KR102166927B1 - Use of a peptide as a therapeutic agent for autoimmune disease - Google Patents
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- KR102166927B1 KR102166927B1 KR1020180110485A KR20180110485A KR102166927B1 KR 102166927 B1 KR102166927 B1 KR 102166927B1 KR 1020180110485 A KR1020180110485 A KR 1020180110485A KR 20180110485 A KR20180110485 A KR 20180110485A KR 102166927 B1 KR102166927 B1 KR 102166927B1
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Abstract
본 발명은 치료제로서의 펩타이드의 용도에 관한 것으로, 본 발명의 펩타이드들은 자가면역질환에 관련된 T 세포(T cell)의 활성 및 Th17 세포(T helper 17 cell) 분화를 유의적으로 억제시키고, 염증성 사이토카인 IL-6 분비를 감소시키며, 관절염 동물모델에서 현저한 관절염 치료 및 개선 효과를 갖는 것을 확인하였으므로, 상기 펩타이드들은 염증성 질환 또는 류마티스 관절염과 같은 다양한 자가면역질환 치료제에 유효성분으로 이용될 수 있다.The present invention relates to the use of the peptide as a therapeutic agent, wherein the peptides of the present invention significantly inhibit the activity of T cells and differentiation of T helper 17 cells related to autoimmune diseases, and inflammatory cytokines Since it has been confirmed that IL-6 secretion is reduced and has a remarkable arthritis treatment and improvement effect in an arthritis animal model, the peptides can be used as active ingredients in the treatment of various autoimmune diseases such as inflammatory diseases or rheumatoid arthritis.
Description
본 발명은 자가면역질환 치료제로서의 펩타이드의 용도에 관한 것으로, 보다 구체적으로 본 발명의 일반식 1로 기재되는 아미노산 서열로 구성된 펩타이드, 및 상기 펩타이드의 염증성 질환 또는, 류마티스 관절염 등을 포함하는 자가면역질환치료 용도에 관한 것이다.The present invention relates to the use of a peptide as a therapeutic agent for autoimmune diseases, and more specifically, a peptide composed of an amino acid sequence represented by the
자가면역질환은 인체의 면역계가 이상을 일으켜, 자기세포가 자기세포를 공격하는 것이다. 인간의 면역계는 기본적으로 인체에 침입한 미생물 및 암세포 발생 등에 대하여 외부 항원으로 인식하고, 이를 공격하여 제거하는 강력한 힘을 지녔지만 자기 관용성이 있어서 자기세포에 대해서는 공격하지 않는다. 이를 인체의 자기 관용(self-tolerance) 현상이라 한다. 그러나 면역계의 자기 관용이 파괴될 경우, 인체는 자기세포(또는 자가항원)에 반응하는 자가반응 T 세포가 활성화되고 자가항체(autoantibody)가 생성되면서 끊임없이 자기세포를 파괴하며 염증 및 면역반응을 일으키게 된다.In autoimmune diseases, the body's immune system causes abnormalities, and the magnetic cells attack the magnetic cells. The human immune system basically recognizes the occurrence of microorganisms and cancer cells that invade the human body as external antigens, and has a strong power to attack and remove them, but because of its self-tolerance, it does not attack its own cells. This is called a phenomenon of self-tolerance of the human body. However, when the self-tolerance of the immune system is destroyed, the human body activates the autoreactive T cells that respond to the self cells (or autoantigens) and produces an autoantibody, constantly destroying the self cells and causing inflammation and immune responses. .
면역계에서 항원에 특이적으로 반응하는 세포에는 T 세포와 B 세포가 있다. T 세포는 항원제시세포(antigen presenting cell)에 의해 제시되는 특정 항원을 만났을 때 그 항원에 따라 반응을 나타내게 되는데, 항원제시세포에서 제시되는 항원이 'non-self'로 인식이 되면 이를 제거하려는 면역반응을 나타내고, 'self'로 인식되면 면역반응이 무시되는 관용성을 보인다. T 세포가 항원에 대하여 활성화되면, 대부분 B 세포가 잇달아 활성화되며 B 세포는 형질세포(plasma cell)로 변하여 인식한 특정항원에 대하여 특이적으로 반응하는 항체를 생성하게 된다. 따라서 인체에 관용성이 깨지면서 자가면역이 발생될 경우 T 세포가 자가항원을 비정상적으로 인식하여 활성화되고, B 세포도 활성화되면서 자가항원에 반응하는 자가항체를 생성하게 되며, 우리 몸에서는 자기세포를 공격하는 면역반응이 일어나게 된다.Cells that specifically respond to antigens in the immune system include T cells and B cells. When T cells encounter a specific antigen presented by an antigen presenting cell, they react according to the antigen. When the antigen presented by the antigen presenting cell is recognized as'non-self', the immunity to remove it Represents a response, and when recognized as'self', the immune response is neglected and shows tolerance. When T cells are activated against an antigen, most of the B cells are activated one after another, and the B cells turn into plasma cells to generate antibodies that specifically react to the recognized specific antigen. Therefore, when autoimmunity occurs due to breakdown of tolerance in the human body, T cells abnormally recognize and activate autoantigens, and B cells are also activated to produce autoantibodies that respond to autoantigens. An immune response occurs.
또한, 이와 유사하게 장기 이식 환자에서도 장기 이식 후 면역계가 이식된 조직을 'non-self'로 인식하면 이식된 장기를 공격하여 제거하고자 하는 장기이식거부반응이 일어나게 된다. 이를 억제하기 위해 면역세포의 활성화를 억제하고 면역세포가 이식된 장기로 이동하는 것을 억제하는 등 다양한 면역억제제를 사용하고 있으나, 지속적인 면역억제제의 사용은 여러 가지 부작용을 초래한다.Similarly, even in organ transplant patients, if the immune system recognizes the transplanted tissue as'non-self' after the transplant, an organ transplant rejection reaction to attack and remove the transplanted organ occurs. In order to suppress this, various immunosuppressants are used, such as suppressing the activation of immune cells and suppressing the migration of immune cells to the transplanted organs, but continuous use of immunosuppressants causes various side effects.
한편, 최근 CD4+ T 세포 계통인 Th17 세포가 자가 면역질환의 염증 유발과 진행에 핵심적인 역할을 한다는 것이 밝혀지고 있으며, 이러한 Th17 세포의 중요성은 이 세포에서 분비된 IL-17이 자가면역질환과 직접적인 관계가 있는 것으로 밝혀짐으로서 더욱 커지고 있다.Meanwhile, it has been recently revealed that Th17 cells, the CD4+ T cell lineage, play a key role in the induction and progression of autoimmune diseases, and the importance of these Th17 cells is that IL-17 secreted from these cells is directly related to autoimmune diseases. It's getting bigger as it turns out to be related.
또한, Th17 세포는 골파괴의 주요 원인인 RANKL 및 여러 염증성 사이토카인을 유도하고(Chabaud and Miossec, 2001; Connell and McInnes, 2006), 이를 통해 염증 및 관절파괴 기전을 더욱더 활성화 하는 것으로 알려져 있다. 따라서, Th17 세포는 류마티스관절염을 포함하는 자가면역질환, 골질환에 관련된 신호전달 과정에서 핵심 병인 세포로 인정 받고 있으므로, Th17 세포 분화를 효과적으로 억제하는 후보물질의 발굴이 요구되고 있다.In addition, Th17 cells are known to induce RANKL and several inflammatory cytokines, which are the main causes of bone destruction (Chabaud and Miossec, 2001; Connell and McInnes, 2006), and further activate the mechanisms of inflammation and joint destruction through this. Therefore, Th17 cells are recognized as key pathogens in the signaling process related to autoimmune diseases and bone diseases, including rheumatoid arthritis, and thus, discovery of candidate substances that effectively inhibit Th17 cell differentiation is required.
또한, IL-6(interleukin-6)는 염증과 감염 반응뿐 아니라 대사, 재생 그리고 신경 과정에도 관여하는 사이토카인으로, 최근 류마티스 관절염, 크론병 등의 자가면역질환 등에서 주로 연구되고 있으며, Th17 세포의 분화에 관여하여 Th17/Treg 세포의 균형에 작용을 한다고 알려져 있다.In addition, IL-6 (interleukin-6) is a cytokine that is involved in metabolism, regeneration, and neural processes as well as inflammation and infection reactions. Recently, it is mainly studied in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. It is known to be involved in differentiation and act on the balance of Th17/Treg cells.
또한, IL-6는 파골 전구세포(osteoclast precursor)인 골수 대식세포(bone marrow macrophage)를 염증 장소로 유인하고 파골세포로 분화하도록 자극하며, 분화된 파골세포를 활성화하여 주위골을 흡수하도록 한다고 알려져 있으므로, 자가면역질환 및 골질환 치료제 개발에 주요한 타겟으로 인식되고 있다.In addition, IL-6 is known to attract bone marrow macrophages, which are osteoclast precursors, to the site of inflammation, stimulate them to differentiate into osteoclasts, and activate differentiated osteoclasts to absorb surrounding bones. Therefore, it is recognized as a major target for the development of autoimmune diseases and bone disease treatments.
아울러, 류마티스 관절염은 다발성 관절염을 특징으로 하는 염증성 질환으로서, 자가면역현상이 주요 기전으로 알려져 있다. 증상을 살펴보면, 관절 활막(synovial membrane) 조직에 염증이 발생되면서, 대식세포, 수지상세포 및 T 림프구, B 림프구 등이 활막 조직으로 이동하고, 그 결과 관절액이 증가하여 관절이 부으면서 통증이 나타나게 된다. 이러한 염증이 지속되면서 염증성 활막조직이 증생(hyperplasia)하게 되면 뼈와 연골을 파괴하여 관절 구조가 변형되고 운동 장애가 발생된다. 또한 다양한 연구결과에 의하면, 류마티스 관절염 환자에게서 염증성 사이토카인이 활막 섬유세포와 연골세포에서 콜라겐 분해효소 및 중성 프로테아제(protease)를 생산하고 생산된 이들 효소들은 콜라겐과 프로테오글라이칸(proteoglycan)을 파괴하여 관절연골을 파괴시키는 것으로 알려져 있다. In addition, rheumatoid arthritis is an inflammatory disease characterized by multiple arthritis, and an autoimmune phenomenon is known as a major mechanism. As a result, as inflammation occurs in the synovial tissue of the joint, macrophages, dendritic cells, T lymphocytes, and B lymphocytes move to the synovial tissue, and as a result, the joint fluid increases, resulting in pain as the joint becomes swollen. If such inflammation continues and the inflammatory synovial tissue becomes hyperplasia, bone and cartilage are destroyed, the joint structure is deformed, and movement disorders occur. In addition, various studies have shown that in rheumatoid arthritis patients, inflammatory cytokines produce collagen-degrading enzymes and neutral proteases in synovial fibroblasts and chondrocytes, and these enzymes destroy collagen and proteoglycans. It is known to destroy articular cartilage.
이에, 본 발명자들은 치료제로서의 부작용을 최소화시키면서 유효한 치료 효과를 갖는 새로운 자가면역질환 치료제를 개발하기 위해 노력한 결과, 본 발명에서 제조한 펩타이드가 염증성 질환 및, 류마티스 관절염을 포함하는 자가면역질환 치료에 유용하게 사용될 수 있음을 밝힘으로써, 본 발명을 완성하였다.Accordingly, the present inventors have made efforts to develop a novel autoimmune disease therapeutic agent having an effective therapeutic effect while minimizing side effects as a therapeutic agent. As a result, the peptide prepared in the present invention is useful for the treatment of inflammatory diseases and autoimmune diseases including rheumatoid arthritis. By revealing that it can be used to complete the present invention.
본 발명의 목적은 염증성 질환 및 자가면역질환(autoimmune disease) 예방 및 치료용 펩타이드를 제공하기 위한 것이다.It is an object of the present invention to provide a peptide for preventing and treating inflammatory diseases and autoimmune diseases.
상기 목적을 달성하기 위하여, 본 발명은 In order to achieve the above object, the present invention
하기 서열번호 1로 기재되는 일반식 1의 아미노산 서열로 구성된 펩타이드, 및 상기 펩타이드를 유효성분으로 함유하는 염증성 질환 및 자가면역질환 예방 및 치료용 약학적 조성물, 또는 염증성 질환 및 자가면역질환 예방 및 개선용 건강식품을 제공한다.Peptide consisting of the amino acid sequence of
[일반식 1][General Formula 1]
(X1-X2-X3)n (X 1 -X 2 -X 3 ) n
상기 식에서, X1은 아르기닌(Arginine; R), 히스티딘(Histidine; H) 및 라이신(Lysine; K)으로 이루어진 군으로부터 선택되는 어느 하나이고, In the above formula, X 1 is any one selected from the group consisting of arginine (R), histidine (H) and lysine (Lysine; K),
X2는 아스파르트산(Aspartic acid; D) 또는 글루탐산(Glutamic acid; E)이며,X 2 is Aspartic acid (D) or Glutamic acid (E),
X3은 글라이신(Glycine; G), 알라닌(Alanine; A), 발린(Valine; V), 메티오닌(Methionine; M), 아이소류신(Isoleucine; I) 및 류신(Leucine; L)으로 이루어진 군으로부터 선택되는 어느 하나이고, X 3 is selected from the group consisting of glycine (G), alanine (A), valine (V), methionine (M), isoleucine (I) and leucine (L) Is any one
n은 1 내지 10의 정수이며, 단 상기 일반식 1의 아미노산 서열이 서열번호 2로 기재되는 RDG를 포함하고, 동시에 n=1 또는 2 경우는 제외함. n is an integer of 1 to 10, provided that the amino acid sequence of the
본 발명의 펩타이드들은 자가면역질환에 관련된 T 세포(T cell)의 활성 및 Th17 세포(T helper 17 cell) 분화를 유의적으로 억제시키고, IL-6 분비를 현저히 억제시키며, 관절염 동물모델에서 관절염 치료 및 개선 효과를 갖는 것을 확인하였으므로, 상기 펩타이드들은 염증성 질환 또는 류마티스 관절염과 같은 다양한 자가면역질환 치료제에 유효성분으로 이용될 수 있다.The peptides of the present invention significantly inhibit T cell activity and
도 1은 본 발명의 합성 펩타이드에 의한 활성 T 세포 population(%)을 나타낸 도이다.
도 2는 본 발명의 합성 펩타이드에 의한 T 세포 활성화 억제율(%)을 나타낸 도이다.
도 3은 본 발명의 합성 펩타이드에 Th17 세포 분화 억제 효능을 나타낸 도이다.
도 4는 본 발명의 합성 펩타이드에 의한 염증성 사이토카인 IL-6 감소 효과를 확인한 도이다.
도 5는 콜라겐 유도 관절염 마우스 모델의 제조과정 및 본 발명에 따른 펩타이드의 투여 시기를 개략적으로 나타낸 모식도이다.
도 6은 본 발명의 Pep1 펩타이드의 관절염 개선 효과를 나타낸 도이다.
도 7은 본 발명의 Pep4 펩타이드의 관절염 개선 효과를 나타낸 도이다.
도 8은 본 발명의 Pep6 펩타이드의 관절염 개선 효과를 나타낸 도이다.
도 9는 본 발명의 Pep7 펩타이드의 관절염 개선 효과를 나타낸 도이다.
도 10은 본 발명의 Pep8 펩타이드의 관절염 개선 효과를 나타낸 도이다.
도 11은 본 발명의 펩타이드의 관절염 개선 효과를 비교한 도이다.1 is a diagram showing the active T cell population (%) by the synthetic peptide of the present invention.
Figure 2 is a diagram showing the inhibition rate (%) of T cell activation by the synthetic peptide of the present invention.
3 is a diagram showing the effect of inhibiting Th17 cell differentiation in the synthetic peptide of the present invention.
Figure 4 is a diagram confirming the effect of reducing the inflammatory cytokine IL-6 by the synthetic peptide of the present invention.
Figure 5 is a schematic diagram showing the manufacturing process of the collagen-induced arthritis mouse model and the administration timing of the peptide according to the present invention.
6 is a diagram showing the effect of improving arthritis of the Pep1 peptide of the present invention.
7 is a diagram showing the effect of improving arthritis of the Pep4 peptide of the present invention.
8 is a diagram showing the effect of improving arthritis of the Pep6 peptide of the present invention.
9 is a diagram showing the effect of improving arthritis of the Pep7 peptide of the present invention.
10 is a diagram showing the effect of improving arthritis of the Pep8 peptide of the present invention.
11 is a diagram comparing the arthritis improvement effect of the peptide of the present invention.
이하, 본 발명의 용어는 하기와 같이 정의한다.Hereinafter, the terms of the present invention are defined as follows.
본 발명에서, 천연적으로 존재하는 아미노산에 대한 통상의 1문자 및 3문자 코드가 사용될 뿐만 아니라, Aib(α-아미노이소부티르산), Sar(N-methylglycine) 등과 같은 다른 아미노산에 대해 일반적으로 허용되는 3문자 코드가 사용된다. 또한 본 명세서에서 약어로 언급된 아미노산은 IUPAC-IUB 명명법에 따라 기재되었다.In the present invention, not only the usual 1-letter and 3-letter codes for naturally occurring amino acids are used, but also generally acceptable for other amino acids such as Aib (α-aminoisobutyric acid), Sar (N-methylglycine), etc. A 3-letter code is used. In addition, amino acids referred to as abbreviations herein have been described according to the IUPAC-IUB nomenclature.
본 발명의 “펩타이드(peptide)”는 아마이드 결합(또는 펩타이드 결합)으로 연결된 2개 이상의 아미노산으로 이루어진 폴리머를 의미하며, 본 발명의 목적상, 염증성 질환, 자가면역질환 치료 효과를 가지는 펩타이드를 의미한다.“Peptide” of the present invention means a polymer consisting of two or more amino acids linked by an amide bond (or peptide bond), and for the purposes of the present invention, it means a peptide having an effect of treating inflammatory diseases and autoimmune diseases. .
본 발명의, "안정성"은 생체 내 단백질 절단효소의 공격으로부터 본 발명의 펩타이드를 보호하는 인 비보 안정성뿐만 아니라, 저장 안정성(예컨대, 상온 저장 안정성)도 의미한다.In the present invention, "stability" means not only in vivo stability that protects the peptide of the present invention from attack by protein cleavage enzymes in vivo, but also storage stability (eg, room temperature storage stability).
본 발명의, "예방"은 본 발명에 따른 약학적 조성물의 투여에 의해 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.In the present invention, "prevention" refers to any action that suppresses or delays the onset of a disease by administration of the pharmaceutical composition according to the present invention.
본 발명의, "치료"는 본 발명에 따른 약학적 조성물의 투여에 의해 질환에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.In the present invention, "treatment" refers to any action in which symptoms of a disease are improved or advantageously changed by administration of the pharmaceutical composition according to the present invention.
본 발명의, "개체"는 질환의 치료를 필요로 하는 대상을 의미하며, 보다 구체적으로 인간 또는 비-인간인 영장류, 생쥐(mouse), 개, 고양이, 말 및 소 등의 포유류를 의미한다.In the present invention, "individual" refers to a subject in need of treatment of a disease, and more specifically refers to mammals such as human or non-human primates, mice, dogs, cats, horses and cattle.
본 발명의 "개선"이란 치료되는 상태와 관련된 파라미터, 예를 들면, 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.The term "improvement" of the present invention means any action that at least reduces the severity of a parameter associated with the condition being treated, for example a symptom.
이하, 본 발명을 보다 상세히 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명은 The present invention
하기 서열번호 1로 기재되는 일반식 1의 아미노산 서열로 구성된 펩타이드, 및 상기 펩타이드를 유효성분으로 함유하는 염증성 질환 또는 자가면역질환 예방 및 치료용 약학적 조성물을 제공한다:It provides a peptide consisting of the amino acid sequence of the
[일반식 1][General Formula 1]
(X1-X2-X3)n (X 1 -X 2 -X 3 ) n
상기 식에서, X1은 positive charged amino acid인 아르기닌(Arginine; R), 히스티딘(Histidine; H) 및 라이신(Lysine; K)으로 이루어진 군으로부터 선택되는 어느 하나이고, X2는 negative charged amino acid인 아스파르트산(Aspartic acid; D) 또는 글루탐산(Glutamic acid; E)이며, X3은 글라이신(Glycine; G), 알라닌(Alanine; A), 발린(Valine; V), 메티오닌(Methionine; M), 아이소류신(Isoleucine; I) 및 류신(Leucine; L)으로 이루어진 군으로부터 선택되는 어느 하나이고, n은 1 내지 10의 정수이며, 단 상기 일반식 1의 아미노산 서열이 서열번호 2로 기재되는 RDG를 포함하고, 동시에 n=1 또는 2 경우는 제외함.In the above formula, X 1 is any one selected from the group consisting of positively charged amino acids arginine (Arginine; R), histidine (H) and lysine (Lysine; K), and X 2 is a negative charged amino acid aspart Aspartic acid (D) or glutamic acid (E), X 3 is glycine (G), alanine (Alanine; A), valine (V), methionine (M), isoleucine (Isoleucine; I) and leucine (Leucine; L) is any one selected from the group consisting of, n is an integer of 1 to 10, provided that the amino acid sequence of the
상기 펩타이드는 상기 일반식 1을 이용하여 다양한 펩타이드를 제조할 수 있으며, 이는 모두 본 발명에 포함된다. 또한, 상기 X1은 아르기닌(Arginine; R) 또는 히스티딘(Histidine; H)이고, 상기 X3은 글라이신(Glycine; G) 또는 알라닌(Alanine; A)인 것이 바람직하나 이에 한정되지 않는다.The peptides can be prepared by using the
또한, 상기 n은 1 내지 6의 정수인 것이 바람직하고, 1 내지 3인 것이 보다 바람직하다. In addition, n is preferably an integer of 1 to 6, and more preferably 1 to 3.
상기 본 발명의 펩타이드는 당해 분야에서 널리 공지된 다양한 방법으로 획득할 수 있다. 일례로서, 폴리뉴클레오타이드 재조합과 단백질 발현 시스템을 이용하여 제조하거나 펩타이드 합성과 같은 화학적 합성을 통하여 시험관 내에서 합성하는 방법, 및 무세포 단백질 합성법 등으로 제조될 수 있다.The peptide of the present invention can be obtained by various methods well known in the art. As an example, it may be prepared by using a polynucleotide recombination and protein expression system, or by a method for in vitro synthesis through chemical synthesis such as peptide synthesis, and a cell-free protein synthesis method.
또한, 보다 나은 화학적 안정성, 강화된 약리 특성(반감기, 흡수성, 역가, 효능 등), 변경된 특이성(예를 들어, 광범위한 생물학적 활성 스펙트럼), 감소된 항원성을 획득하기 위하여, 펩타이드의 N- 또는 C-말단에 보호기가 결합되어 있을 수 있다. 바람직하게, 상기 보호기는 아세틸기, 플루오레닐 메톡시 카르보닐기, 포르밀기, 팔미토일기, 미리스틸기, 스테아릴기 또는 폴리에틸렌 글리콜(PEG)일 수 있으나, 펩타이드의 개질, 특히 펩타이드의 안정성 증진시킬 수 있는 성분이라면, 제한없이 포함할 수 있다.In addition, in order to obtain better chemical stability, enhanced pharmacological properties (half-life, absorption, titer, efficacy, etc.), altered specificity (e.g., broad biological activity spectrum), reduced antigenicity, the N- or C of the peptide -A protective group may be attached to the end. Preferably, the protecting group may be an acetyl group, a fluorenyl methoxycarbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, or polyethylene glycol (PEG), but the modification of the peptide, especially the stability of the peptide Any component that can be included may be included without limitation.
상기 염증성 질환은 아토피, 건선, 피부염, 알레르기, 관절염, 비염, 중이염, 인후염, 편도염, 방광염, 신장염, 골반염, 크론병, 궤양성 대장염, 강직성 척추염, 전신 홍반성 낭창(systemic lupus erythematodes, SLE), 천식, 부종, 지연성 알레르기(IV형 알레르기), 이식거부, 이식편 대 숙주 질환, 자가면역 뇌척수염, 다발성 경화증, 염증성 장질환, 낭포성 섬유증, 당뇨성 망막증, 허혈성-재관류 손상, 혈관 재협착, 사구체신염, 및 위장관 알레르기로 이루어진 군으로부터 선택되는 것이 바람직하나 이에 한정되지 않는다.The inflammatory diseases include atopy, psoriasis, dermatitis, allergies, arthritis, rhinitis, otitis media, pharyngitis, tonsillitis, cystitis, nephritis, pelvicitis, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematodes (SLE), Asthma, edema, delayed allergy (type IV allergy), transplant rejection, graft versus host disease, autoimmune encephalomyelitis, multiple sclerosis, inflammatory bowel disease, cystic fibrosis, diabetic retinopathy, ischemic-reperfusion injury, vascular restenosis, glomeruli It is preferably selected from the group consisting of nephritis, and gastrointestinal allergy, but is not limited thereto.
상기 자가면역질환은 류마티스 관절염(rheumatoid arthritis), 쇼그렌 증후군(Sjogren's syndrome), 전신 경화증(systemic sclerosis), 다발성 근염(polymyositis), 전신성 혈관염(systemic angitis), 혼합결합조직병(mixed connective tissue disease), 크론병(Crohn's disease), 하시모토병(Hashimoto's disease), 그레이브스병(Grave's disease), 굿파스튜어 증후군(Goodpasture's sydrome), 길랑-바레 증후군(Guillain-Barre syndrom), 특발성 혈소판 감소성 자반증, 과민성 장 증후군, 중증 근무력증, 기면증, 심상성 천포창, 악성 빈혈, 원발성 담즙성 간경변증, 궤양성 대장염, 혈관염, 베게너 육아종증(Wegener's granulomatosis) 및 건선(Psoriasis)으로 이루어진 군으로부터 선택되는 것이 바람직하나 이에 한정되지 않는다.The autoimmune diseases include rheumatoid arthritis, Sjogren's syndrome, systemic sclerosis, polymyositis, systemic angitis, mixed connective tissue disease, Crohn's disease, Hashimoto's disease, Grave's disease, Goodpasture's sydrome, Guillain-Barre syndrom, idiopathic thrombocytopenia purpura, irritable bowel syndrome, Myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia, primary biliary cirrhosis, ulcerative colitis, vasculitis, Wegener's granulomatosis, and psoriasis are preferably selected from the group consisting of, but are not limited thereto.
또한, 본 발명의 펩타이드를 코딩하는 폴리뉴클레오타이드를 사용해도 동일한 치료 효과를 나타낼 수 있으므로, 본 발명의 펩타이드를 코딩하는 폴리뉴클레오타이드도 본 발명에 포함되는 것이 자명한 사항이다. In addition, since the same therapeutic effect can be obtained even when the polynucleotide encoding the peptide of the present invention is used, it is obvious that the polynucleotide encoding the peptide of the present invention is also included in the present invention.
본 발명의 구체적인 실시예에서, 본 발명자들은 상기 일반식 1[(X1-X2-X3)n]을 이용하여 다양한 펩타이드를 제작하였다(표 1 참고).In a specific embodiment of the present invention, the present inventors produced various peptides using the general formula 1 [(X 1 -X 2 -X 3 ) n ] (see Table 1).
또한, 본 발명자들은 상기 펩타이드들의 T 세포 활성 억제 효과를 확인한 결과, 표 1의 펩타이드들은 평균 8%까지 T 세포 활성을 유의적으로 억제하며, 이 중 임의적으로 선별한 펩타이드들의 T 세포 활성 억제 효과는 도 1 내지 도 2에 나타내었다(도 1 내도 도 2 참조).In addition, the present inventors confirmed the T cell activity inhibitory effect of the peptides, the peptides in Table 1 significantly inhibited T cell activity by an average of 8%, of which the randomly selected peptides inhibited T cell activity It is shown in Figs. 1 to 2 (see Fig. 2).
또한, 본 발명자들은 상기 <실시예 1>에서 제작한 합성 펩타이드가 Th17 세포 분화를 억제시키는 효능을 확인한 결과, 본 발명의 펩타이드들은 Th17 세포 분화를 유의적으로 억제하는 것을 확인하였다(도 3 참조).In addition, the present inventors confirmed the efficacy of the synthetic peptide prepared in <Example 1> to inhibit Th17 cell differentiation, and confirmed that the peptides of the present invention significantly inhibited Th17 cell differentiation (see FIG. 3). .
또한, 본 발명자들은 상기 펩타이드들의 IL-6 분비 억제효과를 확인한 결과, 본 발명의 펩타이드들은 양성대조군과 유사하게 IL-6의 분비를 유의적으로 억제하는 것을 확인하였다(도 4 참조).In addition, as a result of confirming the inhibitory effect of the peptides on IL-6 secretion, the present inventors confirmed that the peptides of the present invention significantly inhibited the secretion of IL-6 similar to the positive control group (see FIG. 4).
아울러, 본 발명자들은 류마티스 관절염 동물모델을 제작한 후(도 5 참조), 본 발명의 펩타이드들의 치료 효과를 확인한 결과, 유의적인 관절염 개선 효과를 나타내고, 특히 양성대조군 MTX 대비 유사한 효능이 나타내는 것을 확인하였다(도 6 내지 도 11 참조). In addition, after the present inventors produced an animal model of rheumatoid arthritis (see FIG. 5), as a result of confirming the therapeutic effect of the peptides of the present invention, it was confirmed that a significant arthritis improvement effect was shown, and in particular, similar efficacy compared to the positive control MTX. (See Figs. 6 to 11).
따라서, 본 발명의 펩타이드들은 자가면역질환에 관련된 T 세포(T cell)의 활성 및 Th17 세포(T helper 17 cell) 분화를 유의적으로 억제시키고, IL-6 분비를 양성대조군과 유사하게 억제하여, 관절염 동물모델에서 현저한 관절염 치료 및 개선 효과를 갖는 것을 확인하였으므로, 상기 펩타이드들은 염증성 질환 또는 류마티스 관절염과 같은 다양한 자가면역질환 치료제에 유효성분으로 유용하게 사용될 수 있다.Therefore, the peptides of the present invention significantly inhibit the activity of T cells and differentiation of
한편, 본 발명의 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드는 콜로이드 현탁액, 분말, 식염수, 지질, 리포좀, 미소구체(microspheres), 또는 나노 구형입자와 같은 약학적으로 허용될 수 있는 담체에 운반될 수 있다. 이들은 운반 수단과 복합체를 형성하거나 관련될 수 있고, 지질, 리포좀, 미세입자, 금, 나노입자, 폴리머, 축합 반응제, 다당류, 폴리아미노산, 덴드리머, 사포닌, 흡착 증진 물질 또는 지방산과 같은 당업계에 공지된 운반 시스템을 사용하여 생체 내 운반될 수 있다.On the other hand, the peptide of the present invention or the polynucleotide encoding it may be transported in a pharmaceutically acceptable carrier such as a colloidal suspension, powder, saline, lipid, liposome, microspheres, or nano spherical particles. They can be complexed or associated with a vehicle and are known in the art such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation reagents, polysaccharides, polyamino acids, dendrimers, saponins, adsorption enhancing substances or fatty acids. It can be delivered in vivo using known delivery systems.
이 외에도, 약학적으로 허용되는 담체는 제제시 통상적으로 이용되는 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아, 고무, 인산칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세 결정성 셀룰로스, 폴리비닐 피로리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필 히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함할 수 있으나, 이에 한정되는 것은 아니다. 또한, 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다.In addition, pharmaceutically acceptable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, rubber, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, which are commonly used in formulation. Polyvinyl pyrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like, but are not limited thereto. In addition, a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. may be additionally included in addition to the above components.
본 발명의 약학적 조성물은 목적하는 방법에 따라 경구 투여하거나 비경구투여(예를 들어, 근육 내, 정맥 내, 복강 내, 피하, 피내, 또는 국소에 적용)할 수 있으며, 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 시간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다.The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intramuscularly, intravenously, intraperitoneally, subcutaneously, intradermally, or topically applied) according to a desired method, and the dosage is It depends on the condition and weight, the degree of the disease, the form of the drug, the route of administration and the time, but may be appropriately selected by those skilled in the art.
본 발명의 약학적 조성물은 약학적으로 유효한 양으로 투여한다. 본 발명에 있어서 "약학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효 용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명에 다른 약학적 조성물은 개별 치료제로 투여하거나 다른 염증성 질환, 또는 자가면역질환 치료제와 병용하여 투여될 수 있고 종래의 염증성 질환, 또는 자가면역질환 치료제와는 동시에, 별도로, 또는 순차적으로 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 상기 요소들을 모두 고려하여 부작용 없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type, severity, drug activity of the patient, Sensitivity to drugs, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or administered in combination with other inflammatory disease or autoimmune disease therapeutic agents, and may be administered simultaneously, separately, or sequentially with the conventional inflammatory disease or autoimmune disease therapeutic agent. And can be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.
구체적으로 본 발명의 약학적 조성물의 유효량은 환자의 연령, 성별, 상태, 체중, 체내에 활성 성분의 흡수도, 불활성율, 배설 속도, 질병 종류, 병용되는 약물에 따라 달라질 수 있으며, 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라 증감될 수 있다.Specifically, the effective amount of the pharmaceutical composition of the present invention may vary depending on the patient's age, sex, condition, weight, absorption of the active ingredient in the body, inactivation rate, excretion rate, type of disease, and drugs used in combination, and the route of administration, Obesity may increase or decrease depending on the severity, sex, weight, and age.
아울러, 본 발명은 본 발명의 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 함유하는 염증성 질환 또는 자가면역질환 예방 및 개선용 건강식품을 제공한다.In addition, the present invention provides a health food for preventing and improving inflammatory diseases or autoimmune diseases containing the peptide of the present invention or a polynucleotide encoding the same as an active ingredient.
상기 건강식품은 질환의 예방 또는 개선을 위하여 해당 질환의 발병 단계 이전 또는 발병 후, 치료를 위한 약제와 동시에 또는 별개로서 사용될 수 있다.The health food may be used before or after the onset stage of the disease in order to prevent or improve the disease, and at the same time as or separately from the drug for treatment.
본 발명의 건강식품에서, 유효성분을 식품에 그대로 첨가하거나 다른 식품 또는 식품 성분과 함께 사용될 수 있고, 통상적인 방법에 따라 적절하게 사용될 수 있다. 유효 성분의 혼합량은 그의 사용 목적(예방 또는 개선용)에 따라 적합하게 결정될 수 있다. 일반적으로, 식품 또는 음료의 제조시에 본 발명의 조성물은 원료에 대하여 바람직하게 15 중량% 이하, 바람직하게는 10 중량% 이하의 양으로 첨가될 수 있다. 그러나 건강 및 위생을 목적으로 하거나 또는 건강 조절을 목적으로 하는 장기간의 섭취의 경우에는 상기 양은 상기 범위 이하일 수 있다.In the health food of the present invention, the active ingredient may be added to the food as it is or may be used with other foods or food ingredients, and may be appropriately used according to a conventional method. The mixing amount of the active ingredient may be appropriately determined depending on the purpose of use (for prevention or improvement). In general, in the manufacture of food or beverage, the composition of the present invention may be added in an amount of preferably 15% by weight or less, preferably 10% by weight or less based on the raw material. However, in the case of long-term intake for the purpose of health and hygiene or for the purpose of health control, the amount may be less than the above range.
본 발명의 건강식품은 상기 유효성분을 함유하는 것 외에 특별한 제한없이 다른 성분들을 필수 성분으로서 함유할 수 있다. 예를 들면, 통상의 음료와 같이 여러 가지 향미제 또는 천연 탄수화물 등을 추가 성분으로서 함유할 수 있다. 상술한 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 당 알코올일 수 있다. 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. 상기 천연 탄수화물의 비율은 당업자의 선택에 의해 적절하게 결정될 수 있다.In addition to containing the active ingredient, the health food of the present invention may contain other ingredients as essential ingredients without particular limitation. For example, as in ordinary beverages, various flavoring agents or natural carbohydrates may be included as additional ingredients. Examples of the above-described natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, conventional sugars such as dextrin, cyclodextrin, and the like, and sugar alcohols such as xylitol, sorbitol, and erythritol. As flavoring agents other than those described above, natural flavoring agents (taumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) can be advantageously used. I can. The proportion of the natural carbohydrate can be appropriately determined by the choice of a person skilled in the art.
상기 외에 본 발명의 건강식품은 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 중진제(치즈, 초콜릿 등), 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있으며, 이러한 첨가제의 비율 또한 당업자에 의해 적절히 선택될 수 있다.In addition to the above, the health food of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavors and natural flavoring agents, coloring agents and heavy weight agents (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid and Salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like may be contained. These components may be used independently or in combination, and the proportion of these additives may also be appropriately selected by those skilled in the art.
이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by examples and experimental examples.
단, 하기 실시예 및 실험예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 한정되는 것은 아니다.However, the following examples and experimental examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples and experimental examples.
<실시예 1> 펩타이드의 제작<Example 1> Preparation of peptide
하기 [일반식 1]을 기초로 다양한 펩타이드를 제작하였다. 이후, 고성능 액체크로마토그래피(SHIMADZU Prominence HPLC)를 이용하여 합성된 펩타이드 각각을 순수 분리하였으며, 컬럼은 Shiseido capcell pak C18 Column(4.6 × 50 mm)을 이용하였다. 또한, 질량분석기(HP 1100 series LC/MSD)를 이용하여, 합성된 펩타이드 각각의 질량을 확인하였다.Various peptides were prepared based on the following [General Formula 1]. Then, each of the synthesized peptides was purely separated using high-performance liquid chromatography (SHIMADZU Prominence HPLC), and a Shiseido capcell pak C18 Column (4.6 × 50 mm) was used as a column. In addition, mass spectrometry (HP 1100 series LC/MSD) was used to confirm the mass of each of the synthesized peptides.
[일반식 1][General Formula 1]
(X1-X2-X3)n (X 1 -X 2 -X 3 ) n
상기 식에서, X1은 아르기닌(Arginine; R), 히스티딘(Histidine; H) 및 라이신(Lysine; K)으로 이루어진 군으로부터 선택되는 어느 하나이고, In the above formula, X 1 is any one selected from the group consisting of arginine (R), histidine (H) and lysine (Lysine; K),
X2는 아스파르트산(Aspartic acid; D) 또는 글루탐산(Glutamic acid; E)이며,X 2 is Aspartic acid (D) or Glutamic acid (E),
X3은 글라이신(Glycine; G), 알라닌(Alanine; A), 발린(Valine; V), 메티오닌(Methionine; M), 아이소류신(Isoleucine; I) 및 류신(Leucine; L)으로 이루어진 군으로부터 선택되는 어느 하나이고, X 3 is selected from the group consisting of glycine (G), alanine (A), valine (V), methionine (M), isoleucine (I) and leucine (L) Is any one
n은 1 내지 10의 정수이며, 단 상기 일반식 1의 아미노산 서열이 서열번호 2로 기재되는 RDG를 포함하고, 동시에 n=1 또는 2 경우는 제외함. n is an integer of 1 to 10, provided that the amino acid sequence of the
아울러, 상기 방법으로 합성된 펩타이드를 하기 표 1에 일부 나열하였다.In addition, some of the peptides synthesized by the above method are listed in Table 1 below.
<실험예 1> T 세포 활성 억제 효과 확인<Experimental Example 1> T cell activity inhibition effect confirmation
상기 <실시예 1>에서 제작한 합성 펩타이드의 T 세포 활성 억제 효능을 확인하기 위하여, 마우스의 림프절에서 추출한 T 세포를 사용하여 ex vivo 활성 억제 실험을 수행하였다.In order to confirm the T cell activity inhibition effect of the synthetic peptide prepared in <Example 1>, an ex vivo activity inhibition experiment was performed using T cells extracted from mouse lymph nodes.
구체적으로, 먼저, T 세포의 활성화를 유도하기 위하여 96 well plate에 CD3 항체를 coating하여 4℃에서 overnight 동안 incubation 하여 CD3항체가 붙어있는 96 well을 제작하였다. 그 후, 마우스에서 추출한 naive T 세포를 96 well plate에 1×105/well 씩 seeding 하고 상기 <실시예 1>에서 제작한 각 합성 펩타이드를 처리하여 18시간 동안 배양한 후 flow cytometry 방법으로 활성 T 세포의 population을 확인하였다. 이를 위해, 배양한 각각의 그룹에서 동일한 숫자의 세포를 collection 하고 PBS로 wash 과정을 거친 뒤, helper T 세포 마커인 rabbit anti-mouse CD4와 T 세포의 활성화 마커인 rabbit anti-mouse CD69 항체를 사용하여 staining 과정을 수행하였다. PBS로 washing한 뒤, CD4+CD69+ T 세포 population 을 분석하였다. Specifically, first, in order to induce activation of T cells, CD3 antibody was coated on a 96 well plate and incubated overnight at 4°C to prepare 96 wells with CD3 antibody attached. Thereafter, naive T cells extracted from mice were seeded at 1×10 5 /well in a 96 well plate, treated with each of the synthetic peptides prepared in Example 1, and cultured for 18 hours, and then activated T by flow cytometry. The population of cells was confirmed. To this end, the same number of cells were collected from each cultured group and washed with PBS, and then rabbit anti-mouse CD4, a helper T cell marker, and rabbit anti-mouse CD69 antibody, a T cell activation marker were used. The staining process was performed. After washing with PBS, the CD4+CD69+ T cell population was analyzed.
그 결과, 상기 <실시예 1>에서 합성한 펩타이드는 평균 8%까지 T 세포 활성을 유의적으로 억제하는 것을 확인하였다.As a result, it was confirmed that the peptide synthesized in <Example 1> significantly inhibited T cell activity up to an average of 8%.
또한, 상기 <실시예 1>에서 합성한 펩타이드 중, 표 2에 나타낸 펩타이드의 T 세포 활성 억제효과에 대해서는 도 1 내지 도 2에 나타내었다.In addition, among the peptides synthesized in <Example 1>, the effects of the peptides shown in Table 2 on inhibiting T cell activity are shown in FIGS. 1 to 2.
구체적으로, 활성화를 유도하지 않은 그룹 (1.6%)에 비해 CD3 항체로 활성화 시킨 그룹에서 활성 T 세포가 85.2%로 증가하였고, 각 합성 펩타이드를 처리한 그룹에서는 77 ~ 82 % 까지 감소하는 것을 확인하였다. 또한, 각각의 합성 펩타이드의 활성 T 세포 억제율은 <실시예 1>에서 합성한 펩타이드와 동일하게 약 8%임을 확인하였다.Specifically, it was confirmed that the active T cells increased to 85.2% in the group activated with CD3 antibody compared to the group that did not induce activation (1.6%), and decreased by 77 to 82% in the group treated with each synthetic peptide. . In addition, it was confirmed that the inhibition rate of active T cells of each synthetic peptide was about 8%, the same as that of the peptide synthesized in <Example 1>.
따라서, 본원발명의 합성 펩타이드는 T 세포 활성을 유의적으로 억제하여 자가면역질환 치료에 사용될 수 있음을 확인하였다(도 1 내지 도 2).Therefore, it was confirmed that the synthetic peptide of the present invention can be used for the treatment of autoimmune diseases by significantly inhibiting T cell activity (FIGS. 1 to 2 ).
<실험예 2> Th 17 세포 분화 억제 효과 확인<Experimental Example 2>
상기 <실시예 1>에서 제작한 합성 펩타이드가 Th17 세포 분화를 억제시키는 효능을 확인하기 위하여, 마우스의 림프절에서 추출한 naive CD4+ T 세포에 TCR activation과 함께 IL-6 20 ng/ml과 TGF-beta 5 ng/ml을 처리하여 Th17 세포로 분화를 유도하였다. To confirm the efficacy of the synthetic peptide prepared in <Example 1> to inhibit Th17 cell differentiation, IL-6 20 ng/ml and TGF-
동시에 상기 <실험예 1>의 표 2에 개시된 펩타이드 3종 (Pep1, Pep6, Pep8) 을 10 ~ 1000 ng/ml의 농도로 각각 처리하였다. 그런 다음, 3일동안 incubation 한 뒤, CD4+IL-17+ T 세포 population 을 분석하였다. At the same time, the three peptides (Pep1, Pep6, Pep8) disclosed in Table 2 of <Experimental Example 1> were each treated at a concentration of 10 to 1000 ng/ml. Then, after incubation for 3 days, the CD4+IL-17+ T cell population was analyzed.
그 결과, 도 3에 나타낸 바와 같이, Th17 세포로 분화를 유도하지 않은 그룹 (1.2%)에 비해 Th17 분화를 유도한 그룹에서 약 2.5배 증가하는 경향이 보였으며 (3.14%), Pep1, Pep6, Pep8 펩타이드를 각각 처리한 그룹에서는 분화를 유도하지 않은 그룹과 유사하게 Th17 세포의 비율이 감소하는 것을 확인하였다(도 3).As a result, as shown in Figure 3, compared to the group that did not induce differentiation into Th17 cells (1.2%), there was a tendency to increase about 2.5 times in the group inducing Th17 differentiation (3.14%), Pep1, Pep6, It was confirmed that the proportion of Th17 cells decreased in the group treated with the Pep8 peptide, similar to the group that did not induce differentiation (FIG. 3).
<실험예 3> 염증성 사이토카인 IL-6 감소 효과 확인<Experimental Example 3> Confirmation of the inflammatory cytokine IL-6 reduction effect
상기 <실시예 1>에서 제작한 합성 펩타이드가 염증성 사이토카인인 IL-6 분비를 억제시키는 효능을 확인하기 위하여, THP-1 monocytic cell line을 PMA 50 ng/ml을 48시간 동안 처리하여 M1 macrophage 로 분화시켰다. 분화된 M1 macrophage 에 LPS 10 ng/ml 과 IFN-gamma 20 ng/ml를 처리한 후, 양성대조군인 MTX 또는 본 발명의 합성 펩타이드를 각각 100 ng/ml 의 농도로 co-treatment 하였다. 그런 다음, 24시간 동안 incubation 한 뒤, cultured sup을 사용하여 IL-6 ELISA를 실시하였다. In order to confirm the efficacy of the synthetic peptide prepared in <Example 1> in inhibiting the secretion of IL-6, an inflammatory cytokine, the THP-1 monocytic cell line was treated with 50 ng/ml of PMA for 48 hours into M1 macrophage. Differentiated. After treating the differentiated M1 macrophage with 10 ng/ml of LPS and 20 ng/ml of IFN-gamma, the positive control MTX or the synthetic peptide of the present invention were co-treated at a concentration of 100 ng/ml, respectively. Then, after incubation for 24 hours, IL-6 ELISA was performed using cultured sup.
그 결과, 도 4에 나타낸 바와 같이, 본 발명의 Pep2, Pep3, Pep5, Pep7, Pep8 펩타이드에 의해 양성대조군과 유사하게 IL-6가 유의적으로 감소되는 것을 확인하였다(도 4). As a result, as shown in FIG. 4, it was confirmed that IL-6 was significantly reduced by the peptides of the present invention Pep2, Pep3, Pep5, Pep7, and Pep8 similar to the positive control group (FIG. 4).
<실험예 4> Collagen-induced arthritis (CIA) mouse model을 이용한 류마티스 관절염 치료 효과 확인<Experimental Example 4> Confirmation of the treatment effect of rheumatoid arthritis using a Collagen-induced arthritis (CIA) mouse model
<4-1> 류마티스 관절염 마우스 모델의 제작<4-1> Preparation of rheumatoid arthritis mouse model
상기 <실시예 1>에서 제작한 펩타이드의 류마티스 관절염 개선 효과를 확인하기 위하여, 공지 문헌(Nat Protoc. 2007;2(5):1269-75.)을 참고하여 류마티스 관절염 마우스 모델을 제작하였다.In order to confirm the rheumatoid arthritis improvement effect of the peptide prepared in <Example 1>, a rheumatoid arthritis mouse model was prepared with reference to the publicly known literature (Nat Protoc. 2007;2(5):1269-75.).
구체적으로, CIA mouse model은 인간의 류마티스 관절염과 유사한 특징을 보이는 자가면역질환 관절염 모델로 류마티스 관절염 동물실험에서 가장 흔히 쓰이는 마우스 모델이다. CIA 마우스 모델은 먼저, 소의 제 2형 콜라겐(Bovine type II collagen, Chondrex, USA)과 프로인트 완전 보조제(Freund’s complete adjuvant, Chondrex, USA)를 1:1로 혼합하여 에멀젼화한 후, 에멀젼화된 콜라겐 용액 50 ul를 6주령의 DBA/1J 마우스 꼬리에 피내 주사하여 1차 면역(immunization) 시켰다. 1차 면역 후, 2주 째에 소의 제 2형 콜라겐과 프로인트 불완전 보조제(Freund’s incomplete adjuvant, Chondrex, USA)를 1:1로 혼합하여 에멀젼화한 후, 에멀젼화된 콜라겐 용액 50 ul를 마우스 꼬리에 피내 주사하여 2차 면역(boosting)을 유도하였다. 2차 면역 후, 다음날부터 1주일에 3회씩 각 펩타이드를 복강 투여하여 펩타이드의 류마티스 관절염 치료효과를 관찰하였다. 투여 펩타이드는 표 2에 개시된 펩타이드 5종(Pep1, Pep4, Pep6, Pep7, Pep8)로 선정하였다(도 5).Specifically, the CIA mouse model is an autoimmune arthritis model showing characteristics similar to that of human rheumatoid arthritis, and is the most commonly used mouse model in rheumatoid arthritis animal experiments. The CIA mouse model was first emulsified by mixing bovine type II collagen (Chondrex, USA) and Freund's complete adjuvant (Chondrex, USA) in a 1:1 ratio, and then emulsified. 50 ul of collagen solution was injected intradermally into the tail of a 6-week-old DBA/1J mouse for primary immunization. After the first immunization, at the 2nd week, a 1:1 mixture of
<4-2> 류마티스 관절염 마우스 모델을 이용한 치료 효과 확인<4-2> Confirmation of treatment effect using a mouse model of rheumatoid arthritis
본 발명의 펩타이드 처리에 따른 류마티스 관절염 진행 추이를 살피고자, 시간의 경과에 따른 류마티스 관절염의 심화 정도를 류마티스 관절염 진행 지수로 평가하여 측정하였다.In order to examine the progression of rheumatoid arthritis according to the peptide treatment of the present invention, the degree of intensification of rheumatoid arthritis over time was evaluated and measured as the rheumatoid arthritis progression index.
구체적인 실험 조건에 대해서 알지 못하는 관찰자 두 명이 일주일에 세 번씩, 관절염 진행 정도를 평가하였다. 이때, 관절염 진행 지수는, 하기 표 2의 Rossoliniec 등에 의한 관절염 진행 평가 기준에 따라 각 다리당 0점 내지 4점으로 평가하여 총 0점 내지 16점(네 다리 합산)으로 나타내었으며, 이후, 두 명의 관찰자가 평가한 결과의 평균 값을 산출하여 관절염의 중증도를 수치화하였다. Two observers who were not aware of the specific experimental conditions evaluated the progression of arthritis three times a week. At this time, the arthritis progression index was evaluated as 0 to 4 points for each leg according to the criteria for arthritis progression evaluation by Rossoliniec in Table 2 below, and was expressed as a total of 0 to 16 points (sum of four legs). The average value of the results evaluated by the observer was calculated to quantify the severity of arthritis.
그 결과, 도 6 내지 도 11에 나타낸 바와 같이 정상 마우스(normal) 그룹과 비교하여, CIA를 유발한 마우스(Vehicle control; PBS)에서 관절염 스코어가 현저하게 증가하는 것을 알 수 있으며, 펩타이드 5종(Pep1, Pep4, Pep6, Pep7, Pep8)을 각각 복강투여한 그룹에서 관절염 개선 효능이 나타나는 것을 확인하였다. 또한, 양성대조군 MTX 대비 유사한 효능이 나타내는 것을 확인하였다(도 6 내지 도 11). As a result, as shown in Figs. 6 to 11, it can be seen that the arthritis score is significantly increased in the mice (Vehicle control; PBS) inducing CIA, compared with the normal group of mice, 5 kinds of peptides ( Pep1, Pep4, Pep6, Pep7, Pep8) were confirmed to show the effect of improving arthritis in the group administered intraperitoneally. In addition, it was confirmed that similar efficacy compared to the positive control MTX was shown (FIGS. 6 to 11 ).
따라서, 본 발명의 펩타이드가 자가면역질환 치료제로 사용할 수 있음을 확인하였다.Therefore, it was confirmed that the peptide of the present invention can be used as a therapeutic agent for autoimmune diseases.
<110> Kine Sciences <120> Use of a peptide as a therapeutic agent for autoimmune disease <130> PB2018-182 <150> KR 10-2017-0118952 <151> 2017-09-15 <160> 4 <170> KoPatentIn 3.0 <210> 1 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> peptide <220> <221> MISC_FEATURE <222> (1) <223> Xaa is Arginine, Histidine or Lysine <220> <221> MISC_FEATURE <222> (2) <223> Xaa is Aspartic acid or Glutamic acid <220> <221> MISC_FEATURE <222> (3) <223> Xaa is Glycine, Alanine, Valine or Methionine <400> 1 Xaa Xaa Xaa 1 <210> 2 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 2 Arg Asp Gly 1 <210> 3 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 3 Arg Glu Ala 1 <210> 4 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 4 Lys Glu Met 1 <110> Kine Sciences <120> Use of a peptide as a therapeutic agent for autoimmune disease <130> PB2018-182 <150> KR 10-2017-0118952 <151> 2017-09-15 <160> 4 <170> KoPatentIn 3.0 <210> 1 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> peptide <220> <221> MISC_FEATURE <222> (1) <223> Xaa is Arginine, Histidine or Lysine <220> <221> MISC_FEATURE <222> (2) <223> Xaa is Aspartic acid or Glutamic acid <220> <221> MISC_FEATURE <222> (3) <223> Xaa is Glycine, Alanine, Valine or Methionine <400> 1 Xaa Xaa Xaa One <210> 2 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 2 Arg Asp Gly One <210> 3 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 3 Arg Glu Ala One <210> 4 <211> 3 <212> PRT <213> Artificial Sequence <220> <223> peptide <400> 4 Lys Glu Met One
Claims (10)
[일반식 1]
(X1-X2-X3)n
상기 식에서, X1은 아르기닌(Arginine; R), 히스티딘(Histidine; H) 및 라이신(Lysine; K)으로 이루어진 군으로부터 선택되는 어느 하나이고, X2는 아스파르트산(Aspartic acid; D) 또는 글루탐산(Glutamic acid; E)이며, X3은 글라이신(Glycine; G), 알라닌(Alanine; A), 발린(Valine; V) 및 메티오닌(Methionine; M)으로 이루어진 군으로부터 선택되는 어느 하나이고;
n은 3 내지 6의 정수이며; 및
단 하기의 경우는 제외함:
i) X1은 히스티딘(Histidine; H)이고, X2는 아스파르트산(Aspartic acid; D) 또는 글루탐산(Glutamic acid; E)이며, X3은 알라닌(Alanine; A) 또는 발린(Valine; V)이고, n은 3 내지 6의 정수인 경우;
ii) X1은 아르기닌(Arginine; R) 또는 히스티딘(Histidine; H)이고, X2는 글루탐산(Glutamic acid; E)이며, X3은 글라이신(Glycine; G)이고, n은 3 내지 6의 정수인 경우;
iii) X1은 라이신(Lysine; K)이고, X2는 아스파르트산(Aspartic acid; D)이며, X3은 발린(Valine; V) 또는 메티오닌(Methionine; M)이고, n은 3 내지 6의 정수인 경우; 및
iv) 상기 일반식 1의 아미노산 서열이 서열번호 2로 기재되는 RDG, 서열번호 3으로 기재되는 REA 및 서열번호 4로 기재되는 KEM이고, n은 3 내지 6의 정수인 경우.
Peptide consisting of the amino acid sequence of general formula 1 represented by the following SEQ ID NO: 1.
[General Formula 1]
(X 1 -X 2 -X 3 ) n
In the above formula, X 1 is any one selected from the group consisting of arginine (R), histidine (H), and lysine (Lysine; K), and X 2 is aspartic acid (D) or glutamic acid ( Glutamic acid; E), X 3 is any one selected from the group consisting of glycine (G), alanine (A), valine (V), and methionine (M);
n is an integer from 3 to 6; And
However, the following cases are excluded:
i) X 1 is Histidine (H), X 2 is Aspartic acid (D) or Glutamic acid (E), and X 3 is Alanine (A) or Valine (V) And, n is an integer of 3 to 6;
ii) X 1 is arginine (R) or histidine (H), X 2 is glutamic acid (E), X 3 is glycine (G), and n is an integer of 3 to 6 Occation;
iii) X 1 is Lysine (K), X 2 is Aspartic acid (D), X 3 is Valine (V) or Methionine (M), and n is 3 to 6 If it is an integer; And
iv) When the amino acid sequence of Formula 1 is RDG represented by SEQ ID NO: 2, REA represented by SEQ ID NO: 3, and KEM represented by SEQ ID NO: 4, and n is an integer of 3 to 6.
The peptide according to claim 1, wherein X 1 is arginine (R) or histidine (H).
The peptide according to claim 1, wherein X 3 is glycine (G) or alanine (A).
The method of claim 1, wherein the N- or C-terminus of the peptide is from the group consisting of an acetyl group, a fluorenylmethoxy carbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, and polyethylene glycol (PEG). Peptide, characterized in that bonded to the protecting group selected.
[일반식 1]
(X1-X2-X3)n
상기 식에서, X1은 아르기닌(Arginine; R), 히스티딘(Histidine; H) 및 라이신(Lysine; K)으로 이루어진 군으로부터 선택되는 어느 하나이고, X2는 아스파르트산(Aspartic acid; D) 또는 글루탐산(Glutamic acid; E)이며, X3은 글라이신(Glycine; G), 알라닌(Alanine; A), 발린(Valine; V) 및 메티오닌(Methionine; M)으로 이루어진 군으로부터 선택되는 어느 하나이고;
n은 3 내지 6의 정수이며; 및
단 하기의 경우는 제외함:
i) X1은 히스티딘(Histidine; H)이고, X2는 아스파르트산(Aspartic acid; D) 또는 글루탐산(Glutamic acid; E)이며, X3은 알라닌(Alanine; A) 또는 발린(Valine; V)이고, n은 3 내지 6의 정수인 경우;
ii) X1은 아르기닌(Arginine; R) 또는 히스티딘(Histidine; H)이고, X2는 글루탐산(Glutamic acid; E)이며, X3은 글라이신(Glycine; G)이고, n은 3 내지 6의 정수인 경우;
iii) X1은 라이신(Lysine; K)이고, X2는 아스파르트산(Aspartic acid; D)이며, X3은 발린(Valine; V) 또는 메티오닌(Methionine; M)이고, n은 3 내지 6의 정수인 경우; 및
iv) 상기 일반식 1의 아미노산 서열이 서열번호 2로 기재되는 RDG, 서열번호 3으로 기재되는 REA 및 서열번호 4로 기재되는 KEM이고, n은 3 내지 6의 정수인 경우.
A pharmaceutical composition for preventing and treating inflammatory diseases or autoimmune diseases containing as an active ingredient a peptide consisting of the amino acid sequence of the general formula 1 represented by SEQ ID NO: 1.
[General Formula 1]
(X 1 -X 2 -X 3 ) n
In the above formula, X 1 is any one selected from the group consisting of arginine (R), histidine (H), and lysine (Lysine; K), and X 2 is aspartic acid (D) or glutamic acid ( Glutamic acid; E), X 3 is any one selected from the group consisting of glycine (G), alanine (A), valine (V), and methionine (M);
n is an integer from 3 to 6; And
However, the following cases are excluded:
i) X 1 is Histidine (H), X 2 is Aspartic acid (D) or Glutamic acid (E), and X 3 is Alanine (A) or Valine (V) And, n is an integer of 3 to 6;
ii) X 1 is arginine (R) or histidine (H), X 2 is glutamic acid (E), X 3 is glycine (G), and n is an integer of 3 to 6 Occation;
iii) X 1 is Lysine (K), X 2 is Aspartic acid (D), X 3 is Valine (V) or Methionine (M), and n is 3 to 6 If it is an integer; And
iv) When the amino acid sequence of Formula 1 is RDG represented by SEQ ID NO: 2, REA represented by SEQ ID NO: 3, and KEM represented by SEQ ID NO: 4, and n is an integer of 3 to 6.
The method of claim 7, wherein the inflammatory disease is atopy, psoriasis, dermatitis, allergy, arthritis, rhinitis, otitis media, sore throat, tonsillitis, cystitis, nephritis, pelvic inflammatory disease, Crohn's disease, ulcerative colitis, ankylosing spondylitis, systemic lupus erythematosus (systemic lupus erythematodes, SLE), asthma, edema, delayed allergy (type IV allergy), transplant rejection, graft versus host disease, autoimmune encephalomyelitis, multiple sclerosis, inflammatory bowel disease, cystic fibrosis, diabetic retinopathy, ischemic-reperfusion injury , Vascular restenosis, glomerulonephritis, and gastrointestinal allergy, characterized in that selected from the group consisting of, pharmaceutical composition.
The method of claim 7, wherein the autoimmune disease is rheumatoid arthritis, Sjogren's syndrome, systemic sclerosis, polymyositis, systemic angitis, mixed connective tissue disease ( mixed connective tissue disease), Crohn's disease, Hashimoto's disease, Grave's disease, Goodpasture's sydrome, Guillain-Barre syndrom, idiopathic platelet reduction It is characterized by being selected from the group consisting of purpura, irritable bowel syndrome, myasthenia gravis, narcolepsy, pemphigus vulgaris, pernicious anemia, primary biliary cirrhosis, ulcerative colitis, vasculitis, Wegener's granulomatosis, and psoriasis. To, pharmaceutical composition.
[일반식 1]
(X1-X2-X3)n
상기 식에서, X1은 아르기닌(Arginine; R), 히스티딘(Histidine; H) 및 라이신(Lysine; K)으로 이루어진 군으로부터 선택되는 어느 하나이고, X2는 아스파르트산(Aspartic acid; D) 또는 글루탐산(Glutamic acid; E)이며, X3은 글라이신(Glycine; G), 알라닌(Alanine; A), 발린(Valine; V) 및 메티오닌(Methionine; M)으로 이루어진 군으로부터 선택되는 어느 하나이고;
n은 3 내지 6의 정수이며; 및
단 하기의 경우는 제외함:
i) X1은 히스티딘(Histidine; H)이고, X2는 아스파르트산(Aspartic acid; D) 또는 글루탐산(Glutamic acid; E)이며, X3은 알라닌(Alanine; A) 또는 발린(Valine; V)이고, n은 3 내지 6의 정수인 경우;
ii) X1은 아르기닌(Arginine; R) 또는 히스티딘(Histidine; H)이고, X2는 글루탐산(Glutamic acid; E)이며, X3은 글라이신(Glycine; G)이고, n은 3 내지 6의 정수인 경우;
iii) X1은 라이신(Lysine; K)이고, X2는 아스파르트산(Aspartic acid; D)이며, X3은 발린(Valine; V) 또는 메티오닌(Methionine; M)이고, n은 3 내지 6의 정수인 경우; 및
iv) 상기 일반식 1의 아미노산 서열이 서열번호 2로 기재되는 RDG, 서열번호 3으로 기재되는 REA 및 서열번호 4로 기재되는 KEM이고, n은 3 내지 6의 정수인 경우.
Health food for preventing and improving inflammatory diseases or autoimmune diseases containing as an active ingredient a peptide consisting of the amino acid sequence of General Formula 1 represented by SEQ ID NO: 1:
[General Formula 1]
(X 1 -X 2 -X 3 ) n
In the above formula, X 1 is any one selected from the group consisting of arginine (R), histidine (H), and lysine (Lysine; K), and X 2 is aspartic acid (D) or glutamic acid ( Glutamic acid; E), X 3 is any one selected from the group consisting of glycine (G), alanine (A), valine (V), and methionine (M);
n is an integer from 3 to 6; And
However, the following cases are excluded:
i) X 1 is Histidine (H), X 2 is Aspartic acid (D) or Glutamic acid (E), and X 3 is Alanine (A) or Valine (V) And, n is an integer of 3 to 6;
ii) X 1 is arginine (R) or histidine (H), X 2 is glutamic acid (E), X 3 is glycine (G), and n is an integer of 3 to 6 Occation;
iii) X 1 is Lysine (K), X 2 is Aspartic acid (D), X 3 is Valine (V) or Methionine (M), and n is 3 to 6 If it is an integer; And
iv) When the amino acid sequence of Formula 1 is RDG represented by SEQ ID NO: 2, REA represented by SEQ ID NO: 3, and KEM represented by SEQ ID NO: 4, and n is an integer of 3 to 6.
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2020515095A JP2020533375A (en) | 2017-09-15 | 2018-09-14 | Use of peptides as therapeutic agents for autoimmune and bone diseases |
| CA3075471A CA3075471C (en) | 2017-09-15 | 2018-09-14 | Use of peptides as therapeutic agent for autoimmune diseases and bone diseases |
| US16/645,957 US11730788B2 (en) | 2017-09-15 | 2018-09-14 | Use of peptides as therapeutic agent for autoimmune diseases and bone diseases |
| AU2018333776A AU2018333776B2 (en) | 2017-09-15 | 2018-09-14 | Use of peptides as therapeutic agent for autoimmune diseases and bone diseases |
| PCT/KR2018/010874 WO2019054809A2 (en) | 2017-09-15 | 2018-09-14 | Use of peptides as therapeutic agent for autoimmune diseases and bone diseases |
| JP2022085612A JP7408175B2 (en) | 2017-09-15 | 2022-05-25 | Uses of peptides as therapeutic agents for autoimmune and bone diseases |
| US18/300,230 US20240009264A1 (en) | 2017-09-15 | 2023-04-13 | Use of peptides as therapeutic agent for autoimmune diseases and bone diseases |
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| KR1020170118952 | 2017-09-15 | ||
| KR20170118952 | 2017-09-15 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030195141A1 (en) * | 2002-02-04 | 2003-10-16 | Ronald Mathison | Anti-inflammatory peptides |
| US20160168202A1 (en) * | 2007-10-12 | 2016-06-16 | King's College London | Cyclic peptides as ADAM protease inhibitors |
| WO2017155234A1 (en) * | 2016-03-09 | 2017-09-14 | 주식회사 바이오펩 | Peptide for preventing or treating inflammatory diseases and use thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030195141A1 (en) * | 2002-02-04 | 2003-10-16 | Ronald Mathison | Anti-inflammatory peptides |
| US20160168202A1 (en) * | 2007-10-12 | 2016-06-16 | King's College London | Cyclic peptides as ADAM protease inhibitors |
| WO2017155234A1 (en) * | 2016-03-09 | 2017-09-14 | 주식회사 바이오펩 | Peptide for preventing or treating inflammatory diseases and use thereof |
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