KR102537551B1 - A conjugate comprising sialic acid or a derivative thereof bonded on the surface of dendrimer core, and monosaccharide or disaccharide, and use thereof - Google Patents
A conjugate comprising sialic acid or a derivative thereof bonded on the surface of dendrimer core, and monosaccharide or disaccharide, and use thereof Download PDFInfo
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- KR102537551B1 KR102537551B1 KR1020200155515A KR20200155515A KR102537551B1 KR 102537551 B1 KR102537551 B1 KR 102537551B1 KR 1020200155515 A KR1020200155515 A KR 1020200155515A KR 20200155515 A KR20200155515 A KR 20200155515A KR 102537551 B1 KR102537551 B1 KR 102537551B1
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- KR
- South Korea
- Prior art keywords
- conjugate
- monosaccharide
- disaccharide
- influenza virus
- present
- Prior art date
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- 150000002772 monosaccharides Chemical class 0.000 title claims abstract description 54
- 150000002016 disaccharides Chemical class 0.000 title claims abstract description 53
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- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 239000000412 dendrimer Substances 0.000 title claims description 21
- 229920000736 dendritic polymer Polymers 0.000 title claims description 21
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- 235000013305 food Nutrition 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 24
- TYALNJQZQRNQNQ-UHFFFAOYSA-N #alpha;2,6-sialyllactose Natural products O1C(C(O)C(O)CO)C(NC(=O)C)C(O)CC1(C(O)=O)OCC1C(O)C(O)C(O)C(OC2C(C(O)C(O)OC2CO)O)O1 TYALNJQZQRNQNQ-UHFFFAOYSA-N 0.000 claims description 21
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Abstract
본 발명은 코어와 그의 표면에 결합된 시알산 또는 이의 유도체와 단당류 또는 이당류를 포함하는 결합체 및 그의 용도에 관한 것이다. 본 발명에서 제공하는 결합체는 인플루엔자 바이러스의 표면에 존재하는 헤마글루티닌과 결합하여 인플루엔자 바이러스의 감염과정을 억제함으로써, 인플루엔자 바이러스 감염증을 예방 또는 치료할 수 있을 뿐만 아니라, 항 바이러스 제제에 대하여 내성을 나타내는 인플루엔자 바이러스에 대하여도 그의 감염증을 예방 또는 치료할 수 있으므로, 인플루엔자 바이러스 감염증의 예방 또는 치료용 제제의 개발에 널리 활용될 수 있다.The present invention relates to a conjugate comprising a core, sialic acid or a derivative thereof bonded to its surface, and a monosaccharide or disaccharide, and uses thereof. The conjugate provided in the present invention binds to hemagglutinin present on the surface of influenza virus and inhibits the infection process of influenza virus, thereby preventing or treating influenza virus infection, and exhibiting resistance to antiviral agents. Influenza virus infections can also be prevented or treated, so it can be widely used in the development of agents for preventing or treating influenza virus infections.
Description
본 발명은 덴드리머 코어와 그의 표면에 결합된 시알산 또는 이의 유도체와 단당류 또는 이당류를 포함하는 결합체 및 그의 용도에 관한 것이다.The present invention relates to a dendrimer core, a conjugate comprising sialic acid or a derivative thereof bonded to its surface, and a monosaccharide or disaccharide, and a use thereof.
인플루엔자 바이러스(Influenza virus)는 오르소믹소 계통(Family Orthomyxoviridae)에 속하는 RNA 바이러스로서 혈청형은 A형, B형, C형 등 3가지로 구분된다. 그 중 B형과 C형은 사람에서만 감염이 확인되고 있으며, A형은 사람, 말, 돼지, 기타 포유류 그리고 다양한 종류의 가금과 야생조류에서 감염이 확인되고 있다. A형 인플루엔자 바이러스의 혈청형은 바이러스 표면의 두 가지 단백질인 혈구응집소(Hemagglutinin; HA)와 뉴라미니다제(Neuraminidase:NA)의 종류에 따라 구분되는데, 지금까지 144종류(HA 단백질 16종과 NA 단백질 9종)가 알려져 있다. HA는 바이러스가 체세포에 부착하는 역할을 하며, NA는 바이러스가 세포 내로 침투할 수 있도록 한다. 이러한 인플루엔자 바이러스는 매년 겨울이면 새로운 항원성을 지닌 인플루엔자 바이러스가 유행하며 사람을 포함한 가축, 조류에 거쳐 바이러스가 유행하며 이러한 바이러스의 모니터링은 매우 중요하다. 따라서 이에 따른 특이성과 민감성이 높은 프라이머와 프로브의 개발이 요구되고 있다.Influenza virus is an RNA virus belonging to the Orthomyxoviridae family, and its serotypes are classified into three types: A, B, and C. Among them, types B and C have been confirmed to be infected only in humans, and type A has been confirmed to be infected in humans, horses, pigs, other mammals, and various types of poultry and wild birds. Serotypes of type A influenza virus are classified according to the types of two proteins on the surface of the virus, hemagglutinin (HA) and neuraminidase (NA). So far, 144 types (16 HA proteins and NA 9 proteins) are known. HA serves to attach viruses to somatic cells, and NA enables viruses to penetrate cells. Influenza viruses with new antigenicity are prevalent every winter, and viruses are prevalent in livestock and birds, including humans, and monitoring of these viruses is very important. Accordingly, there is a demand for the development of primers and probes with high specificity and sensitivity.
최근 관심이 집중되고 있는 신종 인플루엔자 A(H1N1) 바이러스는 "신종 플루" 또는 "신종 플루 바이러스"라고도 하는데, 이는 사람, 돼지, 조류 인플루엔자 바이러스의 유전물질이 혼합되어 있는 새로운 형태의 바이러스로서 2009년 4월 처음 발견되었다. 바이러스의 전파 경로에 대해서는 아직까지 명확하게 밝혀지지 않았지만, 기존의 계절 인플루엔자 바이러스와 유사하게 비말(飛沫) 감염, 곧 감염된 사람의 기침이나 재채기 등을 통하여 주로 사람 대 사람으로, 감염자와 가까운 접촉자 사이(약 2m이내)에서 전파되는 것으로 알려져 있다. 또한, 음식의 경우 70 이상으로 가열 조리하면 음식에 존재하는 바이러스가 사멸하는 것으로 알려져 있다.The novel influenza A (H1N1) virus, which has recently attracted attention, is also called "swine flu" or "swine flu virus", which is a new type of virus in which the genetic material of human, swine, and avian influenza viruses is mixed. was first discovered in May. Although the transmission route of the virus has not been clearly identified yet, similar to the existing seasonal influenza virus, droplet infection, that is, mainly person-to-person through coughing or sneezing of an infected person, between an infected person and close contacts ( It is known to spread within about 2 m). Also, for food, 70 It is known that viruses present in food are killed when cooked with more heat.
상기 신종 플루 바이러스의 잠복기는 대략 1~7일 사이로 추정되고, 증상으로는 확진 환자에게서 발열, 오한, 두통, 기침, 인후통, 콧물, 호흡곤란 등의 상기도 증상, 근육통, 관절통, 피로감, 구토 또는 설사 등이 나타난다고 알려져 있다. 보통 증상이 발생하기 하루 전부터 발생 후 7일까지 전염력이 있는 것으로 보고되었으며, 어린이의 경우는 10일 이상으로 길어질 수도 있다. 상기 신종 플루 바이러스의 감염으로 인한 피해를 감소시키기 위하여, 신종 플루 바이러스의 감염을 조기에 진단할 수 있는 방법을 개발하려는 연구가 활발히 진행되어왔다. 예를 들어, 한국공개특허 제2011-0064174호에는 타종 인플루엔자 바이러스를 제외한 신종 인플루엔자 바이러스 A/ H1N1에만 특이적인 단클론 항체와 이를 생산하는 융합 세포, 상기 단클론 항체를 포함한 진단 키트 및 이를 이용한 신종 인플루엔자 바이러스 A/H1N1을 진단하는 방법이 개시되어 있고, 한국공개특허 제2011-0096940호에는 신종 인플루엔자 바이러스의 헤마글루티닌(HA) 항원에 대한 항체를 이용한 신속 면역크로마토그라피법을 이용하여 A형 신종 인플루엔자 바이러스(Influenza A, H1N1)를 진단할 수 있는 진단 키트가 개시되어 있으며, 한국공개특허 제2011-0127034호에는 인플루엔자 A형 바이러스를 검출하기 위한 인플루엔자 A형 바이러스 공통 PCR 프라이머 및 돼지 유래 인플루엔자(신종플루, A/Korea/01/2009(H1N1)) 바이러스 검출 특이 PCR 프라이머를 이용하여 신종플루(A/Korea/01/ 2009(H1N1)) 바이러스를 신속하고 정확하게 검출할 수 있는 방법이 개시되어 있다. The incubation period of the swine flu virus is estimated to be between 1 and 7 days, and symptoms include fever, chills, headache, cough, sore throat, runny nose, dyspnea, muscle pain, arthralgia, fatigue, vomiting or It is known to cause diarrhea. They are usually reported to be contagious from 1 day before onset of symptoms to 7 days after onset, and may be as long as 10 days or more in children. In order to reduce the damage caused by the H1N1 influenza virus infection, studies have been actively conducted to develop a method for early diagnosis of H1N1 influenza virus infection. For example, Korean Patent Publication No. 2011-0064174 discloses a monoclonal antibody specific only to new influenza virus A/H1N1 excluding other types of influenza viruses, a fusion cell producing the same, a diagnostic kit including the monoclonal antibody, and a new influenza virus A using the same. A method for diagnosing /H1N1 is disclosed, and Korean Patent Publication No. 2011-0096940 uses a rapid immunochromatography method using an antibody against the hemagglutinin (HA) antigen of the new influenza virus. (Influenza A, H1N1) is disclosed, and Korean Patent Publication No. 2011-0127034 discloses influenza A virus common PCR primers and swine-derived influenza (swine flu, A/Korea/01/2009 (H1N1)) virus detection A method for rapidly and accurately detecting a swine flu (A/Korea/01/2009 (H1N1)) virus using specific PCR primers is disclosed.
그러나, 이처럼 바이러스의 감염을 진단한다 하여도 감염된 인플루엔자 바이러스를 치료할 수 있는 제제로는 오셀타미비르(Oseltamivir, 상품명 타미플루), 자나미비어(Zanamivir, 상품명 리렌자) 등에 불과하고, 이러한 제제를 사용하여도 이에 대한 내성을 갖는 바이러스가 발생됨에 따라, 상기 바이러스를 치료하는 방법의 개발은 여전히 미미한 실정이다.However, even if the virus infection is diagnosed, only Oseltamivir (trade name Tamiflu) and Zanamivir (Zanamivir (trade name Relenza)) are only agents that can treat the infected influenza virus, and even if these agents are used As a virus having resistance to this is generated, development of a method for treating the virus is still insignificant.
이러한 배경하에서, 본 발명자들은 독성이 적으면서 인플루엔자 바이러스 감염증을 효과적으로 치료하는 방법을 개발하고자 예의 연구노력한 결과, 코어(core)와 그의 표면에 결합된 시알산 또는 이의 유도체와 단당류 또는 이당류를 포함하고, 상기 시알산 또는 이의 유도체와 단당류 또는 이당류는 소정의 간격으로 배열된 것을 특징으로 하는 결합체를 사용할 경우, 인플루엔자 바이러스 감염증을 치료할 수 있을 뿐만 아니라, 종래의 항 바이러스 제제에 대하여 내성을 나타내는 바이러스에 의한 감염까지도 치료할 수 있음을 확인하고, 본 발명을 완성하였다.Under this background, the present inventors have made diligent research efforts to develop a method for effectively treating influenza virus infections with low toxicity. When the sialic acid or derivative thereof and the monosaccharide or disaccharide are arranged at predetermined intervals, influenza virus infection can be treated as well as infection caused by a virus that is resistant to conventional antiviral agents. It was confirmed that it can be treated even, and the present invention was completed.
본 발명은 코어와 그의 표면에 결합된 시알산 또는 이의 유도체와 단당류 또는 이당류를 포함하고, 상기 시알산 또는 이의 유도체는 각각 1.0 내지 6.0 nm의 간격으로 배열된 것을 특징으로 하는 결합체를 제공하는 것이다.The present invention provides a conjugate comprising a core, sialic acid or a derivative thereof and a monosaccharide or disaccharide bonded to its surface, wherein the sialic acid or derivative thereof is arranged at intervals of 1.0 to 6.0 nm, respectively.
본 발명의 다른 목적은 상기 결합체를 포함하는 인플루엔자 바이러스 감염증 예방 또는 치료용 약학 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating influenza virus infection comprising the conjugate.
본 발명의 또 다른 목적은 상기 결합체를 포함하는 인플루엔자 바이러스 감염증 예방 또는 개선용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for preventing or improving influenza virus infection comprising the conjugate.
본 발명의 또 다른 목적은 상기 결합체를 인플루엔자 바이러스 감염이 의심되거나 또는 인플루엔자 바이러스에 감염된 개체에 투여하는 단계를 포함하는 인플루엔자 바이러스 감염증을 예방 또는 치료하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for preventing or treating influenza virus infection comprising administering the conjugate to a subject suspected of having or infected with influenza virus.
본 발명의 또 다른 목적은 상기 결합체를 분리된 인플루엔자 바이러스에 처리하는 단계를 포함하는, 인플루엔자 바이러스의 감염을 억제하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for inhibiting influenza virus infection, comprising treating the isolated influenza virus with the conjugate.
본 발명에서 제공하는 결합체는 인플루엔자 바이러스의 표면에 존재하는 헤마글루티닌과 결합하여 인플루엔자 바이러스의 감염과정을 억제함으로써, 인플루엔자 바이러스 감염증을 예방 또는 치료할 수 있을 뿐만 아니라, 항 바이러스 제제에 대하여 내성을 나타내는 인플루엔자 바이러스에 대하여도 그의 감염증을 예방 또는 치료할 수 있으므로, 인플루엔자 바이러스 감염증의 예방 또는 치료용 제제의 개발에 널리 활용될 수 있다.The conjugate provided in the present invention binds to hemagglutinin present on the surface of influenza virus and inhibits the infection process of influenza virus, thereby preventing or treating influenza virus infection, and exhibiting resistance to antiviral agents. Influenza virus infections can also be prevented or treated, so it can be widely used in the development of agents for preventing or treating influenza virus infections.
도 1은 NaCNBH3를 사용한, 6‘-sialyllactose 및 PAMAM 덴드리머(G4)의 1차 아미노기의 환원성 아미노화 그리고 생성된 중합체와 환원성 단당류 또는 이당류의 NaCNBH3를 이용한 환원성 아미노화를 나타낸 반응식이다.
도 2는 결합체의 특성을 1H-NMR 방법으로 분석한 결과를 나타낸 스펙트럼이다.
도 3은 본 발명에서 합성한 다양한 중합체 중에서 대표적인 6’-sialyllactose 내지 rhamnose와 PAMAM 덴드리머(G4) 결합체의 구조를 나타낸 것이다.
도 4는 6'-시알릴락토스 및 단당류 또는 이당류와 에틸렌 디아민 코어(G4)를 갖는 PAMAM 덴드리머 결합체에서 6'-시알릴락토스 및 단당류 또는 이당류 분포의 규칙성을 나타낸 것이다.
도 5는 6'-시알릴락토스 및 단당류 또는 이당류의 PAMAM 덴드리머(G4) 결합체와 HA 사이의 반응성을 분석한 결과로서, HA에 대한 중합체의 결합 친화력(in response units, RU)을 나타내는 그래프이다.1 is a reaction scheme showing reductive amination of primary amino groups of 6'-sialyllactose and PAMAM dendrimer (G4) using NaCNBH 3 and reductive amination of the resulting polymer and reducing monosaccharide or disaccharide using NaCNBH 3 .
2 is a spectrum showing the results of analyzing the characteristics of the conjugate by the 1 H-NMR method.
Figure 3 shows the structure of representative 6'-sialyllactose to rhamnose and PAMAM dendrimer (G4) conjugates among various polymers synthesized in the present invention.
Figure 4 shows the regularity of distribution of 6'-sialyllactose and monosaccharide or disaccharide and 6'-sialyllactose and monosaccharide or disaccharide in a PAMAM dendrimer conjugate having an ethylene diamine core (G4).
5 is a graph showing the binding affinity (in response units, RU) of the polymer to HA, as a result of analyzing the reactivity between 6'-sialyllactose and a PAMAM dendrimer (G4) conjugate of a monosaccharide or disaccharide and HA.
상술한 목적을 달성하기 위한 일 실시양태로서, 본 발명은 코어(core)와 그의 표면에 결합된 시알산 또는 그의 유도체와 단당류 또는 이당류를 포함하고, 상기 시알산 또는 그의 유도체와 단당류 또는 이당류는 서로 일정한 간격으로 배열된 것을 특징으로 하는, 결합체를 제공한다.As one embodiment for achieving the above object, the present invention includes a core, sialic acid or a derivative thereof, and a monosaccharide or disaccharide bound to a surface thereof, wherein the sialic acid or a derivative thereof and the monosaccharide or disaccharide are mutually linked. It provides a combination, characterized in that arranged at regular intervals.
본 발명의 용어 코어(core)란, 시알산 또는 그의 유도체와 결합하여, 상기 시알산 또는 그의 유도체와 단당류 또는 이당류가 서로 일정한 간격으로 배열될 수 있게 하는 지지체로서의 역할을 수행하는 물질을 의미한다.The term core of the present invention refers to a material that binds to sialic acid or a derivative thereof and serves as a support that allows the sialic acid or derivative thereof and a monosaccharide or disaccharide to be aligned at regular intervals.
본 발명에 있어서, 상기 코어를 구성하는 물질은 시알산 또는 그의 유도체 및 단당류 또는 이당류와 결합할 수 있는 반응기를 포함하는 한 특별히 이에 제한되지 않으나, 일 예로서, 폴리아미도아민(polyamidoamine, PAMAM), 폴리하이드록시부티레이트, 폴리하이드록시발레르에이트, 폴리라이신, 폴리락트산, 폴리글리콜리드, 폴리카프로락톤, 폴리프로필렌퓨머레이트, 폴리다이옥세논, 폴리뉴클레오티드, 이들의 공중합체을 단독으로 또는 조합하여 사용할 수 있다.In the present invention, the material constituting the core is not particularly limited as long as it includes a reactive group capable of bonding with sialic acid or a derivative thereof and a monosaccharide or disaccharide, but, for example, polyamidoamine (PAMAM), Polyhydroxybutyrate, polyhydroxyvalerate, polylysine, polylactic acid, polyglycolide, polycaprolactone, polypropylene fumarate, polydioxenone, polynucleotide, and copolymers thereof may be used alone or in combination.
본 발명에 있어서, 상기 코어는 그의 표면에 복수개의 시알산 또는 그의 유도체와 단당류 또는 이당류가 결합하여, 서로 일정한 간격으로 배열되어야 한다. In the present invention, a plurality of sialic acids or derivatives thereof and monosaccharides or disaccharides are bound to the surface of the core, and should be arranged at regular intervals.
본 발명에서 제공하는 상기 코어의 형태는 특별히 이에 제한되지 않으나, 일 예로서, 상기 코어 구성물질의 고분자체로 구성된 구상의 형태가 될 수 있고, 다른 예로서, 상기 코어 구성물질의 선형 고분자체가 다수의 폴딩을 통해 중첩된 형태가 될 수도 있으며, 또 다른 예로서, 상기 코어 구성물질을 기반 화합물로 사용하여 형성된 덴드리머 형태가 될 수도 있다. The shape of the core provided in the present invention is not particularly limited thereto, but as an example, it may be a spherical shape composed of a polymer of the core constituent material, and as another example, a plurality of linear polymers of the core constituent material It may be in an overlapping form through folding, or as another example, it may be in the form of a dendrimer formed by using the core component as a base compound.
본 발명의 용어 "덴드리머(dendrimer)"란, 기반 화합물이 나무(dendron)가지 모양의 분자사슬로 중첩되어 구형의 구조를 이루는 거대분자를 의미하는데, 정확한 분자량과 구조를 갖는 나노 크기의 입자 형성이 용이하고, 최외각에 반응기를 다수 보유하고 있기 때문에, 화학적 또는 물리적으로 독특한 특성을 나타내며, 표면의 밀집된 말단기에 다양한 유도체와 반응기를 도입하는 것이 가능하다. 특히, 덴드리머는 선형 고분자 형태에 비해서 조절이 쉽고, 구조 예측이 용이하여 다양한 분야에 적용하는 것이 가능하다.The term "dendrimer" in the present invention refers to a macromolecule that forms a spherical structure by overlapping a molecular chain in the shape of a tree (dendron) with base compounds. Formation of nano-sized particles with precise molecular weight and structure is It is easy, and since it has a large number of reactive groups on the outermost layer, it exhibits chemically or physically unique properties, and it is possible to introduce various derivatives and reactive groups into dense terminal groups on the surface. In particular, dendrimers can be applied to various fields because they are easier to control and predict the structure than linear polymers.
덴드리머를 형성하는 기반 화합물의 중첩 수준에 따라, 덴드리머의 세대를 특정할 수 있으며 1세대 덴드리머(G1), 2세대 덴드리머(G2), 3세대 덴드리머(G3), 4세대 덴드리머(G4) 및 5세대 덴드리머(G5)라 표현할 수 있다. 즉, 기반 화합물이 1개 추가로 결합됨에 따라, 세대수로 1세대씩 증가한다.Depending on the overlap level of the base compounds forming the dendrimer, the generation of the dendrimer can be specified, and there are 1st generation dendrimers (G1), 2nd generation dendrimers (G2), 3rd generation dendrimers (G3), 4th generation dendrimers (G4) and 5th generation dendrimers. It can be expressed as a dendrimer (G5). That is, as one additional base compound is combined, the number of generations increases by one generation.
본 발명에 있어서, 상기 덴드리머는 상술한 코어를 구성하는 물질을 기반 화합물로 사용할 수 있는데, 상기 기반 화합물은 표면에 복수개의 시알산 또는 그의 유도체와 단당류 또는 이당류가 결합하여, 서로 일정한 간격으로 배열될 수 있는 코어를 형성할 수 있는 한 특별히 이에 제한되지 않으나, 일 예로서, 폴리아미도아민, 폴리라이신, 폴리뉴클레오티드 등이 될 수 있고, 다른 예로서, 폴리아미도아민이 될 수 있다.In the present invention, the dendrimer may use the above-described material constituting the core as a base compound, wherein a plurality of sialic acids or derivatives thereof and monosaccharides or disaccharides are bonded to the surface of the base compound and arranged at regular intervals. It is not particularly limited thereto as long as it can form a core, but as an example, it may be polyamidoamine, polylysine, polynucleotide, etc., and as another example, it may be polyamidoamine.
본 발명의 용어 시알산(sialic acid)이란, 시알린산 또는 뉴라민산 이라고도 호칭되며, 피루브산과 만노사민의 알돌축합체인 노이람산이 n-아세틸화, n-글리콜화 또는 o-아세틸화된 화학구조를 갖는 아미노당의 일종을 의미한다. The term sialic acid of the present invention, also called sialic acid or neuraminic acid, has a chemical structure in which noyramic acid, an aldol condensate of pyruvic acid and mannosamine, is n-acetylated, n-glycolized, or o-acetylated. It means a kind of amino sugar having.
본 발명에 있어서, 상기 시알산은 바이러스의 헤마글루티닌(HA)과 결합하여 그의 기능을 억제하는 리간드로서 사용될 수 있는데, 상기 리간드로는 시알산 뿐만 아니라 그의 유도체가 사용될 수도 있다.In the present invention, the sialic acid can be used as a ligand that binds to hemagglutinin (HA) of a virus and inhibits its function, and not only sialic acid but also derivatives thereof may be used as the ligand.
본 발명의 용어 유도체(derivative)란, 목적 화합물의 일부를 화학적으로 변화시켜서 얻어지는 유사한 화합물을 의미하는데, 대체로 목적 화합물 중의 수소원자 또는 특정 원자단이 다른 원자 또는 원자단에 의하여 치환된 화합물이 될 수 있다.The term derivative of the present invention refers to a similar compound obtained by chemically changing a part of the target compound, and may be a compound in which a hydrogen atom or a specific atomic group in the target compound is substituted with another atom or atomic group.
본 발명에 있어서, 상기 유도체는 시알산의 유도체로 해석될 수 있는데, 상기 시알산의 유도체는 바이러스의 HA와 결합하여 그의 기능을 억제할 수 있는 한, 특별히 이에 제한되지 않으나, 일 예로서, 시알산에 당류가 결합된 시알릴올리고당이 될 수 있고, 다른 예로서, 3'-시알릴락토스(3'-Sialyllactose), 6'-시알릴락토스(6'-Sialyllactose), 시알릴락토-N-테트라오스(sialyl lacto-N-tetraose), 디시알릴락토-N-테트라오스(disialyl lacto-N-tetraose) 등이 될 수 있다.In the present invention, the derivative can be interpreted as a sialic acid derivative, and the sialic acid derivative is not particularly limited thereto, as long as it binds to the HA of the virus and inhibits its function. It may be a sialyl oligosaccharide in which a saccharide is bound to an acid, and as other examples, 3'-sialyllactose, 6'-sialyllactose, sialyllactose-N- It may be sialyl lacto-N-tetraose, disialyl lacto-N-tetraose, and the like.
본 발명에 있어 단당류 및 이당류는 환원성을 갖는 당으로 바람직하게는 단당류인 람노스(rhamnose), 글루코스(glucose), 갈락토스(galactose)가 있고, 이당류는 락토스(lactose), 말토스(maltose)가 존재하나 이들에 한정되지 않으며, 또한 삼당류도 포함될수 있다. In the present invention, monosaccharides and disaccharides are reducing sugars, preferably monosaccharides such as rhamnose, glucose, and galactose, and disaccharides include lactose and maltose. However, it is not limited to these, and trisaccharides may also be included.
본 발명의 용어 결합체(conjugate)란, 하나의 코어에 다수의 시알산 또는 그의 유도체와 단당류 또는 이당류가 결합된 형태의 물질을 의미한다. 구체적으로, 상기 결합체는 시알산 또는 그의 유도체와 단당류 또는 이당류가 일정한 간격으로 코어에 결합된 형태일 수 있다. 또한, 본 발명의 결합체는 시알산 또는 그의 유도체와 단당류 또는 이당류가 코어의 반응기를 통해 결합되거나, 또는 링커를 통해 다수의 시알산 또는 그의 유도체와 단당류 또는 이당류가 코어에 결합된 형태일 수 있다. 이때, 상기 코어의 반응기는 시알산 또는 그의 유도체와 단당류 또는 이당류가 코어에 결합될 수 있는 한, 특별히 제한되지 않으며, 당업계에 공지된 반응기를 사용할 수 있다.The term conjugate of the present invention refers to a material in which a plurality of sialic acids or derivatives thereof and monosaccharides or disaccharides are bonded to one core. Specifically, the conjugate may be in a form in which sialic acid or a derivative thereof and a monosaccharide or disaccharide are bound to a core at regular intervals. In addition, the conjugate of the present invention may have a form in which sialic acid or a derivative thereof and a monosaccharide or disaccharide are bonded through a reactive group of the core, or a plurality of sialic acid or a derivative thereof and a monosaccharide or disaccharide are bonded to the core through a linker. At this time, the reactor of the core is not particularly limited as long as sialic acid or a derivative thereof and a monosaccharide or disaccharide can be bound to the core, and a reactor known in the art can be used.
상술한 바와 같이, 상기 코어는 시알산 또는 그의 유도체와 단당류 또는 이당류가 결합될 수 있는 한, 그의 구성물질 또는 형태면에서 제한되지 않기 때문에, 상기 결합체는 코어와 시알산 또는 그의 유도체와 단당류 또는 이당류의 다양한 조합에 의하여, 다양한 형태로 형성될 수 있다. As described above, since the core is not limited in terms of its constituent material or form as long as sialic acid or a derivative thereof and a monosaccharide or disaccharide can be bonded, the conjugate can be a core, sialic acid or a derivative thereof, and a monosaccharide or disaccharide. By various combinations of, it can be formed in various shapes.
본 발명에 있어서, 상기 코어는 그의 표면에 복수개의 시알산, 시알릴락토스 또는 이들의 유도체가 결합하여, 서로 동일한 간격으로 배열되어야 하기 때문에, 일정 수준 이상의 직경을 갖고 있는 것이 바람직하다. 상기 코어의 직경은 그의 표면에 복수개의 시알산, 시알릴락토스 또는 이들의 유도체가 결합하여, 서로 동일한 간격으로 배열될 수 있는 한, 특별히 이에 제한되지 않으나, 일 예로서, 1.0 내지 6.0 nm가 될 수 있고, 다른 예로서, 3.5 내지 5.5 nm가 될 수 있으며, 또 다른 예로서, 4.0 내지 6.0 nm가 될 수 있고, 또 다른 예로서, 4.5 내지 5.4 nm가 될 수 있다.In the present invention, since a plurality of sialic acid, sialyllactose, or derivatives thereof are bound to the surface of the core and must be arranged at equal intervals, it is preferable to have a diameter of a certain level or more. The diameter of the core is not particularly limited thereto, as long as a plurality of sialic acid, sialyllactose or derivatives thereof are bonded to its surface and arranged at equal intervals, but, for example, may be 1.0 to 6.0 nm. As another example, it may be 3.5 to 5.5 nm, as another example, it may be 4.0 to 6.0 nm, and as another example, it may be 4.5 to 5.4 nm.
본 발명의 일 실시예에 의하면, 먼저 에틸렌 디아민 코어(G4)를 갖는 PAMAM 덴드리머의 아미노기로 6SL의 환원당의 알데히드 그룹을 환원성 아미노화 하였고, 이때 생성된 중합체에 다시 단당류 또는 이당류로 환원성 아미노화하여 다양한 형태의 6'-시알릴락토스 및 단당류 또는 이당류와 에틸렌 디아민 코어(G4)를 갖는 PAMAM 덴드리머의 결합체를 제조하고(도 1). 이에 포함된 6SL의 수를 결정하였다(표 1).According to one embodiment of the present invention, first, the aldehyde group of the reducing sugar of 6SL is reductively aminated with the amino group of the PAMAM dendrimer having an ethylene diamine core (G4), and then the resulting polymer is reductively aminated again with a monosaccharide or disaccharide to obtain various A conjugate of 6'-sialyllactose and a monosaccharide or disaccharide in the form of a PAMAM dendrimer having an ethylene diamine core (G4) was prepared (FIG. 1). The number of 6SLs included in it was determined (Table 1).
이어, 상기 결합체의 인플루엔자 바이러스 감염억제능을 시험관 조건에서 분석한 결과, H1N1 바이러스의 감염억제 효능을 확인하였다(표 3). Then, as a result of analyzing the ability of the conjugate to inhibit influenza virus infection in vitro, the inhibitory effect of H1N1 virus was confirmed (Table 3).
다음으로, HA에 대한 결합체의 결합 친화력을 분석한 결과, 모두 HA 단백질과 높은 결합친화도를 나타냄을 확인하였다(표 4).Next, as a result of analyzing the binding affinity of the conjugates to HA, it was confirmed that all exhibited high binding affinity to the HA protein (Table 4).
다른 실시양태로서, 본 발명은 상기 결합체를 포함하는 인플루엔자 바이러스 감염증 예방 또는 치료용 약학 조성물을 제공한다.As another embodiment, the present invention provides a pharmaceutical composition for preventing or treating influenza virus infection comprising the conjugate.
본 발명에서 제공하는 약학 조성물에 포함된 결합체의 함량은 인플루엔자 바이러스 감염증을 예방 또는 치료하는 효과를 나타낼 수 있는 한 특별히 이에 제한되지 않으나, 일 예로서, 총 조성물의 중량 대비 0.0001 내지 50 중량%가 될 수 있고, 다른 예로서, 0.01 중량% 내지 10 중량%가 될 수 있다.The content of the conjugate included in the pharmaceutical composition provided in the present invention is not particularly limited as long as it can exhibit an effect of preventing or treating influenza virus infection, but for example, it may be 0.0001 to 50% by weight based on the weight of the total composition. and, as another example, it may be 0.01 wt % to 10 wt %.
본 발명의 약학 조성물은 약학 조성물의 제조에 통상적으로 사용하는 약학적으로 허용가능한 담체, 부형제 또는 희석제를 추가로 포함할 수 있고, 상기 담체는 비자연적 담체(non-naturally occuring carrier)를 포함할 수 있다. The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent commonly used in the preparation of pharmaceutical compositions, and the carrier may include a non-naturally occurring carrier. there is.
상기 약학 조성물은, 각각 통상의 방법에 따라 산제, 과립제, 정제, 캡슐제, 현탁액, 에멀젼, 시럽, 에어로졸 등의 경구형 제형, 외용제, 좌제 및 멸균 주사용액의 형태로 제형화하여 사용될 수 있다. 본 발명에서, 상기 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 락토즈, 덱스트로즈, 수크로스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 미정질 셀룰로스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제제는 적어도 하나 이상의 부형제 예를 들면, 전분, 칼슘카보네이트(calcium carbonate), 수크로스(sucrose) 또는 락토오스(lactose), 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트, 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상 제제로는 현탁제, 내용액제, 유제, 시럽제 등이 해당되는 데 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, 동결건조 제제, 좌제가 포함된다. 비수성용제, 현탁제로는 프로필렌글리콜(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 may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories and sterile injection solutions according to conventional methods, respectively. In the present invention, carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, it is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations contain at least one excipient such as starch, calcium carbonate, sucrose or lactose. It is prepared by mixing lactose and gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid formulations for oral use include suspensions, solutions for internal use, emulsions, syrups, etc., and various excipients such as wetting agents, sweeteners, aromatics, preservatives, etc. may be included in addition to water and liquid paraffin, which are commonly used simple diluents. there is. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents. As a base for the suppository, witepsol, macrogol, tween 61, cacao butter, laurin paper, glycerogeratin and the like may be used.
또 다른 실시양태로서, 본 발명은 상기 결합체 또는 상기 결합체를 포함하는 약학 조성물을, 인플루엔자 바이러스 감염증의 발병이 의심되거나 또는 인플루엔자 바이러스 감염증이 발병된 개체에 투여하는 단계를 포함하는, 인플루엔자 바이러스 감염증을 예방 또는 치료하는 방법을 제공한다.In another embodiment, the present invention provides prevention of influenza virus infection, comprising administering the conjugate or a pharmaceutical composition containing the conjugate to a subject suspected of having an influenza virus infection or having an influenza virus infection. Or provide a method of treatment.
본 발명의 결합체 또는 이를 포함하는 약학 조성물은 약학적으로 유효한 양으로 투여될 수 있으며, 본 발명의 용어, "약학적으로 유효한 양"이란, 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분하며 부작용을 일으키지 않을 정도의 양을 의미하며, 유효 용량 수준은 환자의 성별, 연령, 체중, 건강상태, 질병의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 방법, 투여 시간, 투여 경로, 및 배출 비율, 치료 기간, 배합 또는 동시에 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 당업자에 의해 용이하게 결정될 수 있다.The conjugate of the present invention or a pharmaceutical composition containing the same can be administered in a pharmaceutically effective amount, and the term "pharmaceutically effective amount" of the present invention refers to treating a disease at a reasonable benefit/risk ratio applicable to medical treatment. The effective dose level is the patient's sex, age, weight, health condition, disease type, severity, drug activity, drug sensitivity, administration method, and administration time. , route of administration, and excretion rate, duration of treatment, combination or factors including drugs used concurrently and other factors well known in the medical arts can be readily determined by those skilled in the art.
일 예로서, 본 발명의 결합체는, 일 예로서, 1회 투여시 1×107 내지 1×1011개, 다른 예로서 1×108 내지 5×1010개, 또 다른 예로서 5×108 내지 2×1010개가 투여될 수 있으나, 이에 제한되지 않는다.As an example, the conjugate of the present invention is administered in a single administration in an amount of 1×10 7 to 1×10 11 , another example is 1×10 8 to 5×10 10 , and another example is 5×10 8 to 2×10 10 may be administered, but is not limited thereto.
다른 예로서, 본 발명의 약학 조성물을 기준으로 하는 경우에는, 고형분을 기준으로 1일 0.0001 내지 100 mg/체중 kg으로, 더욱 구체적으로 0.001 내지 100 mg/체중 kg으로 투여할 수 있다. 투여는 상기 권장 투여량을 하루에 한 번 투여할 수도 있고, 수회 나누어 투여할 수도 있다.As another example, based on the pharmaceutical composition of the present invention, 0.0001 to 100 mg/kg of body weight per day based on solid content, and more specifically, 0.001 to 100 mg/kg of body weight may be administered. As for administration, the recommended dose may be administered once a day, or may be administered in several divided doses.
본 발명의 인플루엔자 바이러스 감염증의 예방 또는 치료 방법에서, 상기 약학 조성물을 투여하는 투여 경로 및 투여 방식은 특별히 제한되지 않으며, 목적하는 해당 부위에 상기 결합체를 포함하는 약학 조성물이 도달할 수 있는 한 임의의 투여 경로 및 투여 방식에 따를 수 있다. 구체적으로, 상기 약학 조성물은 경구 또는 비경구의 다양한 경로를 통하여 투여될 수 있으며, 그 투여 경로의 비제한적인 예로는, 구강, 직장, 국소, 정맥내, 복강내, 근육내, 동맥내, 경피, 비측내 또는 흡입 등을 통하여 투여되는 것을 들 수 있다.In the method for preventing or treating influenza virus infection of the present invention, the administration route and administration method for administering the pharmaceutical composition are not particularly limited, and any desired site can be reached as long as the pharmaceutical composition containing the conjugate can be reached. It may depend on the route of administration and mode of administration. Specifically, the pharmaceutical composition may be administered through various oral or parenteral routes, and non-limiting examples of the route of administration include oral, rectal, topical, intravenous, intraperitoneal, intramuscular, intraarterial, transdermal, and those administered through intranasal or inhalation.
또 다른 실시양태로서, 본 발명은 상기 결합체를 포함하는 인플루엔자 바이러스 감염증 예방 또는 개선용 식품 조성물을 제공한다.As another embodiment, the present invention provides a food composition for preventing or improving influenza virus infection comprising the conjugate.
본 발명의 용어 "개선"이란, 본 발명의 결합체를 포함하는 조성물의 투여로 치료되는 상태와 관련된 파라미터, 예를 들면 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.The term "improvement" of the present invention refers to any activity that at least reduces a parameter related to a condition to be treated, for example, the severity of a symptom, by administration of a composition comprising the conjugate of the present invention.
본 발명의 용어 "식품"이란, 육류, 소시지, 빵, 초콜릿, 캔디류, 스낵류, 과자류, 피자, 라면, 기타 면류, 껌류, 아이스크림류를 포함한 낙농제품, 각종 스프, 음료수, 차, 드링크제, 알코올음료, 비타민 복합제, 건강 기능 식품 및 건강 식품 등이 있으며, 통상적인 의미에서의 식품을 모두 포함한다.The term "food" in the present invention means meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages , vitamin complexes, health functional foods and health foods, etc., and include all foods in the conventional sense.
본 발명의 식품 조성물은, 일상적으로 섭취하는 것이 가능하기 때문에 높은 수준으로 인플루엔자 바이러스 감염증을 개선시킬 수 있는 효과를 기대할 수 있으므로, 건강 증진 목적으로 매우 유용하게 사용될 수 있다.Since the food composition of the present invention can be consumed on a daily basis, it can be expected to have an effect of improving influenza virus infection at a high level, so it can be very useful for health promotion purposes.
상기 건강 기능(성) 식품(functional food)이란, 특정보건용 식품(food for special health use, FoSHU)과 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 제조시에는 당 업계에서 통상적으로 첨가하는 원료 및 성분을 첨가하여 제조할 수 있다. 또한 상기 식품의 제형 또한 식품으로 인정되는 제형이면 제한 없이 제조될 수 있다. 본 발명의 식품용 조성물은 다양한 형태의 제형으로 제조될 수 있으며, 일반 약품과는 달리 식품을 원료로 하여 약품의 장기 복용 시 발생할 수 있는 부작용 등이 없는 장점이 있고, 휴대성이 뛰어나므로, 본 발명의 식품은 인플루엔자 바이러스 감염증 개선 효과를 증진시키기 위한 보조제로 섭취가 가능하다.The health functional food (functional food) is the same term as food for special health use (FoSHU), and is a medicine processed to efficiently display bioregulatory functions in addition to nutritional supply, and has high medical effect. means food. Here, 'function (sex)' means obtaining useful effects for health purposes such as regulating nutrients for the structure and function of the human body or physiological functions. The food of the present invention can be prepared by a method commonly used in the art, and can be prepared by adding raw materials and ingredients commonly added in the art during the preparation. In addition, the formulation of the food may also be prepared without limitation as long as the formulation is recognized as a food. The composition for food of the present invention can be prepared in various types of formulations, and unlike general drugs, it has the advantage of not having side effects that may occur when taking drugs for a long time by using food as a raw material, and has excellent portability. The food of the invention can be consumed as an adjuvant to enhance the effect of improving influenza virus infection.
상기 건강 식품(health food)은 일반식품에 비해 적극적인 건강유지나 증진 효과를 가지는 식품을 의미하고, 건강보조식품(health supplement food)은 건강보조 목적의 식품을 의미한다. 경우에 따라, 건강 기능 식품, 건강식품, 건강보조식품의 용어는 호용된다.The health food (health food) means a food having an active health maintenance or promotion effect compared to general food, health supplement food (health supplement food) means a food for the purpose of health supplement. In some cases, the terms health functional food, health food, and health supplement food are used interchangeably.
구체적으로, 상기 건강 기능 식품은 본 발명의 화합물을 음료, 차류, 향신료, 껌, 과자류 등의 식품 소재에 첨가하거나, 캡슐화, 분말화, 현탁액 등으로 제조한 식품으로, 이를 섭취할 경우 건강상 특정한 효과를 가져오는 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 compound of the present invention to food materials such as beverages, teas, spices, chewing gum, confectionery, etc., or encapsulated, powdered, suspended, etc. It means to bring about an effect, but unlike general drugs, it has the advantage of not having side effects that can occur when taking drugs for a long time by using food as a raw material.
상기 식품 조성물은 생리학적으로 허용 가능한 담체를 추가로 포함할 수 있는데, 담체의 종류는 특별히 제한되지 않으며 당해 기술 분야에서 통상적으로 사용되는 담체라면 어느 것이든 사용할 수 있다.The food composition may further include a physiologically acceptable carrier. The type of carrier is not particularly limited, and any carrier commonly used in the art may be used.
또한, 상기 식품 조성물은 식품 조성물에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 추가 성분을 포함할 수 있다. 예들 들어, 비타민 A, C, D, E, B1, B2, B6, B12, 니아신(niacin), 비오틴(biotin), 폴레이트(folate), 판토텐산(panthotenic acid) 등을 포함할 수 있다. 또한, 아연(Zn), 철(Fe), 칼슘(Ca), 크롬(Cr), 마그네슘(Mg), 망간(Mn), 구리(Cu), 크륨(Cr) 등의 미네랄; 및 라이신, 트립토판, 시스테인, 발린 등의 아미노산을 포함할 수 있다. In addition, the food composition may include additional ingredients that are commonly used in food compositions and can improve smell, taste, and vision. For example, vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, and the like may be included. In addition, minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), and chrome (Cr); and amino acids such as lysine, tryptophan, cysteine, and valine.
또한, 상기 식품 조성물은 방부제(소르빈산 칼륨, 벤조산나트륨, 살리실산, 데히드로초산나트륨 등), 살균제(표백분과 고도 표백분, 차아염소산나트륨 등), 산화방지제(부틸히드록시아니졸(BHA), 부틸히드록시톨류엔(BHT) 등), 착색제(타르색소 등), 발색제(아질산 나트륨, 아초산 나트륨 등), 표백제(아황산나트륨), 조미료(MSG 글루타민산나트륨 등), 감미료(둘신, 사이클레메이트, 사카린, 나트륨 등), 향료(바닐린, 락톤류 등), 팽창제(명반, D-주석산수소칼륨 등), 강화제, 유화제, 증점제(호료), 피막제, 검기초제, 거품억제제, 용제, 개량제 등의 식품 첨가물(food additives)을 포함할 수 있다. 상기 첨가물은 식품의 종류에 따라 선별되고 적절한 양으로 사용될 수 있다.In addition, the food composition may include preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), bactericides (bleaching powder, high bleaching powder, sodium hypochlorite, etc.), antioxidants (butylhydroxyanisole (BHA), butyl hydroxy Loxytoluene (BHT), etc.), coloring agents (tar color, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite, etc.), seasonings (MSG sodium glutamate, etc.), sweeteners (dulcin, cyclemate, saccharin) , sodium, etc.), flavoring (vanillin, lactones, etc.), expanding agent (alum, D-potassium hydrogen stannate, etc.), strengthening agent, emulsifier, thickener (thickener), coating agent, gum base agent, foam inhibitor, solvent, improver, etc. food May contain food additives. The additive may be selected according to the type of food and used in an appropriate amount.
본 발명의 식품 조성물의 일 예로 건강음료 조성물로 사용될 수 있으며, 이 경우 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로 함유할 수 있다. 상술한 천연 탄수화물은 포도당, 과당과 같은 모노사카라이드; 말토스, 슈크로스와 같은 디사카라이드; 덱스트린, 사이클로덱스트린과 같은 폴리사카라이드; 자일리톨, 소르비톨, 에리트리톨 등의 당알콜일 수 있다. 감미제는 타우마틴, 스테비아 추출물과 같은 천연 감미제; 사카린, 아스파르탐과 같은 합성 감미제 등을 사용할 수 있다. 상기 천연 탄수화물의 비율은 본 발명의 건강음료 조성물 100 mL 당 일반적으로 약 0.01 ? 0.04 g, 구체적으로 약 0.02 ? 0.03 g이 될 수 있다.An example of the food composition of the present invention may be used as a health beverage composition, and in this case, it may contain various flavoring agents or natural carbohydrates as additional components, like conventional beverages. The aforementioned natural carbohydrates include monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; polysaccharides such as dextrins and cyclodextrins; It may be a sugar alcohol such as xylitol, sorbitol, or erythritol. Sweeteners include natural sweeteners such as thaumatin and stevia extract; Synthetic sweeteners such as saccharin and aspartame may be used. The ratio of the natural carbohydrates is generally about 0.01 per 100 mL of the health drink composition of the present invention. 0.04 g, specifically about 0.02? It can be 0.03 g.
상기 외에 건강음료 조성물은 여러 가지 영양제, 비타민, 전해질, 풍미제, 착색제, 펙트산, 펙트산의 염, 알긴산, 알긴산의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올 또는 탄산화제 등을 함유할 수 있다. 그 밖에 천연 과일주스, 과일주스 음료, 또는 야채 음료의 제조를 위한 과육을 함유할 수 있다. 이러한 성분은 독립적으로 또는 혼합하여 사용할 수 있다. 이러한 첨가제의 비율은 크게 중요하진 않지만 본 발명의 건강음료 조성물 100 중량부당 0.01 내지 0.1 중량부의 범위에서 선택되는 것이 일반적이다.In addition to the above, the health beverage composition includes various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid, salts of pectic acid, alginic acid, salts of alginic acid, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, It may contain alcohol or a carbonating agent, and the like. In addition, it may contain fruit flesh for the manufacture of natural fruit juice, fruit juice beverages, or vegetable beverages. These components may be used independently or in combination. The ratio of these additives is not very important, but is generally selected in the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the health beverage composition of the present invention.
또 다른 실시양태로서, 본 발명은 상기 결합체 또는 상기 결합체를 인플루엔자 바이러스에 처리하는 단계를 포함하는, 인플루엔자 바이러스의 감염을 억제하는 방법을 제공한다.As another embodiment, the present invention provides a method for inhibiting influenza virus infection, comprising treating the conjugate or the influenza virus with the conjugate.
상술한 바와 같이, 본 발명의 결합체는 이에 포함된 시알산 또는 그의 유도체가 인플루엔자 바이러스의 표면에 존재하는 헤마글루티닌과 결합하여 소포를 형성하고, 이로 인하여 상기 바이러스의 부착, 세포내 진입 및 엔도좀 융합/방출 과정을 억제하며, 바이러스의 세포내 진입에 관여하고, 바이러스의 감염에 의하여 증가되는 NA의 발현수준을 저하시키는 효과를 나타낼 수 있다.As described above, in the conjugate of the present invention, sialic acid or a derivative thereof contained therein binds to hemagglutinin present on the surface of influenza virus to form a vesicle, thereby causing the virus to attach, enter cells and enter the endoplasmic reticulum. It inhibits the fusion/release process, is involved in the entry of viruses into cells, and can exhibit the effect of lowering the expression level of NA, which is increased by viral infection.
따라서, 본 발명의 결합체는 시험관 조건(in vitro), 생체내 조건(in vivo) 또는 탈체 조건(ex vivo)에서 인플루엔자 바이러스의 감염을 억제하기 위하여 사용할 수 있다.Accordingly, the conjugate of the present invention can be used to inhibit influenza virus infection in vitro, in vivo, or ex vivo.
특히, 목적하는 세포에 대한 인플루엔자 바이러스의 감염성 연구를 수행하기 위하여 시험관 조건(in vitro) 또는 탈체 조건(ex vivo)에서 인플루엔자 바이러스의 감염을 억제하고자 하는 경우, 상기 결합체를 적절한 농도로 완충액에 희석시킨 후, 바이러스 용액 또는 바이러스에 감염된 세포에 처리하여, 상기 세포에 대한 인플루엔자 바이러스의 감염을 억제할 수 있다.In particular, in the case of inhibiting influenza virus infection in vitro or ex vivo in order to conduct influenza virus infectivity studies on cells of interest, diluting the conjugate in a buffer at an appropriate concentration Afterwards, the virus solution or virus-infected cells are treated to inhibit influenza virus infection of the cells.
이하 본 발명을 실시예를 통하여 보다 상세하게 설명한다. 그러나 이들 실시예는 본 발명을 예시적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail through examples. However, these examples are intended to illustrate the present invention by way of example, and the scope of the present invention is not limited to these examples.
실시예 1: 시알릴락토스와 단당류 또는 이당류 및 PAMAM 덴드리머의 결합체의 합성Example 1: Synthesis of Conjugation of Sialyllactose with Monosaccharide or Disaccharide and PAMAM Dendrimer
먼저 에틸렌 디아민 코어(G4)를 갖는 PAMAM 덴드리머의 아미노기로 6SL의 환원당의 알데히드 그룹을 환원성 아미노화 하였고, 이때 생성된 중합체에 다시 단당류 또는 이당류로 환원성 아미노화하여 다양한 형태의 6'-시알릴락토스 및 단당류 또는 이당류와 에틸렌 디아민 코어(G4)를 갖는 PAMAM 덴드리머의 결합체를 제조하였다(도 1).First, the aldehyde group of the reducing sugar of 6SL was reductively aminated with the amino group of the PAMAM dendrimer having an ethylene diamine core (G4), and at this time, the resulting polymer was reductively aminated again with a monosaccharide or disaccharide to obtain various types of 6'-sialyllactose and A conjugate of a monosaccharide or disaccharide and a PAMAM dendrimer having an ethylene diamine core (G4) was prepared (FIG. 1).
대략적으로, 50mM NaCNBH3을 포함하는 0.1M 소듐 보레이트 완충액(pH 9.5)에서, PAMAM 덴드리머(G4)와 서로 다른 양의 6'-시알릴락토스를 혼합하였고, 이때 생성된 물질 각각을 50mM NaCNBH3을 포함하는 0.1M 소듐 보레이트 완충액(pH 9.5) 하에서, 다양한 양의 단당류 또는 이당류를 가하여 반응시켰다(표 1). 1단계와 2단계 반응에서 각각은 모두 반응액을 서서히 교반하면서, 암소 및 실온에서 5일 동안 연속적으로 반응시켰다. 반응이 종료된 후, 적절한 크기(MWCO 3 K)의 Amicon centrifugal filters (Millipore)를 사용하여 여과함으로써, 반응하지 않은 제제를 제거하고, 탈이온수로 용매를 교체하였다. 여과 후, 용액을 동결건조시키고, 얻어진 백색 분말의 시료를 사용 시까지 건조하여 저장하였다.Approximately, in 0.1M sodium borate buffer (pH 9.5) containing 50mM NaCNBH 3 , PAMAM dendrimer (G4) and different amounts of 6'-sialyllactose were mixed, and each of the resulting materials was mixed with 50mM NaCNBH 3 Under a 0.1M sodium borate buffer solution (pH 9.5) containing, various amounts of monosaccharide or disaccharide were added and reacted (Table 1). In each of the first and second reactions, the reaction solution was continuously reacted for 5 days in the dark and at room temperature while slowly stirring the reaction solution. After the reaction was completed, unreacted agents were removed by filtration using Amicon centrifugal filters (Millipore) of appropriate size (MWCO 3 K), and the solvent was replaced with deionized water. After filtration, the solution was lyophilized and a sample of the obtained white powder was dried and stored until use.
실시예 2: 6'-시알릴락토스 및 단당류 또는 이당류와 PAMAM 덴드리머(G4) 결합체의 특성분석Example 2: Characterization of 6'-Sialyllactose and Monosaccharide or Disaccharide and PAMAM Dendrimer (G4) Conjugates
상기 실시예 1에서 합성된 6'-시알릴락토스 및 단당류 또는 이당류와 PAMAM 덴드리머(G4)결합체의 특성을 1H-NMR 및 DLS(dynamic light scattering)를 사용하여 분석하였다.The properties of the conjugate of 6'-sialyllactose and monosaccharide or disaccharide and PAMAM dendrimer (G4) synthesized in Example 1 were analyzed using 1 H-NMR and dynamic light scattering (DLS).
실시예 2-1: Example 2-1: 1One H-NMR 분석H-NMR analysis
PAMAM(G4) 덴드리머, 6'-시알릴락토스 및 단당류 또는 이당류의 결합체에 대한 NMR 스펙트럼은 Bruker AVANCE III 700 분광기를 사용하여 중수소 옥사이드(D2O)에서 측정하였고(도 2), 상기 데이터 분석을 통해 PAMAM 덴드리머(G4)에 결합된 6'-시알릴락토스 및 단당류 또는 이당류의 평균값을 산출하였다(표 2 및 도 2).NMR spectra for the PAMAM (G4) dendrimer, 6'-sialyllactose and monosaccharide or disaccharide conjugates were measured in deuterium oxide (D 2 O) using a Bruker AVANCE III 700 spectrometer (FIG. 2), and the data analysis Through this, the average values of 6'-sialyllactose and monosaccharide or disaccharide bound to the PAMAM dendrimer (G4) were calculated (Table 2 and FIG. 2).
concrete
Number of 6'-sialyllactose
Number of monosaccharides and disaccharides
20SL-G4
20.1
-
10R-20SL-G4
20.1
Rhamnose 10.0
20R-20SL-G4
20.1
Rhamnose 19.8
30R-20SL-G4
20.1
Rhamnose 27.5
10G-20SL-G4
20.1
Glucose 10.1
20G-20SL-G4
20.1
Glucose 20.0
30G-20SL-G4
20.1
Glucose 27.3
10L-20SL-G4
20.1
Lactose 9.8
20L-20SL-G4
20.1
Lactose 19.8
30L-20SL-G4
20.1
Lactose 27.0
10M-20SL-G4
20.1
Maltose 10.0
20M-20SL-G4
20.1
Maltose 19.9
30M-20SL-G4
20.1
Maltose 27.1
16SL-G4
16.0
-
10R-16SL-G4
16.0
Rhamnose 10.1
20R-16SL-G4
16.0
Rhamnose 20.0
30R-16SL-G4
16.0
Rhamnose 27.6
10G-16SL-G4
16.0
Glucose 10.0
20G-16SL-G4
16.0
Glucose 19.9
30G-16SL-G4
16.0
Glucose 27.4
상기 얻어진 결과로부터, 합성된 중합체의 구조를 예상할 수 있었다(도 3).From the results obtained above, the structure of the synthesized polymer could be predicted (FIG. 3).
실시예 2-2: DLS(dynamic light scattering) 분석Example 2-2: DLS (dynamic light scattering) analysis
PAMAM 덴드리머(G4), 6'-시알릴락토스 및 단당류 또는 이당류 결합체의 규칙성과 크기는 Beckman Coulter DelsaMax PRO(Brea, California, USA)를 사용한 DLS(dynamic light scattering)에 의해 얻어진 유체역학적 직경(hydrodynamic diameter)과 다분산성(polydispersity)의 데이터 분석을 통하여 판단하였다(표 3 및 도 4). 간단히 살펴보면, 시료를 pH 7.4의 10 mM PBS에 녹이고 20℃에서 5 duplicate의 셋트로 했으며 DelsaMax Analysis Software version 1.0을 사용하여 데이터를 획득하였다.The regularity and size of PAMAM dendrimer (G4), 6'-sialyllactose and mono- or disaccharide conjugates were determined by hydrodynamic diameter obtained by dynamic light scattering (DLS) using Beckman Coulter DelsaMax PRO (Brea, California, USA). ) and polydispersity data analysis (Table 3 and Figure 4). Briefly, the samples were dissolved in 10 mM PBS at pH 7.4 and set of 5 duplicates at 20°C, and data were acquired using DelsaMax Analysis Software version 1.0.
concrete
hydrodynamic diameter (nm)
Polydispersity (%Pd)
PAMAM G4
5.4 ± 0.20
20.5 ± 2.10
20SL-G4
5.8 ± 0.10
24.6 ± 0.35
10R-20SL-G4
6.0 ± 0.15
22.1 ± 1.70
20R-20SL-G4
6.0 ± 0.10
22.1 ± 0.93
30R-20SL-G4
6.1 ± 0.0
23.1 ± 0.60
10G-20SL-G4
5.8 ± 0.06
23.5 ± 1.63
20G-20SL-G4
5.9 ± 0.15
22.4 ± 2.31
30G-20SL-G4
6.0 ± 0.12
22.6 ± 2.84
10L-20SL-G4
5.9 ± 0.10
26.1 ± 2.70
20L-20SL-G4
6.1 ± 0.10
22.5 ± 0.50
30L-20SL-G4
6.2 ± 0.10
24.7 ± 0.90
10M-20SL-G4
5.9 ± 0.20
25.6±2.50
20M-20SL-G4
6.2 ± 0.10
23.3 ± 0.60
30M-20SL-G4
6.2 ± 0.10
25.8 ± 1.10
16SL-G4
5.8 ± 0.15
22.0 ± 2.30
10R-16SL-G4
6.0 ± 0.20
23.1 ± 1.10
20R-16SL-G4
6.0 ± 0.10
25.0±2.50
30R-16SL-G4
6.1 ± 0.10
26.0 ± 0.80
10G-16SL-G4
6.2 ± 0.20
25.1 ± 3.20
20G-16SL-G4
6.2 ± 0.10
26.6 ± 4.80
30G-16SL-G4
6.1 ± 0.20
25.2±2.80
상기의 결과와 같이, PAMAM 덴드리머(G4)의 6'-시알릴락토스 및 단당류 또는 이당류 결합체는 PAMAM 덴드리머(G4)와 비교하여 양호한 규칙성을 나타내었다.As the above results, the 6'-sialyllactose and monosaccharide or disaccharide conjugates of the PAMAM dendrimer (G4) exhibited good regularity compared to the PAMAM dendrimer (G4).
실시예 3: 시험관 조건에서 시알릴락토스와 단당류 또는 이당류 및 PAMAM 덴드리머(G4) 결합체의 인플루엔자 바이러스 감염 억제분석Example 3: Analysis of Influenza Virus Infection Inhibition of Sialyllactose and Monosaccharide or Disaccharide and PAMAM Dendrimer (G4) Conjugates in In Vitro Conditions
먼저, PBS를 이용하여 시험하고자 하는 결합체의 반-로그 연속 희석액(half-log serial dilution)을 제조하였다. 상기 제조된 희석액 50 ㎕를 동일부피의 1 × 103 TCID50의 인플루엔자 H1N1 균주(A/PR/8/34))와 혼합하였다. 상기 혼합액을 37℃에서 1시간 동안 배양하고, 이어 1.5 × 105세포수/㎖의 MDCK 세포를 100 ㎕씩 가한 다음, 5% CO2 및 37℃ 조건에서 18시간 동안 추가로 배양하였다. 배양이 종료된 후, 상기 배양된 MDCK 세포에 고정액(아세톤:PBS=4:1, v/v)을 가하고 10 내지 15분 동안 고정시켰다. 이어, 항-NP 마우스 항체(Millipore) 및 항-마우스 염소 항체-HRP 결합체(Jackson Immunoresearch)를 사용한 ELISA 분석을 수행하여, 상기 각 MDCK 세포에 포함된 인플루엔자 핵 단백질(NP)을 검출하였다. 이때, 음성 대조군(미감염 세포, 감염율 0%) 및 양성 대조군(억제제 없이 감염된 세포, 감염율 100%)에 대한 흡광도를 사용하여 상기 각 MDCK 세포에 대한 감염율을 산출하고, 상기 산출된 감염율의 통계분석은 GraphPad Prism 6.0 (GraphPad Software, San Diego, CA)을 사용하여 수행하였다(표 4).First, a half-log serial dilution of the conjugate to be tested was prepared using PBS. 50 μl of the prepared dilution was mixed with an equal volume of 1 × 10 3 TCID50 of influenza H1N1 strain (A/PR/8/34)). The mixed solution was incubated at 37°C for 1 hour, and then 100 μl of MDCK cells at 1.5 × 10 5 cells/ml was added thereto, and further cultured at 5% CO 2 and 37°C for 18 hours. After the incubation was completed, a fixative (acetone: PBS = 4: 1, v/v) was added to the cultured MDCK cells and fixed for 10 to 15 minutes. Subsequently, ELISA analysis using an anti-NP mouse antibody (Millipore) and an anti-mouse goat antibody-HRP conjugate (Jackson Immunoresearch) was performed to detect influenza nuclear protein (NP) contained in each of the MDCK cells. At this time, the infection rate for each MDCK cell was calculated using the absorbance for the negative control group (uninfected cells,
표 4에서 보는 바와 같이 시험관 조건에서 시알릴락토스와 단당류 또는 이당류 및 PAMAM 덴드리머(G4) 결합체는 전반적으로 강한 인플루엔자 바이러스 감염 억제 효능을 나타내었다.As shown in Table 4, in vitro conditions, sialyllactose, monosaccharide or disaccharide, and PAMAM dendrimer (G4) conjugates exhibited strong influenza virus infection inhibitory efficacy overall.
concrete
IC 50 (μM)
CC 50 (μM)
20SL-G4
1.7
310.1
10R-20SL-G4
1.8
974.9
20R-20SL-G4
2.0
899.3
30R-20SL-G4
3.2
>1000
10G-20SL-G4
1.5
733.7
20G-20SL-G4
2.5
961.8
30G-20SL-G4
4.9
>1000
10L-20SL-G4
1.9
857.5
20L-20SL-G4
4.7
>1000
30L-20SL-G4
10.3
>1000
10M-20SL-G4
5.5
698.5
20M-20SL-G4
4.8
>1000
30M-20SL-G4
15.1
>1000
16SL-G4
0.5
622.1
10R-16SL-G4
0.3
899.3
20R-16SL-G4
0.8
>1000
30R-16SL-G4
1.5
>1000
10G-16SL-G4
0.7
701.6
20G-16SL-G4
0.7
951.6
30G-16SL-G4
2.0
>1000
실시예 4: HA에 대한 시알릴락토스와 단당류 또는 이당류 및 PAMAM 덴드리머(G4) 결합체 결합체의 결합 친화력 분석Example 4: Binding Affinity Analysis of Sialyllactose and Monosaccharide or Disaccharide and PAMAM Dendrimer (G4) Conjugate Conjugates for HA
표준 아민 커플 링 프로토콜(GE healthcare, Uppsala, Sweden)에 따라 H1N1 바이러스의 표면항원인 HA 단백질을 CM5 칩에 고정시키고, 이로부터 시알릴락토스와 단당류 또는 이당류 및 PAMAM 덴드리머(G4) 결합체와 HA 단백질 간의 분자반응/속도 데이터를 수득하는 SPR(Surface plasmon resonance) 분석을 통해, HA와 시알릴락토스와 단당류 또는 이당류 및 PAMAM 덴드리머(G4) 결합체의 결합 친화력을 분석하였다.According to a standard amine coupling protocol (GE healthcare, Uppsala, Sweden), the HA protein, which is the surface antigen of the H1N1 virus, was immobilized on a CM5 chip, and from this, the relationship between sialyllactose and a monosaccharide or disaccharide and the PAMAM dendrimer (G4) complex and the HA protein was immobilized. The binding affinity of HA, sialyllactose, monosaccharide or disaccharide, and PAMAM dendrimer (G4) conjugate was analyzed by surface plasmon resonance (SPR) analysis to obtain molecular response/rate data.
대략적으로, CM5 칩 표면의 카르복시 메틸기는 N-에틸-N-(디메틸아미노프로필) 카르보디이미드와 N-히드록시석신이미드의 동일몰량 혼합물(최종농도 0.05M) 35㎖을 가하여(유속, 5㎖/분) 활성화시켰다. 그런 다음, HA를 100 mM 소듐아세테이트 완충액(pH 5.0) 완충액에 50㎍/㎖가 되도록 가하고, 상기 활성화된 CM5 칩 표면에 가하였다. 이어, 35㎕의 1M 에탄올아민을 처리하여 상기 CM5 칩 표면의 미반응 부위를 불활성화 시켰다. Roughly, the carboxymethyl group on the surface of the CM5 chip was determined by adding 35 ml of an equimolar mixture of N-ethyl-N-(dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide (final concentration 0.05 M) (flow rate, 5 ml/min) was activated. Then, HA was added to 50 μg/ml of 100 mM sodium acetate buffer (pH 5.0) and applied to the surface of the activated CM5 chip. Subsequently, unreacted areas on the surface of the CM5 chip were inactivated by treatment with 35 μl of 1M ethanolamine.
한편, N-에틸-N-(디메틸아미노프로필) 카르보디이미드와 N-히드록시숙신이미드(최종농도 0.05M)의 동일몰량 혼합물(최종농도 0.05M) 35㎖을 가한 다음(유속, 5㎖/분), 35㎕의 1M 에탄올아민을 처리하여 대조군을 제작하였다.On the other hand, 35 ml of an equimolar mixture (final concentration 0.05 M) of N-ethyl-N-(dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide (final concentration 0.05 M) was added (flow rate, 5 ml /min), 35 μl of 1M ethanolamine was treated to prepare a control group.
다음으로, 6-SL PAMAM 결합체를 HBS-EP 완충액(0.01 M HEPES, 0.15 M NaCl, 3 mM EDTA, 0.005% surfactant P20, pH 7.4)에 희석시켰다. 서로 다른 수준의 시알릴락토스와 단당류 또는 이당류 및 PAMAM 덴드리머(G4) 결합체의 희석액을 50㎕/분의 유속으로 상기 HA가 결합된 CM5 칩에 가하였다. 그런 다음, 상기 CM5 칩에 HBS-EP 완충액을 가하여, 해리를 촉진시켰다. 3분이 경과한 후, 상기 CM5 칩에 2 M NaCl 50 ㎕를 가하여, 상기 CM5 칩의 표면을 재생하였다. 반응결과는 BIAcore 3000 control 및 BIAevaluation software (version 4.0.1)를 사용한 BIAcore 3000 (GE healthcare, Uppsala, Sweden)를 이용하여 분석하였고, 25℃에서 시간(센서 그램)의 함수로 표시하였다(도 5).Next, the 6-SL PAMAM conjugate was diluted in HBS-EP buffer (0.01 M HEPES, 0.15 M NaCl, 3 mM EDTA, 0.005% surfactant P20, pH 7.4). Dilutions of different levels of sialyllactose and monosaccharide or disaccharide and PAMAM dendrimer (G4) conjugates were added to the HA-bound CM5 chip at a flow rate of 50 µl/min. Then, HBS-EP buffer was added to the CM5 chip to promote dissociation. After 3 minutes had elapsed, 50 μl of 2 M NaCl was added to the CM5 chip to regenerate the surface of the CM5 chip. The reaction results were analyzed using BIAcore 3000 (GE healthcare, Uppsala, Sweden) using BIAcore 3000 control and BIAevaluation software (version 4.0.1), and expressed as a function of time (sensorgram) at 25 ° C (Fig. 5) .
도 5에서 보듯이, 사용된 시알릴락토스와 단당류 또는 이당류 및 PAMAM 덴드리머(G4) 결합체는 대부분 HA 단백질과 높은 결합 친화도를 나타냄을 확인하였다. As shown in FIG. 5, it was confirmed that most of the sialyllactose, monosaccharide or disaccharide, and PAMAM dendrimer (G4) conjugates exhibited high binding affinity to the HA protein.
특히, 단당류인 람노스(rhamnose) 또는 글루코스(glucose)가 10개 그리고 시알릴락토스가 16개 존재하는 중합체에서 HA 단백질과 가장 높은 결합친화도를 나타냄을 확인하였다.In particular, it was confirmed that a polymer containing 10 monosaccharide rhamnose or glucose and 16 sialyllactose showed the highest binding affinity with HA protein.
Claims (12)
상기 덴드리머 코어(core)는 에틸렌 디아민 코어(G4)를 갖는 폴리아미도아민(polyamidoamine, PAMAM) 덴드리머이고,
상기 시알산은 6'-시알릴락토스이고,
상기 단당류 또는 이당류는 람노스(rhamnose), 글루코스(glucose), 갈락토스(galactose), 락토스(lactose) 및 말토스(maltose)로 이루어지는 군에서 선택되는 1종 이상을 포함하고,
상기 덴드리머 코어(core)의 표면에 결합된 시알산은 16 내지 20개이고,
상기 덴드리머 코어(core)의 표면에 결합된 단당류 또는 이당류는 10 내지 30개인 것인, 결합체.
A conjugate composed of a dendrimer core and sialic acid bonded to its surface and a monosaccharide or disaccharide,
The dendrimer core is a polyamidoamine (PAMAM) dendrimer having an ethylene diamine core (G4),
The sialic acid is 6'-sialyllactose,
The monosaccharide or disaccharide includes at least one selected from the group consisting of rhamnose, glucose, galactose, lactose and maltose,
16 to 20 sialic acids bonded to the surface of the dendrimer core,
The conjugate of 10 to 30 monosaccharides or disaccharides bound to the surface of the dendrimer core.
상기 결합체의 직경은 5.2 내지 6.4 nm 인 것인, 결합체.
According to claim 1,
The conjugate having a diameter of 5.2 to 6.4 nm.
상기 결합체의 다분산성은 18.4 내지 31.4 %Pd인 것인, 결합체.
According to claim 1,
The polydispersity of the conjugate is 18.4 to 31.4% Pd, the conjugate.
A pharmaceutical composition for preventing or treating influenza virus infection, comprising the conjugate of any one of claims 1 to 3.
A food composition for preventing or improving influenza virus infection, comprising the conjugate of any one of claims 1 to 3.
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PCT/KR2021/017016 WO2022108368A1 (en) | 2020-11-19 | 2021-11-18 | Conjugate comprising sialic acid or derivative thereof bonded to surface of dendrimer core, and use thereof |
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