Artificial <220> <223> Linker <400> 12 gatgatgatg ataagacccg gggtggtgga agtggtggaa gt 42 <210> 13 <211> 14 <212> PRT <213> Artificial <220> <223> Linker <400> 13 Asp Asp Asp Asp Lys Thr Arg Gly Gly Gly Ser Gly Gly Ser 1 5 10 <210> 14 <211> 651 <212> DNA <213> Artificial <220> <223> Monomeric human Fc <400> 14 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 tcgcccccat cccgtgagga gatgaccaag aaccaggtca gcctgaggtg ccacgtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacaagacca cgaagcccgt gctggactcc gacggctcct tcgagctcaa gagcgcgctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcagaagagc ctctccctgt cccctggtaa a 651 <210> 15 <211> 217 <212> PRT <213> Artificial <220> <223> Monomeric human Fc <400> 15 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys 1 5 10 15 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Arg Cys His Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser Asp Gly Ser Phe Glu Leu 165 170 175 Lys Ser Ala Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215 <210> 16 <211> 1220 <212> DNA <213> Artificial <220> <223> MacT <400> 16 agagatctcc tttgccccag agatcacaat ggacgacttc ctctatctct acgatctagt 60 caggaagttc gacggagaag gtgacgatac catgttcacc actgataatg agaagattag 120 ccttttcaat ttcagaaaga atgctaaccc acagatggtt agagaggctt acgcagcagg 180 tctcatcaag acgatctacc cgagcaataa tctccaggag atcaaatacc ttcccaagaa 240 ggttaaagat gcagtcaaaa gattcaggac taactgcatc aagaacacag agaaagatat 300 atttctcaag atcagaagta ctattccagt atggacgatt caaggcttgc ttcacaaacc 360 aaggcaagta atagagattg gagtctctaa aaaggtagtt cccactgaat caaaggccat 420 ggagtcaaag attcaaatag aggacctaac agaactcgcc gtaaagactg gcgaacagtt 480 catacagagt ctcttacgac tcaatgacaa gaagaaaatc ttcgtcaaca tggtggagca 540 cgacacgctt gtctactcca aaaatatcaa agatacagtc tcagaagacc aaagggcaat 600 tgagactttt caacaaaggg taatatccgg aaacctcctc ggattccatt gcccagctat 660 ctgtcacttt attgtgaaga tagtggaaaa ggaaggtggc tcctacaaat gccatcattg 720 cgataaagga aaggccatcg ttgaagatgc ctctgccgac agtggtccca aagatggacc 780 cccacccacg aggagcatcg tggaaaaaga agacgttcca accacgtctt caaagcaagt 840 ggattgatgt gacgcaagac gtgacgtaag tatctgagct agtttttatt tttctactaa 900 tttggtcgtt tatttcggcg tgtaggacat ggcaaccggg cctgaatttc gcgggtattc 960 tgtttctatt ccaacttttt cttgatccgc agccattaac gacttttgaa tagatacgct 1020 gacacgccaa gcctcgctag tcaaaagtgt accaaacaac gctttacagc aagaacggaa 1080 tgcgcgtgac gctcgcggtg acgccatttc gccttttcag aaatggataa atagccttgc 1140 ttcctattat atcttcccaa attaccaata cattacacta gcatctgaat ttcataacca 1200 atctcgatac accaaatcgt 1220 <210> 17 <211> 520 <212> DNA <213> Artificial <220> <223> RD29B <400> 17 aattttactc aaaatgtttt ggttgctatg gtagggacta tggggttttc ggattccggt 60 ggaagtgagt ggggaggcag tggcggaggt aagggagttc aagattctgg aactgaagat 120 ttggggtttt gcttttgaat gtttgcgttt ttgtatgatg cctctgtttg tgaactttga 180 tgtattttat ctttgtgtga aaaagagatt gggttaataa aatatttgct tttttggata 240 agaaactctt ttagcggccc attaataaag gttacaaatg caaaatcatg ttagcgtcag 300 atatttaatt attcgaagat gattgtgata gatttaaaat tatcctagtc aaaaagaaag 360 agtaggttga gcagaaacag tgacatctgt tgtttgtacc atacaaatta gtttagatta 420 ttggttaaca tgttaaatgg ctatgcatgt gacatttaga ccttatcgga attaatttgt 480 agaattatta attaagatgt tgattagttc aaacaaaaat 520 SEQUENCE LISTING <110> POSTECH ACADEMY-INDUSTRY FOUNDATION <120> Kit for screening for therapeutic agent for preventing or treating Corona-virus infection by using of esterase activity of Corona-19 virus spike protein and pharmaceutical composition comprising material selected therefrom <130> 1069405 <150> KR 10-2020-0080622 <151> 2020-06-30 <160> 17 <170> PatentIn version 3.2 <210> 1 <211> 3594 <212> DNA <213> Artificial <220> <223> Sf <400> 1 gttaacctta ccaccagaac tcagttaccc ccagcataca ctaattcttt cacacgtggt 60 gtttactacc ctgacaaagt tttcagaagc agcgttttac acagcactca ggatttattc 120 ctacctttct tttccaacgt gacctggttc catgctatac atgtatctgg gaccaatggt 180 accaagaggt ttgataaccc ggtcctacca tttaatgatg gagtctattt tgcctccact 240 gagaagtcta atataataag aggctggatt tttggaacta ctcttgattc gaagacccag 300 agtctactta ttgttaataa cgctacaaat gttgttatca aagtatgtga atttcaattc 360 tgtaatgatc cattcttggg tgtttactac cacaaaaaca acaaaagttg gatggaaagt 420 gagtttcggg tttatagcag tgcgaataat tgcacttttg agtacgtctc ccaacct ttt 480 cttatggacc ttgaaggaaa gcagggaaat ttcaagaatc ttcgcgaatt tgtgtttaag 540 aatatcgatg gttatttcaa gatatattct aagcacacgc ctattaattt agtgcgagat 600 ctccctcagg gtttttcggc gctggaacca ttggtagatt tgccgatagg aatcaatatc 660 actaggttcc agactttact tgctctgcat agaagttact tgacccctgg agatagctca 720 tcaggttgga cagctggtgc ggcagcttat tacgtggggt atcttcagcc taggacgttc 780 ctattaaaat ataatgaaaa tggaaccatt acagatgctg tagactgtgc acttgaccct 840 ctctcagaaa caaagtgtac gttgaaatcc ttcacggtag aaaaagggat ctaccaaacg 900 tctaacttca gagtccagcc aacagaatct attgtgagat ttcccaatat tacaaacttg 960 tgccctttcg gagaagtttt taacgccacc aggtttgcat cggtttatgc ttggaacagg 1020 aaaagaatca gcaactgtgt tgctgattat agtgtcctat ataactccgc atccttttcc 1080 actttcaagt gttacggagt ttctcctact aaattaaatg atctctgctt tactaatgtc 1140 tatgcagatt catttgtaat cagaggtgat gaggtcagac aaatcgctcc agggcagact 1200 ggaaagattg ctgattataa ttataagctt cctgatgatt ttacaggctg cgttatagca 1260 tggaattcta ataatcttga ctctaaggtg gggggaaatt ataattacct gtatagactg 1320 tttagg aaga gcaatctcaa gcctttcgag agagacattt caactgagat ctaccaggcg 1380 ggaagcactc cgtgtaatgg tgttgagggt tttaattgtt actttccttt acagtcatac 1440 ggtttccaac ccacgaatgg ggttggttac caaccgtacc gagtagtagt actttctttc 1500 gagcttctac atgccccagc aactgtttgt ggacctaaga agtctactaa tttggttaaa 1560 aataagtgtg tcaattttaa tttcaatgga cttacgggca caggagttct tactgagtct 1620 aacaagaagt ttctgccttt ccagcagttc ggcagagata ttgctgacac tactgatgct 1680 gtgcgtgatc cacagacact tgaaattctt gacattacac catgttcttt tggtggcgtg 1740 agtgttataa ctcccggaac aaatacctcc aaccaggtgg ctgttctgta tcaggacgtg 1800 aactgtacag aagtccctgt tgcaattcat gcagatcagc ttactcctac ctggcgtgtt 1860 tattctacgg gttccaatgt ttttcaaaca cgtgcaggct gcttgatagg ggctgaacat 1920 gtcaacaact catatgaatg cgacataccc ataggtgcag gtatatgcgc tagttatcag 1980 actcagacca attctccgcg gcgggcacga agtgtagcta gtcaatccat cattgcctac 2040 actatgtcac ttggtgcaga aaattcagtt gcttactcta ataactctat tgccataccc 2100 acaaatttta ctattagtgt taccacagaa attctaccag tgtctatgac caagacatca 2160 gttgactgta c aatgtatat ttgcggggat tcaactgagt gctcgaatct gttgttgcaa 2220 tacggcagtt tttgtaccca attgaaccgg gctctgactg gaatagctgt ggaacaagat 2280 aaaaacaccc aagaagtttt tgcacaagtc aaacaaattt ataaaacacc accaattaaa 2340 gatttcggtg gtttcaactt ctcacaaata ctgccagatc cgagcaaacc aagcaagagg 2400 tcattcattg aagacctact tttcaacaaa gtgacacttg cagatgctgg cttcattaaa 2460 cagtatggtg attgcttggg ggatattgct gctagagacc tcatttgtgc acaaaagttt 2520 aacgggctga cagtgttgcc acctttgttg acagatgaga tgattgctca gtacacttct 2580 gcactgctcg ctggtacaat cacatctggg tggacctttg gtgcaggtgc tgccttacaa 2640 ataccatttg ctatgcagat ggcttatagg ttcaatggta tcggagttac acagaacgtt 2700 ctctatgaga accaaaaatt gattgccaac caattcaata gtgccattgg caagattcag 2760 gactcacttt caagcacagc gagtgcactt ggaaagttgc aagatgtggt caaccagaat 2820 gcacaagctt taaacacgct tgtgaaacaa ctcagctcca actttggggc aatttcaagt 2880 gttttgaatg atatcctttc acgtcttgat aaagtggaag ccgaggtgca aattgacagg 2940 ttgatcacag gccgacttca aagtttgcag acttatgtga ctcaacaatt aattagggca 3000 gcagaaatcc gcgcttc ggc taatctggcg gctactaaaa tgtcagagtg tgtacttgga 3060 caatctaaac gagttgattt ttgcggaaag ggctatcatc tcatgtcctt ccctcagtca 3120 gcgcctcacg gtgtagtgtt cttgcacgtg acttacgttc ctgcacaaga aaagaatttc 3180 acaactgctc cggccatttg tcatgatgga aaagcccact ttccgcgtga aggtgtcttt 3240 gtttcgaatg gcacacactg gtttgtaacc caaaggaatt tttatgagcc acaaatcatt 3300 acgacggaca acacttttgt gtctggtaat tgtgatgttg taatcggaat cgtcaacaac 3360 accgtttacg atcctttgca gcctgagtta gattctttca aagaggagct ggataagtat 3420 ttcaagaatc atacatcacc Legatgttgat ctcggtgata tctctggaat taatgcttca 3480 gttgtgaaca ttcaaaagga gattgaccgc ctcaatgagg ttgccaagaa tttgaatgaa 3540 tcgctcatcg atctccaaga actt g223 3521194 <n f 210 Pu 210 Ptg Artificial <2 Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser 1 5 10 15 Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val 20 25 30 Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr 35 40 45 Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe 50 55 60 Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr 65 70 75 80 Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp 85 90 95 Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val 100 105 110 Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val 115 120 125 Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val 130 135 140 Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe 145 150 155 160 Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu 165 170 175 Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His 180 185 190 Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu 195 200 205 Glu Pro Leu V al Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln 210 215 220 Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser 225 230 235 240 Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln 245 250 255 Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp 260 265 270 Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu 275 280 285 Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg 290 295 300 Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu 305 310 315 320 Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr 325 330 335 Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val 340 345 350 L eu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser 355 360 365 Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser 370 375 380 Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr 385 390 395 400 Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly 405 410 415 Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly 420 425 430 Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro 435 440 445 Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro 450 455 460 Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr 465 470 475 480 Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val 485 490 495 Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro 500 505 510 Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe 515 520 525 Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe 530 535 540 Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala 545 550 555 560 Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser 565 570 575 Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln 580 585 590 Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala 595 600 605 Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly 610 615 620 Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His 625 630 6 35 640 Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys 645 650 655 Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val 660 665 670 Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn 675 680 685 Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr 690 695 700 Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser 705 710 715 720 Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn 725 730 735 Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu 740 745 750 Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala 755 760 765 Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly 770 775 780 Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg 785 790 795 800 Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala 805 810 815 Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg 820 825 830 Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro 835 840 845 Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala 850 855 860 Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln 865 870 875 880 Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val 885 890 895 Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe 900 905 910 Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser 915 920 925 Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu 930 935 940 Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser 945 950 955 960 Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val 965 970 975 Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr Tyr 980 985 990 Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser Ala Asn 995 1000 1005 Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln Ser Lys 1010 1015 1020 Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser Phe Pro 1025 1030 1035 Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr Tyr Val 1040 1045 1050 Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His 1055 1060 1065 Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn 1070 1075 1080 Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln 1085 109 0 1095 Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val 1100 1105 1110 Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro 1115 1120 1125 Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn 1130 1135 1140 His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn 1145 1150 1155 Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu 1160 1165 1170 Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu 1175 1180 1185 Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro 1190 1195 <210> 3 <211> 1998 <212> DNA <213> Artificial <220> <223> S1 <400> 3 gttaacctta ccaccagaac tcagttaccc ccagcataca ctaattcttt cacacgtggt 60 gtttactacc ctgacaaagt tttcagaagc agcgttttac acagcactca ggatttattc 120 ctacctttct tttccaacgt gacctggttc catgctatac atgtatctgg gaccaatggt 180 accaagaggt ttgataaccc ggtcctacca tttaatgatg gagtctattt tgcctccact 240 gagaagtcta atataataag aggctggatt tttggaacta ctcttgattc gaagacccag 300 agtctactta ttgttaataa cgctacaaat gttgttatca aagtatgtga atttcaattc 360 tgtaa tgatc cattcttggg tgtttactac cacaaaaaca acaaaagttg gatggaaagt 420 gagtttcggg tttatagcag tgcgaataat tgcacttttg agtacgtctc ccaacctttt 480 cttatggacc ttgaaggaaa gcagggaaat ttcaagaatc ttcgcgaatt tgtgtttaag 540 aatatcgatg gttatttcaa gatatattct aagcacacgc ctattaattt agtgcgagat 600 ctccctcagg gtttttcggc gctggaacca ttggtagatt tgccgatagg aatcaatatc 660 actaggttcc agactttact tgctctgcat agaagttact tgacccctgg agatagctca 720 tcaggttgga cagctggtgc ggcagcttat tacgtggggt atcttcagcc taggacgttc 780 ctattaaaat ataatgaaaa tggaaccatt acagatgctg tagactgtgc acttgaccct 840 ctctcagaaa caaagtgtac gttgaaatcc ttcacggtag aaaaagggat ctaccaaacg 900 tctaacttca gagtccagcc aacagaatct attgtgagat ttcccaatat tacaaacttg 960 tgccctttcg gagaagtttt taacgccacc aggtttgcat cggtttatgc ttggaacagg 1020 aaaagaatca gcaactgtgt tgctgattat agtgtcctat ataactccgc atccttttcc 1080 actttcaagt gttacggagt ttctcctact aaattaaatg atctctgctt tactaatgtc 1140 tatgcagatt catttgtaat cagaggtgat gaggtcagac aaatcgctcc agggcagact 1200 ggaaagattg ctgattataa ttataagctt cctgatgatt ttacaggctg cgttatagca 1260 tggaattcta ataatcttga ctctaaggtg gggggaaatt ataattacct gtatagactg 1320 tttaggaaga gcaatctcaa gcctttcgag agagacattt caactgagat ctaccaggcg 1380 ggaagcactc cgtgtaatgg tgttgagggt tttaattgtt actttccttt acagtcatac 1440 ggtttccaac ccacgaatgg ggttggttac caaccgtacc gagtagtagt actttctttc 1500 gagcttctac atgccccagc aactgtttgt ggacctaaga agtctactaa tttggttaaa 1560 aataagtgtg tcaattttaa tttcaatgga cttacgggca caggagttct tactgagtct 1620 aacaagaagt ttctgccttt ccagcagttc ggcagagata ttgctgacac tactgatgct 1680 gtgcgtgatc cacagacact tgaaattctt gacattacac catgttcttt tggtggcgtg 1740 agtgttataa ctcccggaac aaatacctcc aaccaggtgg ctgttctgta tcaggacgtg 1800 aactgtacag aagtccctgt tgcaattcat gcagatcagc ttactcctac ctggcgtgtt 1860 tattctacgg gttccaatgt ttttcaaaca cgtgcaggct gcttgatagg ggctgaacat 1920 gtcaacaact catatgaatg cgacataccc ataggtgcag gtatatgcgc tagttatcag 1980 actcagacca attctccg 1998 <210> 4 <211> 666 <212> PRT <213> Artificial <220> <223> S1 <400> 4 Val A sn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser 1 5 10 15 Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val 20 25 30 Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr 35 40 45 Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe 50 55 60 Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr 65 70 75 80 Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp 85 90 95 Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val 100 105 110 Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val 115 120 125 Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val 130 135 140 Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe 145 150 155 160 Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu 165 170 175 Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His 180 185 190 Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu 195 200 205 Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln 210 215 220 Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser 225 230 235 240 Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln 245 250 255 Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp 260 265 270 Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu 275 280 285 Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg 290 295 300 Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu 305 310 3 15 320 Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr 325 330 335 Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val 340 345 350 Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser 355 360 365 Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser 370 375 380 Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr 385 390 395 400 Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly 405 410 415 Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly 420 425 430 Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro 435 440 445 Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro 450 455 460 Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr 465 470 475 480 Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val 485 490 495 Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro 500 505 510 Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe 515 520 525 Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe 530 535 540 Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala 545 550 555 560 Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser 565 570 575 Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln 580 585 590 Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala 595 600 605 Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly 610 615 620 Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His 625 630 635 640 Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys 645 650 655 Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro 660 665 <210> 5 <211> 1596 <212> DNA <213> Artificial <220> <223> S2 <400> 5 cggcgggcac gaagtgtagc tagtcaatcc atcattgcct acactatgtc acttggtgca 60 gaaaattcag ttgcttactc taataactct attgccatac ccacaaattt tactattagt 120 gttaccacag aaattctacc agtgtctatg accaagacat cagttgactg tacaatgtat 180 atttgcgggg attcaactga gtgctcgaat ctgttgttgc aatacggcag tttttgtacc 240 caattgaacc gggctctgac tggaatagct gtggaacaag ataaaaacac ccaagaagtt 300 tttgcacaag tcaaacaaat ttataaaaca ccaccaatta aagatttcgg tggtttcaac 360 ttctcacaaa tactgccaga tccgagcaaa ccaagcaaga ggtcattcat tgaagaccta 420 cttttca aca aagtgacact tgcagatgct ggcttcatta aacagtatgg tgattgcttg 480 ggggatattg ctgctagaga cctcatttgt gcacaaaagt ttaacgggct gacagtgttg 540 ccacctttgt tgacagatga gatgattgct cagtacactt ctgcactgct cgctggtaca 600 atcacatctg ggtggacctt tggtgcaggt gctgccttac aaataccatt tgctatgcag 660 atggcttata ggttcaatgg tatcggagtt acacagaacg ttctctatga gaaccaaaaa 720 ttgattgcca accaattcaa tagtgccatt ggcaagattc aggactcact ttcaagcaca 780 gcgagtgcac ttggaaagtt gcaagatgtg gtcaaccaga atgcacaagc tttaaacacg 840 cttgtgaaac aactcagctc caactttggg gcaatttcaa gtgttttgaa tgatatcctt 900 tcacgtcttg ataaagtgga agccgaggtg caaattgaca ggttgatcac aggccgactt 960 caaagtttgc agacttatgt gactcaacaa ttaattaggg cagcagaaat ccgcgcttcg 1020 gctaatctgg cggctactaa aatgtcagag tgtgtacttg gacaatctaa acgagttgat 1080 ttttgcggaa agggctatca tctcatgtcc ttccctcagt cagcgcctca cggtgtagtg 1140 ttcttgcacg tgacttacgt tcctgcacaa gaaaagaatt tcacaactgc tccggccatt 1200 tgtcatgatg gaaaagccca ctttccgcgt gaaggtgtct ttgtttcgaa tggcacacac 1260 tggtttgtaa cccaaaggaatttttatgag ccacaaatca ttacgacgga caacactttt 1320 gtgtctggta attgtgatgt tgtaatcgga atcgtcaaca acaccgttta cgatcctttg 1380 cagcctgagt tagattcttt caaagaggag ctggataagt atttcaagaa tcatacatca 1440 cccgatgttg atctcggtga tatctctgga attaatgctt cagttgtgaa cattcaaaag 1500 gagattgacc gcctcaatga ggttgccaag aatttgaatg aatcgctcat cgatctccaa 1560 gaacttggaa agtatgagca gtatatcaag tggcca 1596 <210> 6 <211> 532 <212> PRT <213> Artificial <220> <223> S2 <400> 6 Arg Arg Ala Arg Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met 1 5 10 15 Ser Leu Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala 20 25 30 Ile Pro Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val 35 40 45 Ser Met Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp 50 55 60 Ser Thr Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr 65 70 75 80 Gln Leu Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn 85 90 95 Thr Gln Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro 100 105 110 Ile Lys Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro 115 120 125 Ser Lys Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys 130 135 140 Val Thr Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu 145 150 155 160 Gly Asp Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly 165 170 175 Leu Thr Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr 180 185 190 Thr Ser Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly 195 200 205 Ala Gly Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg 210 215 220 Phe Asn Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys 225 230 235 240 Leu Ile Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser 245 25 0 255 Leu Ser Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn 260 265 270 Gln Asn Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn 275 280 285 Phe Gly Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp 290 295 300 Lys Val Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu 305 310 315 320 Gln Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu 325 330 335 Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val 340 345 350 Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu 355 360 365 Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val 370 375 380 Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile 385 390 395 400 Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser 405 410 415 Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu Pro Gln 420 425 430 Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys Asp Val Val 435 440 445 Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu Gln Pro Glu Leu 450 455 460 Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe Lys Asn His Thr Ser 465 470 475 480 Pro Asp Val Asp Leu Gly Asp Ile Ser Gly Ile Asn Ala Ser Val Val 485 490 495 Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu 500 505 510 Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr 515 520 525 Ile Lys Trp Pro 530 <210> 7 <211> 96 <212> DNA <213> Artificial <220> <223> mCOr1 <400> 7 gtgtctaggc ttgaggaaga tgttagaaat ctcaacgcaa ttgtccagaa acttcaggaa 60 aggttggata ggctggagga aactgttcaa gctaag 96 <210> 8 <211> 32 <212> PRT <213> Val Glug Leu Glue <220> <223> mCor Val Arg Asn Leu Asn Ala Ile Val Gln 1 5 10 15 Lys Leu Gln Glu Arg Leu Asp Arg Leu Glu Glu Thr Val Gln Ala Lys 20 25 30 <210> 9 <211> 272 <212> DNA <213> Artificial <220 > <223> BiP <400> 9 atggctcgct cgtttggagc taacagtacc gttgtgttgg cgatcatctt cttcggtgag 60 tgattttccg atcttcttct ccgatttaga tctcctctac attgttgctt aatctcagaa 120 ccttttttcg ttgttcctgg atctgaatgt gtttgtttgc aatttcacga tcttaaaagg 180 ttagatctcg attggtattg acgattggaa tctttacgat ttcaggatgt ttatttgcgt 240 tgtcctctgc aatagaagag gctacgaagt ta 272 <210> 10 <211> 12 <212> DNA <213> Artificial <220> <223> HDEL <400> 10 cacgatgagc tc 12 <210> 11 <211> 4 <212> PRT <213> Artificial <220> <223> HDEL <400> 11 His Asp Glu Leu 1 <210> 12 <211> 42 <212> DNA <213> Artificial <220> <223> Linker <400> 12 gatgatgatg a taagacccg gggtggtgga agtggtggaa gt 42 <210> 13 <211> 14 <212> PRT <213> Artificial <220> <223> Linker <400> 13 Asp Asp Asp Asp Lys Thr Arg Gly Gly Gly Ser Gly Gly Ser 1 5 10 < 210> 14 <211> 651 <212> DNA <213> Artificial <220> <223> Monomeric human Fc <400> 14 gcacctgaac tcctgggggg accgtcagtc ttcctcttcc ccccaaaacc caaggacacc 60 ctcatgatct cccggacccc tgaggtcaca tgcgtggtgg tggacgtgag ccacgaagac 120 cctgaggtca agttcaactg gtacgtggac ggcgtggagg tgcataatgc caagacaaag 180 ccgcgggagg agcagtacaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 240 caggactggc tgaatggcaa ggagtacaag tgcaaggtct ccaacaaagc cctcccagcc 300 cccatcgaga aaaccatctc caaagccaaa gggcagcccc gagaaccaca ggtgtacacc 360 tcgcccccat cccgtgagga gatgaccaag aaccaggtca gcctgaggtg ccacgtcaaa 420 ggcttctatc ccagcgacat cgccgtggag tgggagagca atgggcagcc ggagaacaac 480 tacaagacca cgaagcccgt gctggactcc gacggctcct tcgagctcaa gagcgcgctc 540 accgtggaca agagcaggtg gcagcagggg aacgtcttct catgctccgt gatgcatgag 600 gctctgcaca accactacac gcaga agagc ctctccctgt cccctggtaa a 651 <210> 15 <211> 217 <212> PRT <213> Artificial <220> <223> Monomeric human Fc <400> 15 Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Lys 1 5 10 15 Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val 20 25 30 Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr 35 40 45 Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu 50 55 60 Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His 65 70 75 80 Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys 85 90 95 Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln 100 105 110 Pro Arg Glu Pro Gln Val Tyr Thr Ser Pro Pro Ser Arg Glu Glu Met 115 120 125 Thr Lys Asn Gln Val Ser Leu Arg Cys His Val Lys Gly Phe Tyr Pro 130 135 140 Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn 145 150 155 160 Tyr Lys Thr Thr Lys Pro Val Leu Asp Ser Asp Gly Ser Phe Glu Leu 165 170 175 Lys Ser Ala Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val 180 185 190 Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln 195 200 205 Lys Ser Leu Ser Leu Ser Pro Gly Lys 210 215 <210> 16 <211> 1220 <212> DNA <213> Artificial <220> <223> MacT <400> 16 agagatctcc tttgccccag agatcacaat ggacgacttc ctctatctct acgatctagt 60 caggaagttc gacggagaag gtgacgatac catgttcacc actgataatg agaagattag 120 ccttttcaat ttcagaaaga atgctaaccc acagatggtt agagaggctt acgcagcagg 180 tctcatcaag acgatctacc cgagcaataa tctccaggag atcaaatacc ttcccaagaa 240 ggttaaagat gcagtcaaaa gattcaggac taactgcatc aagaacacag agaaagatat 300 atttctcaag atcagaagta ctattccagt atggacgatt caaggcttgc ttcacaaacc 360 aaggcaagta atagagattg gagtctctaa aaaggtagtt cccactgaat caaaggccat 420 ggagtcaaag attcaaatag agga cctaac agaactcgcc gtaaagactg gcgaacagtt 480 catacagagt ctcttacgac tcaatgacaa gaagaaaatc ttcgtcaaca tggtggagca 540 cgacacgctt gtctactcca aaaatatcaa agatacagtc tcagaagacc aaagggcaat 600 tgagactttt caacaaaggg taatatccgg aaacctcctc ggattccatt gcccagctat 660 ctgtcacttt attgtgaaga tagtggaaaa ggaaggtggc tcctacaaat gccatcattg 720 cgataaagga aaggccatcg ttgaagatgc ctctgccgac agtggtccca aagatggacc 780 cccacccacg aggagcatcg tggaaaaaga agacgttcca accacgtctt caaagcaagt 840 ggattgatgt gacgcaagac gtgacgtaag tatctgagct agtttttatt tttctactaa 900 tttggtcgtt tatttcggcg tgtaggacat ggcaaccggg cctgaatttc gcgggtattc 960 tgtttctatt ccaacttttt cttgatccgc agccattaac gacttttgaa tagatacgct 1020 gacacgccaa gcctcgctag tcaaaagtgt accaaacaac gctttacagc aagaacggaa 1080 tgcgcgtgac gctcgcggtg acgccatttc gccttttcag aaatggataa atagccttgc 1140 ttcctattat atcttcccaa attaccaata cattacacta gcatctgaat ttcataacca 1200 atctcgatac accaaatcgt 1220 <210> 17 <211> 520 <212> DNA <213> Artificial <220> <223> RD29B <400> 17 aattttactc a aaatgtttt ggttgctatg gtagggacta tggggttttc ggattccggt 60 ggaagtgagt ggggaggcag tggcggaggt aagggagttc aagattctgg aactgaagat 120 ttggggtttt gcttttgaat gtttgcgttt ttgtatgatg cctctgtttg tgaactttga 180 tgtattttat ctttgtgtga aaaagagatt gggttaataa aatatttgct tttttggata 240 agaaactctt ttagcggccc attaataaag gttacaaatg caaaatcatg ttagcgtcag 300 atatttaatt attcgaagat gattgtgata gatttaaaat tatcctagtc aaaaagaaag 360 agtaggttga gcagaaacag tgacatctgt tgtttgtacc atacaaatta gtttagatta 420 ttggttaaca tgttaaatgg ctatgcatgt gacatttaga ccttatcgga attaatttgt 480agaattatta attaagatgt tgattagttc aaacaaaaat 520
Claims (17)
상기 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성을 측정할 수 있는 물질;
을 포함하는, 코로나 바이러스 감염증의 예방 또는 치료용 후보 물질의 스크리닝 키트.Recombinant protein derived from the spike protein of coronavirus; and
a substance capable of measuring the esterase activity of the recombinant protein derived from the spike protein of the corona virus;
A screening kit of candidate substances for the prevention or treatment of coronavirus infection, comprising a.
(i) 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질에 후보 물질을 처리하는 단계;
(ii) 상기 후보 물질을 처리한 코로나 바이러스의 스파이크 단백질 유래 재조합 단백질의 에스터가수분해효소 활성(esterase activity)을 측정하는 단계; 및
(iii) 상기 후보 물질이 에스터가수분해효소 활성을 30% 이상 억제하는 경우, 상기 후보 물질을 코로나 바이러스의 예방 또는 치료용 후보 물질로 선별하는 단계;를 포함하는, 코로나 바이러스 감염증의 예방 또는 치료용 후보 물질을 스크리닝 하는 방법.13. The method of claim 12,
(i) treating a candidate material with a recombinant protein derived from the spike protein of coronavirus;
(ii) measuring the esterase activity of the recombinant protein derived from the spike protein of the corona virus treated with the candidate substance; and
(iii) when the candidate material inhibits esterase activity by 30% or more, selecting the candidate material as a candidate material for prevention or treatment of coronavirus; How to screen for candidates.
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KR20230153147A (en) | 2022-04-28 | 2023-11-06 | 고려대학교 산학협력단 | Drug screening method for SARS-CoV-2 multi-variants treatment |
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KR20230153147A (en) | 2022-04-28 | 2023-11-06 | 고려대학교 산학협력단 | Drug screening method for SARS-CoV-2 multi-variants treatment |
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