KR102219926B1 - Use of a peptide as a therapeutic agent - Google Patents
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- KR102219926B1 KR102219926B1 KR1020170118943A KR20170118943A KR102219926B1 KR 102219926 B1 KR102219926 B1 KR 102219926B1 KR 1020170118943 A KR1020170118943 A KR 1020170118943A KR 20170118943 A KR20170118943 A KR 20170118943A KR 102219926 B1 KR102219926 B1 KR 102219926B1
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Abstract
본 발명은 치료제로서의 펩타이드의 용도에 관한 것으로, 구체적으로 자가면역질환 계열의 관절염 마우스 모델에서 본 발명에 따른 이량체 형태의 펩타이드가 자가면역에 관련된 조절 T 세포 및 Th17 세포의 수를 조절하고, 파골세포로의 분화를 억제하는 것을 확인하였으므로, 본 발명의 펩타이드를 자가면역질환 또는 골대사성 질환의 예방 또는 치료용 조성물로 유용하게 이용할 수 있다.The present invention relates to the use of the peptide as a therapeutic agent, and specifically, in the arthritis mouse model of the autoimmune disease series, the dimeric peptide according to the present invention regulates the number of regulatory T cells and Th17 cells related to autoimmunity, and Since it has been confirmed that the differentiation into cells is inhibited, the peptide of the present invention can be usefully used as a composition for preventing or treating autoimmune diseases or bone metabolic diseases.
Description
본 발명은 치료제로서의 펩타이드의 용도에 관한 것으로, 보다 구체적으로 서열번호 1로 표시되는 아미노산으로 이루어진, 이량체 형태의 펩타이드의 자가면역질환 또는 골 질환 치료제로서의 용도에 관한 것이다.
The present invention relates to the use of a peptide as a therapeutic agent, and more specifically, to the use of a dimeric peptide consisting of an amino acid represented by SEQ ID NO: 1 as a therapeutic agent for autoimmune diseases or bone diseases.
류마티스 관절염(rheumatoid arthritis)은 우리에게 잘 알려진 만성적으로 관절 손상을 일으키는 염증성 질환으로 잘 알려져 있으나, 류마티스 관절염이 또한 자가면역질환 (autoimmune disease)의 하나이다.Rheumatoid arthritis (rheumatoid arthritis) is well known to us as an inflammatory disease that causes chronic joint damage, but rheumatoid arthritis is also one of the autoimmune diseases (autoimmune disease).
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.
최근 건강한 상태의 면역관용의 유지와 관용이 깨지면서 발생하는 자가면역 발생 사이에서 조절 T 세포와 Th17 세포의 활성과 균형이 중요한 요소임이 밝혀 지면서, 조절 T 세포 및 Th17 세포의 기능을 이용하여 자가면역질환을 치료하기 위한 연구가 진행되고 있다. 조절 T 세포의 활성은 면역관용을 유지시키면서 자가면역반응이 발생하지 않도록 하는 억제성 면역을 나타내며, Th17 세포는 활성화되면 자가면역과 염증반응을 일으키는 것으로 잘 알려져 있다. Recently, it has been found that the activity and balance of regulatory T cells and Th17 cells are important factors between maintenance of immune tolerance in a healthy state and the development of autoimmunity that occurs when tolerance is broken. Autoimmune diseases using the functions of regulatory T cells and Th17 cells Research is being conducted to treat The activity of regulatory T cells indicates inhibitory immunity that prevents autoimmune reactions from occurring while maintaining immune tolerance. Th17 cells are well known to cause autoimmune and inflammatory reactions when activated.
자가면역성 근염 (myositis) 등의 자가면역질환 환자에서 IL-17 발현이 높게 나타나면서, IL-17의 생성을 조절하는 Th17 세포의 활성이 전신성 자가면역질환의 주요 원인으로 보고되기 시작했다. 이에 근거하여 자가면역질환 치료 기술에서는 IL-17의 생성을 억제하거나 IL-17에 대한 단일클론항체 등을 이용한 IL-17 활성을 중화시키려는 시도가 전신성 홍반낭창증 연구 등에 활용되고 있다. As IL-17 expression was high in patients with autoimmune diseases such as autoimmune myositis, the activity of Th17 cells that regulate the production of IL-17 began to be reported as a major cause of systemic autoimmune diseases. Based on this, in autoimmune disease treatment technology, attempts to inhibit the production of IL-17 or neutralize IL-17 activity using monoclonal antibodies against IL-17 have been used for research on systemic lupus erythematosus.
조절 T 세포는 전체 보조 T 세포의 5~10%를 차지하는 소수의 세포군으로, 다른 T 세포의 활성화를 저해하는 것으로 알려져 있다. 조절 T 세포가 생체 내에서 자가면역성을 억제한다는 것은 조절 T 세포의 분화 및 기능에 결정적으로 중요한 FoxP3의 유전자가 결핍된 쥐나 실험적으로 조절 T 세포를 결핍시킨 생쥐에서 자연적으로 자가면역질환이 발생됨에 따라 증명되었다. 조절 T 세포는 IL-10, TGF-β, IL-35 등의 억제성 사이토카인을 분비하며, T 세포의 활성에 매우 중요한 IL-2를 흡착함으로써 IL-2의 활성을 억제 조절하는 것으로 보고되고 있다. 특히 조절 T 세포는 자가면역질환에서 주된 원인으로 인식되는 Th17 세포의 활성을 억제한다. 또한, 조절 T 세포는 CTLA-4와 LFA-1라는 공동자극인자의 도움으로 직접 수지상세포 (dendritic cell)에 접촉하여 CD80과 CD86의 발현을 감소시켜 수지상세포의 기능을 억제하는 것으로 보고되고 있다. 따라서 조절 T 세포의 활성을 증가시켜 Th17 세포 등의 자가면역성을 감소시키는 방법으로 자가면역질환 치료제 연구가 이루어지고 있다.
Regulatory T cells are a small group of cells accounting for 5-10% of all helper T cells, and are known to inhibit the activation of other T cells. Regulatory T cells inhibit autoimmunity in vivo as autoimmune diseases occur naturally in mice lacking the FoxP3 gene, which is crucial for the differentiation and function of regulatory T cells, or mice deficient in experimental regulatory T cells. Proved. Regulatory T cells secrete inhibitory cytokines such as IL-10, TGF-β, and IL-35, and are reported to inhibit IL-2 activity by adsorbing IL-2, which is very important for T cell activity. have. In particular, regulatory T cells inhibit the activity of Th17 cells, which are recognized as the main cause in autoimmune diseases. In addition, it has been reported that regulatory T cells directly contact dendritic cells with the help of co-stimulatory factors CTLA-4 and LFA-1 to reduce the expression of CD80 and CD86, thereby inhibiting the function of dendritic cells. Therefore, research on the treatment of autoimmune diseases is being conducted by increasing the activity of regulatory T cells to reduce autoimmunity of Th17 cells.
한편, 류마티스 관절염을 가지고 있는 환자에서 골다공증이 흔하게 동반된다. 류마티스 관절염 환자에서 골다공증의 발생률은 대락 15~20%이며, 일반적으로 유병기간이 10년 이상 길수록, 스테로이드 투여 기간이 길고 관절 장애로 활동이 감소할수록 골다공증의 발생이 높은 것으로 나타난다. Meanwhile, osteoporosis is common in patients with rheumatoid arthritis. The incidence of osteoporosis in rheumatoid arthritis patients is approximately 15-20%. In general, the longer the prevalence period is more than 10 years, the longer the steroid administration period, and the lower the activity due to joint disorders, the higher the incidence of osteoporosis.
골 조직은 콜라겐, 당단백과 같은 세포외기질(extracellular substance)과 조골세포(osteoblast), 파골세포 (osteoclast), 골세포 등 여러 종류의 세포들로 구성되어 있다. 또한, 파골세포에 의한 골 흡수와 조골세포에 의한 새로운 골 기질 형성 및 무기질화 과정이 반복적으로 일어나는 대사기관으로, 조골세포의 활동으로 인한 골 형성이 파골세포의 활동으로 인한 골 흡수보다 많게 된다. 골의 재형성은 성장이 끝난 후 오래된 골을 제거하고 다시 새로운 골로 대치하는 과정으로, 부갑상선 호르몬(PTH), 칼시토닌, 에스트로겐 등과 같은 호르몬과 IGFI(insulin-like growth factor I) 등의 골조직에서 분비되는 다양한 성장인자, TNF-α(tumor necrosis factor-α) 등과 같은 사이토카인(cytokines)을 통해 조골세포와 파골세포의 활성 균형을 조절하며 항상성을 유지시킨다. 이러한 조골세포와 파골세포의 균형이 깨지는 경우 골다공증이나 관절염과 같은 질환이 유발하게 된다.Bone tissue is composed of several types of cells such as extracellular substances such as collagen and glycoprotein, and osteoblasts, osteoclasts, and bone cells. In addition, as a metabolic organ in which bone resorption by osteoclasts and formation of new bone matrix and mineralization by osteoblasts occur repeatedly, bone formation due to the activity of osteoblasts is more than bone resorption due to the activity of osteoclasts. Bone remodeling is the process of removing old bone after growth is complete and replacing it with new bone.It is secreted by hormones such as parathyroid hormone (PTH), calcitonin, estrogen, and bone tissues such as insulin-like growth factor I (IGFI). Through various growth factors, cytokines such as TNF-α (tumor necrosis factor-α), it regulates the active balance of osteoblasts and osteoclasts and maintains homeostasis. If the balance between these osteoblasts and osteoclasts is broken, diseases such as osteoporosis or arthritis are caused.
특히, 조골세포와 파골세포의 균형이 깨지게 되면 파골세포에 의한 지나친 뼈의 파괴가 일어나게 되고 골다공증과 같은 질환으로 이어지게 되는 것이다. 이러한 파골세포는 골대사 과정에서 뼈의 흡수를 담당하는 특화된 세포로서 전구세포인 단핵구(monocyte)나 대식세포(macrophage)로부터 분화 프로그램을 통해서 형성된다. 또한, 파골세포는 αvβ3 인테그린(integrin) 등을 통해 골에 결합하며 산성 환경을 조성하는 한편 각종 콜라게네이즈 (collagenase) 및 프로테아제(protease)를 분비하여 골 흡수(bone resorption)를 일으키므로, 이러한 파골세포를 억제가 골 질환 치료의 효과적인 방법이 될 수 있다.
In particular, when the balance between osteoblasts and osteoclasts is broken, excessive bone destruction by osteoclasts occurs, leading to diseases such as osteoporosis. These osteoclasts are specialized cells responsible for bone absorption during bone metabolism, and are formed from progenitor cells such as monocytes or macrophages through a differentiation program. In addition, osteoclasts bind to bone through αvβ3 integrin, etc., and create an acidic environment, while secreting various collagenases and proteases to cause bone resorption. Cell inhibition can be an effective method of treating bone disease.
이에, 본 발명자들은 치료제로서의 부작용을 최소화시키면서 유효한 치료 효과를 갖는 새로운 치료제를 개발하기 위해 노력한 결과, 이량체 형태의 펩타이드를 제조하였고, 자가면역질환 계열의 관절염 마우스 모델에서 상기 펩타이드가 자가면역에 관련된 조절 T 세포 및 Th17 세포의 수를 조절하고, 파골세포로의 분화를 억제하는 것을 확인하여, 본 발명의 펩타이드를 자가면역질환 또는 골대사성 질환의 예방 또는 치료용 조성물로 유용하게 이용할 수 있음을 밝힘으로써, 본 발명을 완성하였다.
Accordingly, the present inventors have tried to develop a new therapeutic agent having an effective therapeutic effect while minimizing side effects as a therapeutic agent, and as a result, a dimeric peptide was prepared, and the peptide was related to autoimmunity in a mouse model of arthritis of an autoimmune disease series. By controlling the number of regulatory T cells and Th17 cells, and confirming that it inhibits differentiation into osteoclasts, it was revealed that the peptide of the present invention can be usefully used as a composition for preventing or treating autoimmune diseases or bone metabolic diseases. Thus, the present invention was completed.
본 발명의 목적은 서열번호 1로 표시되는 아미노산으로 이루어진 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of autoimmune diseases, comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same as an active ingredient.
본 발명의 다른 목적은 상기 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 골 질환의 예방 또는 치료용 약학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for preventing or treating bone diseases, comprising the peptide or a polynucleotide encoding the same as an active ingredient.
본 발명의 다른 목적은 상기 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 자가면역질환의 예방 또는 개선용 건강기능식품을 제공하는 것이다.Another object of the present invention is to provide a health functional food for preventing or improving autoimmune diseases, comprising the peptide or a polynucleotide encoding the same as an active ingredient.
본 발명의 또 다른 목적은 상기 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 골 질환의 예방 또는 개선용 건강기능식품을 제공하는 것이다.
Another object of the present invention is to provide a health functional food for preventing or improving bone diseases, comprising the peptide or a polynucleotide encoding the same as an active ingredient.
상기 목적을 달성하기 위하여, 본 발명은 서열번호 1로 표시되는 아미노산으로 이루어진 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 자가면역질환의 예방 또는 치료용 약학적 조성물을 제공한다.In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating autoimmune diseases, comprising as an active ingredient a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same.
또한, 본 발명은 상기 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 골 질환의 예방 또는 치료용 약학적 조성물을 제공한다.In addition, the present invention provides a pharmaceutical composition for preventing or treating bone diseases, comprising the peptide or a polynucleotide encoding the same as an active ingredient.
또한, 본 발명은 상기 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 자가면역질환의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving autoimmune diseases, comprising the peptide or a polynucleotide encoding the same as an active ingredient.
또한, 본 발명은 상기 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 골 질환의 예방 또는 개선용 건강기능식품을 제공한다.
In addition, the present invention provides a health functional food for preventing or improving bone diseases, comprising the peptide or a polynucleotide encoding the same as an active ingredient.
본 발명은 자가면역질환 계열의 관절염 마우스 모델에서 본 발명에 따른 이량체 형태의 펩타이드가 자가면역에 관련된 조절 T 세포 및 Th17 세포의 수를 조절하고, 파골세포로의 분화를 억제하는 것을 확인하였으므로, 본 발명의 펩타이드를 자가면역질환 또는 골대사성 질환의 예방 또는 치료용 조성물로 유용하게 이용할 수 있다.The present invention confirmed that the dimeric peptide according to the present invention regulates the number of regulatory T cells and Th17 cells related to autoimmunity and inhibits differentiation into osteoclasts in the arthritis mouse model of the autoimmune disease series, The peptide of the present invention can be usefully used as a composition for preventing or treating autoimmune diseases or bone metabolic diseases.
또한, 본 발명에 따른 이량체 형태의 펩타이드는 매우 작은 크기의 펩타이드로 이루어져, 외부 물질의 투여에 따른 부작용을 최소화할 수 있다.
In addition, the peptide in the form of a dimer according to the present invention is composed of a peptide having a very small size, and side effects caused by administration of foreign substances can be minimized.
도 1은 콜라겐 유도 관절염 마우스 모델의 제조과정 및 본 발명에 따른 이량체 형태의 펩타이드 R6-2의 투여 시기를 개략적으로 나타낸 모식도이다.
도 2는 콜라겐 유도 관절염 마우스 모델에서, 2차 면역 반응 유도 이후, 펩타이드 R6-2 처리에 따른 조절 T 세포(regulatory T cell; Treg 세포)의 수 변화를 확인한 도이다.
도 3은 콜라겐 유도 관절염 마우스 모델에서, 2차 면역 반응 유도 이후, 펩타이드 R6-2 처리에 따른 Th17 세포의 수 변화를 확인한 도이다.
도 4는 펩타이드 R6-2 처리에 따른 대식세포의 파골세포로의 분화 정도를 확인한 도이다.1 is a schematic diagram showing the manufacturing process of a collagen-induced arthritis mouse model and the timing of administration of the dimeric peptide R6-2 according to the present invention.
FIG. 2 is a diagram illustrating a change in the number of regulatory T cells (regulatory T cells; Treg cells) according to peptide R6-2 treatment after induction of a secondary immune response in a collagen-induced arthritis mouse model.
3 is a diagram illustrating a change in the number of Th17 cells according to peptide R6-2 treatment after induction of a secondary immune response in a collagen-induced arthritis mouse model.
4 is a diagram illustrating the degree of differentiation of macrophages into osteoclasts according to peptide R6-2 treatment.
이하, 본 발명을 보다 상세히 설명한다.
Hereinafter, the present invention will be described in more detail.
본 발명은, 서열번호 1로 표시되는 아미노산으로 이루어진, 펩타이드를 제공한다.The present invention provides a peptide consisting of the amino acid represented by SEQ ID NO: 1.
본 발명에서, 상기 "펩타이드(peptide)"는 아마이드 결합(또는 펩타이드 결합)으로 연결된 2개 이상의 아미노산으로 이루어진 폴리머를 의미한다. 펩타이드 치료제에 대한 다양한 연구에도 불구하고, 펩타이드 자체 크기가 너무 커서 표적 조직 또는 세포에 효과적으로 유입되지 못하거나 반감기가 짧아 단기간에 체내에서 소멸되는 단점을 드러내었는바, 본 발명은 약학적으로 유효한 활성을 가짐과 동시에 10개 이하의 아미노산으로 이루어진, 이량체 형태의 펩타이드를 규명하였다는 점에 기술적 의의가 있다.In the present invention, the "peptide" refers to a polymer consisting of two or more amino acids linked by an amide bond (or a peptide bond). Despite various studies on peptide therapeutics, the peptide itself is too large to effectively enter the target tissue or cells, or it has a short half-life and thus disappears in the body in a short period of time. At the same time, it has technical significance in that it has identified a dimeric peptide consisting of 10 or fewer amino acids.
본 발명의 펩타이드는 서열번호 1로 표시되는 아미노산으로 이루어질 수 있고, 상기 서열번호 1로 표시되는 아미노산 서열과 각각 75% 이상, 바람직하게는 80% 이상, 더욱 바람직하게는 90% 이상, 가장 바람직하게는 95% 이상의 서열 상동성을 가지는 아미노산 서열을 포함할 수 있으며, 표적화 서열, 태그 (tag), 표지된 잔기, 반감기 또는 펩타이드 안정성을 증가시키기 위한 특정 목적으로 제조된 아미노산 서열도 추가적으로 포함할 수 있다.The peptide of the present invention may consist of an amino acid represented by SEQ ID NO: 1, and each of the amino acid sequence represented by SEQ ID NO: 1 and 75% or more, preferably 80% or more, more preferably 90% or more, most preferably May include an amino acid sequence having 95% or more sequence homology, and may additionally include an amino acid sequence prepared for a specific purpose to increase a targeting sequence, a tag, a labeled residue, a half-life or peptide stability. .
또한, 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.In addition, 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 폴리에틸렌글리콜(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, potency, etc.), altered specificity (e.g., a broad spectrum of biological activity), 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 a polyethylene glycol (PEG), but the modification of the peptide, especially the stability of the peptide may be improved. Any component that can be included may be included without limitation.
본 발명에서 사용되는 용어, "안정성"은 생체 내 단백질 절단효소의 공격으로부터 본 발명의 펩타이드를 보호하는 인 비보 안정성뿐만 아니라, 저장 안정성 (예컨대, 상온 저장 안정성)도 의미한다.The term "stability" used in the present invention 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 발명에서 사용되는 용어, "폴리뉴클레오타이드(polynucleotide)"는 뉴클레오티드가 결합된 중합체로서, 유전 정보를 전달하는 역할을 한다. 본 발명의 목적상, 서열번호 1의 펩타이드를 코딩하며, 상기 펩타이드를 코딩하는 폴리뉴클레오타이드 서열과 각각 75% 이상, 바람직하게는 85% 이상, 더욱 바람직하게는 90% 이상, 가장 바람직하게는 95% 이상 서열 상동성을 가지는 서열을 포함할 수 있다.The term "polynucleotide" used in the present invention is a polymer to which nucleotides are bound and serves to transmit genetic information. For the purpose of the present invention, each of the polynucleotide sequence encoding the peptide of SEQ ID NO: 1 and 75% or more, preferably 85% or more, more preferably 90% or more, most preferably 95% It may include a sequence having abnormal sequence homology.
본 발명에서 사용되는 용어, "상동성"은 야생형 아미노산 서열 또는 폴리뉴클레오타이드 서열과의 유사한 정도를 나타내기 위한 것으로서, 이러한 상동성의 비교는 당업계에서 널리 알려진 비교 프로그램을 이용하여 수행할 수 있으며, 2개 이상의 서열간 상동성을 백분율 (%)로 계산할 수 있다.
As used in the present invention, the term "homology" is intended to indicate a degree of similarity with a wild-type amino acid sequence or a polynucleotide sequence, and comparison of such homology can be performed using a comparison program well known in the art, 2 The homology between two or more sequences can be calculated as a percentage (%).
또한, 본 발명은 서열번호 1로 표시되는 아미노산으로 이루어진 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 자가면역질환의 예방 또는 치료용 약학적 조성물; 자가면역질환의 치료를 위한 상기 펩타이드의 용도; 및 치료상 유효량의 상기 펩타이드를 개체에게 투여하는 것을 포함하는, 자가면역질환의 치료 방법을 제공한다.In addition, the present invention comprises a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same as an active ingredient, a pharmaceutical composition for preventing or treating autoimmune diseases; The use of the peptide for the treatment of autoimmune diseases; And it provides a method of treating an autoimmune disease comprising administering a therapeutically effective amount of the peptide to the individual.
본 발명에서, 상기 자가면역질환은 전신성 자가면역질환 또는 국소성 자가면역질환일 수 있고, 상기 전신성 자가면역질환은 예를 들어 류마티스 관절염 (rheumatoid arthritis), 전신성 홍반성 낭창 (systemic lupus erythematosus), 쇼그렌 증후군 (Sjogren's syndrome), 전신 경화증(systemic sclerosis), 다발성 근염(polymyositis), 전신성 혈관염(systemic angitis) 또는 혼합결합조직병 (mixed connective tissue disease)일 수 있으며, 상기 국소성 자가면역질환은 다발성 경화증(multiple sclerosis), 크론병(Crohn's disease), 하시모토병(Hashimoto's disease), 그레이브스병(Grave's disease) 또는 건선(Psoriasis)일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the autoimmune disease may be a systemic autoimmune disease or a local autoimmune disease, and the systemic autoimmune disease is, for example, rheumatoid arthritis, systemic lupus erythematosus, or Sjogren syndrome. (Sjogren's syndrome), systemic sclerosis, polymyositis, systemic angitis, or mixed connective tissue disease, and the local autoimmune disease is multiple sclerosis. ), Crohn's disease, Hashimoto's disease, Grave's disease, or Psoriasis, but is not limited thereto.
본 발명에서, 상기 조성물은 조절 T 세포의 수를 증가시키고, Th17 세포의 수를 감소시키는 것이 바람직하다.
In the present invention, it is preferable that the composition increases the number of regulatory T cells and decreases the number of Th17 cells.
또한, 본 발명은 서열번호 1로 표시되는 아미노산으로 이루어진 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 골 질환의 예방 또는 치료용 약학적 조성물; 골 질환의 치료를 위한 상기 펩타이드의 용도; 및 치료상 유효량의 상기 펩타이드를 개체에게 투여하는 것을 포함하는, 골 질환의 치료 방법을 제공한다.In addition, the present invention comprises a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same as an active ingredient, a pharmaceutical composition for preventing or treating bone disease; The use of the peptide for the treatment of bone diseases; And it provides a method of treating a bone disease comprising administering to the individual a therapeutically effective amount of the peptide.
본 발명에서, 상기 골 질환은 예를 들어 뼈전이암(bone metastatic cancer), 고형암 뼈전이, 고형암 뼈전이에 의한 근골격 합병증, 악성 종양으로 인한 과칼슘혈증, 다발성 골수종, 원발성(primary) 뼈 종양, 골다공증, 퇴행성 관절염, 치주질환, 염증성 치조골 흡수질환, 염증성 뼈흡수 질환 또는 파게트병(Paget's disease)일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the bone diseases are, for example, bone metastatic cancer, solid cancer bone metastasis, musculoskeletal complications due to solid cancer bone metastasis, hypercalcemia due to malignant tumors, multiple myeloma, primary bone tumors, Osteoporosis, degenerative arthritis, periodontal disease, inflammatory alveolar bone resorption disease, inflammatory bone resorption disease, or Paget's disease may be, but is not limited thereto.
본 발명에서, 상기 조성물은 파골세포의 수를 감소시키거나, 파골세포 분화를 억제하는 것이 바람직하다.
In the present invention, the composition is preferably to reduce the number of osteoclasts or inhibit osteoclast differentiation.
본 발명에서 사용되는 용어, "예방"은 본 발명에 따른 약학적 조성물의 투여에 의해 질환을 억제시키거나 발병을 지연시키는 모든 행위를 의미한다.The term "prevention" as used in the present invention refers to any action that suppresses disease or delays onset of disease by administration of the pharmaceutical composition according to the present invention.
본 발명에서 사용되는 용어, "치료"는 본 발명에 따른 약학적 조성물의 투여에 의해 질환에 대한 증세가 호전되거나 이롭게 변경되는 모든 행위를 의미한다.The term "treatment" used in the present invention 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 발명에서, "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 구체적인 실시예에서, 본 발명자들은 RDG 단편(RDG monomer)을 이용하여 이량체(dimer) 형태의 펩타이드 R6-2를 제조하였고, 자가면역질환계 관절염 마우스 모델인 콜라겐 유도 관절염 마우스 모델에서 상기 펩타이드에 의하여 자가면역 억제와 관련된 조절 T 세포의 수가 증가하는 반면, 자가면역질환의 원인인 Th17 세포의 수가 감소하는 것을 확인하였으므로(도 2 및 도 3 참조), 본 발명에 따른 펩타이드를 자가면역질환의 예방 또는 치료용 조성물의 유효성분으로 유용하게 이용할 수 있다.In a specific embodiment of the present invention, the present inventors prepared a peptide R6-2 in a dimer form using an RDG monomer, and in the collagen-induced arthritis mouse model, which is an autoimmune disease-based arthritis mouse model, While the number of regulatory T cells associated with autoimmune suppression increased by the peptide, it was confirmed that the number of Th17 cells, which is the cause of autoimmune disease, decreases (see FIGS. 2 and 3), so that the peptide according to the present invention is used as an autoimmune disease. It can be usefully used as an active ingredient of a composition for preventing or treating of.
또한, 본 발명자들은 콜라겐 유도 관절염 마우스 모델에서 상기 펩타이드에 의하여 대식세포의 파골세포로의 분화가 억제되는 것을 확인하였으므로(도 4 참조), 본 발명에 따른 펩타이드를 골 질환의 예방 또는 치료용 조성물의 유효성분으로 유용하게 이용할 수 있다.
In addition, the present inventors confirmed that the differentiation of macrophages into osteoclasts is inhibited by the peptide in a collagen-induced arthritis mouse model (see Fig. 4), so that the peptides according to the present invention are used in the composition for preventing or treating bone diseases. It can be usefully used as an active ingredient.
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, and the like 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 according to a desired method (for example, intramuscularly, intravenously, intraperitoneally, subcutaneously, intradermally, or topically applied), 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 면역 억제제와 병용하여 투여될 수 있고 종래의 면역 억제제와는 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 another immunosuppressant, and may be administered simultaneously, separately or sequentially with a conventional immunosuppressant, and may 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.
또한, 본 발명은 서열번호 1로 표시되는 아미노산으로 이루어진 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 자가면역질환의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving autoimmune diseases, comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same as an active ingredient.
아울러, 본 발명은 서열번호 1로 표시되는 아미노산으로 이루어진 펩타이드 또는 이를 코딩하는 폴리뉴클레오타이드를 유효성분으로 포함하는, 골 질환의 예방 또는 개선용 건강기능식품을 제공한다.In addition, the present invention provides a health functional food for preventing or improving bone diseases, comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same as an active ingredient.
본 발명에서 사용되는 용어, "개선"이란 치료되는 상태와 관련된 파라미터, 예를 들면, 증상의 정도를 적어도 감소시키는 모든 행위를 의미한다.As used herein, the term "improvement" means any action that at least reduces the severity of a parameter related to the condition being treated, for example, symptoms.
이때, 상기 건강기능식품 조성물은 질환의 예방 또는 개선을 위하여 해당 질환의 발병 단계 이전 또는 발병 후, 치료를 위한 약제와 동시에 또는 별개로서 사용될 수 있다.At this time, the health functional food composition may be used before or after the onset stage of the disease in order to prevent or improve the disease, simultaneously with or separately from the drug for treatment.
본 발명의 건강기능식품 조성물에서, 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 functional food composition of the present invention, the active ingredient may be added to 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 건강기능식품 조성물은 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.The health functional food composition of the present invention may contain other ingredients as essential ingredients without particular limitation in addition to containing the active ingredient. For example, as in ordinary beverages, various flavoring agents or natural carbohydrates may be contained as additional ingredients. Examples of the aforementioned natural carbohydrates include monosaccharides such as glucose, fructose, and the like; Disaccharides such as maltose, sucrose, and the like; And polysaccharides, for example, common 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 (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) are 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 건강기능식품 조성물은 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 functional food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavoring agents such as synthetic flavoring agents 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 실시예에 의해 상세히 설명한다.Hereinafter, the present invention will be described in detail by examples.
단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다.
However, the following examples are only illustrative of the present invention, and the contents of the present invention are not limited to the following examples.
<< 실시예Example 1> 1> 펩타이드의Peptide 제작 making
본 실시예에서는, RDG 단편 (RDG monomer)을 이용하여 이량체(dimer) 형태의 중합체 R6-2 (RDGRDG; 서열번호 1)를 제작하였다. 이후, 고성능 액체크로마토그래피 (SHIMADZU Prominence HPLC)를 이용하여 합성된 펩타이드를 순수 분리하였으며, 컬럼은 Shiseido capcell pak C18 Column (4.6 x 50mm)을 이용하였다. 또한, 질량분석기 (HP 1100 series LC/MSD)를 이용하여, 합성된 펩타이드의 질량을 확인하였다.
In this example, a polymer R6-2 (RDGRDG; SEQ ID NO: 1) in a dimer form was prepared using an RDG monomer. Thereafter, the synthesized peptide was purely separated using high-performance liquid chromatography (SHIMADZU Prominence HPLC), and a Shiseido capcell pak C18 Column (4.6 x 50mm) was used as the column. In addition, mass spectrometry (HP 1100 series LC/MSD) was used to confirm the mass of the synthesized peptide.
<< 실시예Example 2> 콜라겐 유도 2> collagen induction 관절염arthritis 마우스 모델 제조 및 Mouse model manufacturing and 펩타이드Peptide 투여 administration
콜라겐 유도 관절염 (Collagen-induced arthritis, CIA) 마우스 모델은 자가면역질환 계열의 관절염 모델로서, 하기와 같이 제조하였다.Collagen-induced arthritis (CIA) mouse model is an autoimmune disease-based arthritis model, and was prepared as follows.
우선, 소의 제2형 콜라겐 (Bovine type II collagen, Chondrex사, 미국)과 프로인트 완전 보조제 (Freund's complete adjuvant, Chondrex사, 미국)를 1:1로 혼합하여 에멀젼화한 후, 상기 에멀젼화된 콜라겐 용액 50 ㎕를 6주령 DBA/1J 마우스의 꼬리에 피내 주사하여 1차 면역 (immunization)을 유도하였다. 1차 면역 후 2주 째에 소의 제2형 콜라겐과 프로인트 불완전 보조제를 1:1로 혼합하여 에멀젼화한 후, 상기 에멀젼화된 콜라겐 용액 50 ㎕를 재차 마우스 꼬리에 피내 주사하여 2차 면역 (boosting)을 유도하였다.First, bovine type II collagen (Chondrex, USA) and Freund's complete adjuvant (Chondrex, USA) were mixed in 1:1 to emulsify, and then the emulsified collagen 50 µl of the solution was injected intradermally into the tail of a 6-week-old DBA/1J mouse to induce primary immunization. Two weeks after the first immunization, bovine type 2 collagen and Freund's incomplete adjuvant were mixed in 1:1 to emulsify, and then 50 µl of the emulsified collagen solution was injected intradermally into the tail of the mouse for the second immunization ( boosting).
2차 면역 후, 그 다음날부터 1주일에 3회씩 상기 <실시예 1>에서 제작한 펩타이드 R6-2를 복강 투여하였으며, 대조군으로 PBS를 처리한 군을 이용하였다. 상기 콜라겐 유도 관절염 마우스 모델의 제조과정 및 펩타이드의 투여 시기는 도 1에 개략적으로 도시하였다.
After the second immunization, the peptide R6-2 prepared in <Example 1> was administered intraperitoneally three times a week from the next day, and a PBS-treated group was used as a control group. The manufacturing process of the collagen-induced arthritis mouse model and the timing of administration of the peptide are schematically illustrated in FIG. 1.
<< 실시예Example 3> 콜라겐 유도 관절염 마우스 모델에서 3> In a mouse model of collagen-induced arthritis 펩타이드에Peptide 의한 조절 T세포의 수 및 활성 증가 확인 Confirmation of increase in number and activity of regulatory T cells by
조절 T 세포(regulatory T cell; Treg 세포)는 우리 몸에서 자가면역을 억제하는 세포로, 자가항원에 대한 반응성이 있을 잠재성의 T세포를 억제하고, 항염증성 사이토카인을 분비하거나 세포와의 직접적인 접촉 등에 의하여 보조 T세포(helper T cell; Th 세포)인 Th1 세포 등의 면역반응을 억제하며, 항원제시세포 중 하나인 수지상세포의 기능을 억제하는 것으로 알려져 있다. 따라서, 콜라겐 유도 관절염 마우스 모델에서 본 발명의 펩타이드 처리가 Treg 세포의 수 및 활성에 미치는 영향을 알아보기 위하여, 하기의 실험을 수행하였다.Regulatory T cells (Treg cells) are cells that suppress autoimmunity in our body. They inhibit latent T cells that may be reactive to autoantigens, secrete anti-inflammatory cytokines, or make direct contact with cells. It is known to suppress immune responses such as Th1 cells, which are helper T cells (Th cells), and to suppress the function of dendritic cells, one of the antigen presenting cells. Therefore, in order to investigate the effect of the peptide treatment of the present invention on the number and activity of Treg cells in a mouse model of collagen-induced arthritis, the following experiment was performed.
구체적으로, 6주령 DBA/1J 마우스의 림프절을 적출한 후, 림프절 내의 naive CD4+ T 세포를 분리하였다. 분리한 naive CD4+ T 세포를 항-CD3 항체 및 항-CD28 항체로 활성화 시킨 후, TGF-β 등의 사이토카인 처리를 통해, Treg 세포로 분화를 유도하였다. 분화된 Treg 세포에 상기 <실시예 1>에서 제작한 R6-2 펩타이드를 처리한 후, 24 시간동안 배양하였다. 24시간 후, 형광 결합된 항-CD25 항체 및 항-Foxp3 항체를 이용하여 Treg 세포를 염색한 후, 유세포 분석기를 통해 분석하여 세포의 분포도를 측정하였다 (도 2).Specifically, after the lymph nodes of 6-week-old DBA/1J mice were excised, naive CD4+ T cells in the lymph nodes were isolated. The isolated naive CD4+ T cells were activated with anti-CD3 antibody and anti-CD28 antibody, and then differentiated into Treg cells through cytokine treatment such as TGF-β. The differentiated Treg cells were treated with the R6-2 peptide prepared in Example 1, and then cultured for 24 hours. After 24 hours, Treg cells were stained using the fluorescently-conjugated anti-CD25 antibody and anti-Foxp3 antibody, and then analyzed through a flow cytometer to measure the distribution of the cells (FIG. 2).
그 결과, 도 2에 나타낸 바와 같이, 분화된 Treg 세포에 R6-2 펩타이드를 투여한 경우, R6-2의 농도에 따라 Treg 세포의 수가 증가하는 것을 확인하였다.
As a result, as shown in FIG. 2, when the R6-2 peptide was administered to differentiated Treg cells, it was confirmed that the number of Treg cells increased according to the concentration of R6-2.
<< 실시예Example 4> 콜라겐 유도 관절염 마우스 모델에서 4> In a mouse model of collagen-induced arthritis 펩타이드에Peptide 의한 by Th17Th17 세포의 수 감소 확인 Confirm a decrease in the number of cells
Th 세포 중 Th17 세포는 IL-17을 분비하는데, IL-17에 대한 수용체가 상피세포, 섬유아세포, B 세포, T 세포, 골수 단핵세포, 골수 기질세포, 혈관내피세포 등 매우 다양한 세포에 존재하고 있기 때문에 IL-17 작용은 다양한 조직에서의 자가면역질환 발생에 주요한 원인 요인으로 인식되고 있다. 따라서, 콜라겐 유도 관절염 마우스 모델에서 본 발명의 펩타이드 처리가 Th17 세포의 수에 미치는 영향을 알아보기 위하여, 하기의 실험을 수행하였다.Among Th cells, Th17 cells secrete IL-17, and receptors for IL-17 exist in a wide variety of cells such as epithelial cells, fibroblasts, B cells, T cells, bone marrow mononuclear cells, bone marrow stromal cells, and vascular endothelial cells. Therefore, IL-17 action is recognized as a major causative factor in the occurrence of autoimmune diseases in various tissues. Therefore, in order to investigate the effect of the peptide treatment of the present invention on the number of Th17 cells in a mouse model of collagen-induced arthritis, the following experiment was performed.
구체적으로, 상기 <실시예 2>에 기재된 방법과 동일한 방법으로 상기 <실시예 1>에서 제작한 펩타이드 R6-2를 콜라겐 유도 관절염 마우스에 1 μM 농도로 복강 투여한 후 림프절을 적출하였다. 적출한 림프절에서 면역세포를 분리한 후, 형광 결합된 항-CD4 항체 및 항-IL-17 항체를 이용하여 Th17 세포를 염색하였고, 유세포 분석기를 통해 분석하여 세포의 수를 측정하였다(도 3).Specifically, peptide R6-2 prepared in <Example 1> was intraperitoneally administered to a collagen-induced arthritis mouse at a concentration of 1 μM in the same manner as described in <Example 2>, and then lymph nodes were removed. After isolation of immune cells from the extracted lymph nodes, Th17 cells were stained using fluorescently-conjugated anti-CD4 antibody and anti-IL-17 antibody, and the number of cells was measured by analyzing through flow cytometry (FIG. 3). .
그 결과, 도 3에 나타낸 바와 같이, 콜라겐 유도 관절염 마우스 모델군(CIA)보다 펩타이드를 투여한 콜라겐 유도 관절염 마우스 모델군(CIA + R6-2)에서 Th17 세포의 수가 현저하게 감소하는 것을 확인하였다.
As a result, as shown in FIG. 3, it was confirmed that the number of Th17 cells significantly decreased in the collagen-induced arthritis mouse model group (CIA + R6-2) administered with the peptide compared to the collagen-induced arthritis mouse model group (CIA).
따라서, 상기 <실시예 2> 및 <실시예 3>의 결과를 통해 자가면역질환계 관절염 모델에서 본 발명의 펩타이드가 Treg 세포의 수 및 활성을 증가시키고, Th17 세포의 수를 감소시키는 효과를 나타내므로, 본 발명의 펩타이드를 자가면역질환의 예방 및 치료에 이용할 수 있음을 확인하였다.
Therefore, through the results of <Example 2> and <Example 3>, the peptide of the present invention increases the number and activity of Treg cells, and decreases the number of Th17 cells in the autoimmune disease-based arthritis model. Therefore, it was confirmed that the peptide of the present invention can be used for the prevention and treatment of autoimmune diseases.
<실시예 5> 펩타이드에 의한 대식세포의 파골세포로의 분화 억제 확인<Example 5> Confirmation of inhibition of differentiation of macrophages into osteoclasts by peptides
뼈 조직에 존재하는 뼈를 분해하는 파골세포와 뼈를 생성하는 조골세포 간의 균형적인 활동이 뼈의 항상성 유지에 중요하며, 상기 두 세포 활성의 균형이 깨지게 되면 파골세포에 의한 지나친 뼈의 파괴가 일어나게 되고 골다공증과 같은 골 질환이 유발된다. 따라서, 대식세포가 파골세포로 분화하는데 있어서 본 발명의 펩타이드가 미치는 영향을 알아보기 위하여, 하기의 실험을 수행하였다.Balanced activity between osteoclasts that degrade bone and osteoblasts that create bone is important for maintaining bone homeostasis, and when the balance of the two cell activities is broken, excessive bone destruction by osteoclasts occurs. And bone diseases such as osteoporosis are caused. Therefore, in order to investigate the effect of the peptides of the present invention on differentiating macrophages into osteoclasts, the following experiment was performed.
구체적으로, R6-2 펩타이드에 의한 파골세포 분화 억제 효능을 세포주 수준에서 확인하기 위하여 대식세포주인 RAW264.7 세포에 RANKL 50 ng/㎖을 처리하여, 파골세포로의 분화를 유도하였고, 동시에 상기 <실시예 1>에서 제작한 R6-2 펩타이드를 농도별로 처리하였다. 분화된 파골세포의 숫자를 확인하기 위하여, TRAP 염색을 진행하였으며, 핵이 3개 이상 관찰되는 파골세포의 숫자를 blind test를 통해 측정하였다.Specifically, in order to confirm the inhibitory effect of osteoclast differentiation by R6-2 peptide at the cell line level, RANKL 50 ng/ml was treated in RAW264.7 cells, a macrophage, to induce differentiation into osteoclasts, and at the same time, the < The R6-2 peptide prepared in Example 1> was treated by concentration. In order to confirm the number of differentiated osteoclasts, TRAP staining was performed, and the number of osteoclasts in which three or more nuclei were observed was measured through a blind test.
파골세포로의 분화 정도를 확인하기 위해, 파골세포의 세포화학적 표지 효소로 주로 사용되는 TRAP (tartrate-resistant acid phosphatase)를 사용하였다. TRAP 염색 후, TRAP 양성 세포의 숫자를 확인함으로써, 파골세포로의 분화 정도를 측정하였다.In order to confirm the degree of differentiation into osteoclasts, TRAP (tartrate-resistant acid phosphatase), which is mainly used as a cytochemical labeling enzyme for osteoclasts, was used. After TRAP staining, the degree of differentiation into osteoclasts was measured by checking the number of TRAP-positive cells.
그 결과, 도 4에 나타낸 바와 같이, RANKL 처리에 의해 TRAP 양성 세포의 숫자가 현저하게 증가하는 바, RANKL에 의한 파골세포의 분화를 확인하였고, R6-2 펩타이드를 처리한 그룹에서는 TRAP 양성 세포의 수가 현저하게 감소하는 것을 확인하였다. 특히, R6-2의 농도 의존적으로 파골세포의 분화가 감소하기 때문에, R6-2 펩타이드에 의한 파골세포 억제 효능을 확인할 수 있었다. 따라서, 상기 결과를 통해 본 발명의 펩타이드가 대식세포의 파골세포로의 분화를 억제하여 파골세포의 수가 과다하게 증가하는 것을 막는 효과를 나타내므로, 본 발명의 펩타이드를 골 질환의 예방 또는 치료에 이용할 수 있음을 확인하였다.
As a result, as shown in FIG. 4, the number of TRAP-positive cells significantly increased by RANKL treatment, and differentiation of osteoclasts by RANKL was confirmed. In the group treated with R6-2 peptide, the number of TRAP-positive cells It was confirmed that the number significantly decreased. In particular, because the differentiation of osteoclasts is reduced in a concentration-dependent manner of R6-2, the efficacy of inhibiting osteoclasts by R6-2 peptide was confirmed. Therefore, through the above results, the peptide of the present invention exhibits the effect of inhibiting the differentiation of macrophages into osteoclasts, thereby preventing an excessive increase in the number of osteoclasts. It was confirmed that it can be.
<110> SOOKMYUNG WOMENS UNIVERSITY Research & Business Development Foundation
<120> Use of a peptide as a therapeutic agent
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<120> Use of a peptide as a therapeutic agent
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Claims (11)
상기 골 질환은 뼈전이암(bone metastatic cancer), 고형암 뼈전이, 고형암 뼈전이에 의한 근골격 합병증, 악성 종양으로 인한 과칼슘혈증, 다발성 골수종, 원발성(primary) 뼈 종양, 골다공증, 치주질환 및 파게트병(Paget's disease)으로 이루어진 군으로부터 선택되는 것이고,
상기 조성물은 파골세포의 수를 감소시키거나, 파골세포 분화를 억제하는 것인, 조성물.
As a pharmaceutical composition for preventing or treating bone diseases, comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same as an active ingredient,
The bone diseases include bone metastatic cancer, solid cancer bone metastasis, musculoskeletal complications due to solid cancer bone metastasis, hypercalcemia due to malignant tumors, multiple myeloma, primary bone tumors, osteoporosis, periodontal disease and Paget's disease. (Paget's disease) is selected from the group consisting of,
The composition is to reduce the number of osteoclasts or inhibit osteoclast differentiation.
메톡시 카르보닐기, 포르밀기, 팔미토일기, 미리스틸기, 스테아릴기, 및 폴리에틸렌글리콜 (PEG)로 이루어진 군으로부터 선택되는 보호기와 결합되어 있는 것을 특징으로 하는, 골 질환의 예방 또는 치료용 약학적 조성물.
The method of claim 1, wherein the N- or C-terminus of the peptide is an acetyl group, fluorenyl
A pharmaceutical for the prevention or treatment of bone diseases, characterized in that it is combined with a protecting group selected from the group consisting of methoxy carbonyl group, formyl group, palmitoyl group, myristyl group, stearyl group, and polyethylene glycol (PEG) Composition.
상기 골 질환은 뼈전이암(bone metastatic cancer), 고형암 뼈전이, 고형암 뼈전이에 의한 근골격 합병증, 악성 종양으로 인한 과칼슘혈증, 다발성 골수종, 원발성(primary) 뼈 종양, 골다공증, 치주질환 및 파게트병(Paget's disease)으로 이루어진 군으로부터 선택되는 것이고,
상기 건강기능식품은 파골세포의 수를 감소시키거나, 파골세포 분화를 억제하는 것인, 건강기능식품.
As a health functional food for preventing or improving bone disease, comprising a peptide consisting of an amino acid represented by SEQ ID NO: 1 or a polynucleotide encoding the same as an active ingredient,
The bone diseases include bone metastatic cancer, solid cancer bone metastasis, musculoskeletal complications due to solid cancer bone metastasis, hypercalcemia due to malignant tumors, multiple myeloma, primary bone tumors, osteoporosis, periodontal disease and Paget's disease. (Paget's disease) is selected from the group consisting of,
The health functional food is to reduce the number of osteoclasts or inhibit osteoclast differentiation.
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