KR20220139751A - Composition for inhibiting angiogenesis using shuramin fragments - Google Patents
Composition for inhibiting angiogenesis using shuramin fragments Download PDFInfo
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- KR20220139751A KR20220139751A KR1020210046133A KR20210046133A KR20220139751A KR 20220139751 A KR20220139751 A KR 20220139751A KR 1020210046133 A KR1020210046133 A KR 1020210046133A KR 20210046133 A KR20210046133 A KR 20210046133A KR 20220139751 A KR20220139751 A KR 20220139751A
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- angiogenesis
- vegf
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- heparin
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Abstract
Description
본 발명은, 수라민 단편을 이용한 혈관신생 억제용 조성물에 관한 것으로, 더욱 상세하게는 수라민 단편과 담즙산(bile acid)이 결합된 화합물 또는 이의 유도체가 혈관내피성장인자의 헤파린 결합 부위에 결합하여 혈관의 신생을 억제하는 효과를 이용한 혈관 신생 관련 질환의 치료, 예방 또는 개선용 조성물에 관한 것이다.The present invention relates to a composition for inhibiting angiogenesis using a suramin fragment, and more particularly, a compound or a derivative thereof in which a suramin fragment and a bile acid are bound to a heparin binding site of vascular endothelial growth factor. It relates to a composition for treatment, prevention or improvement of angiogenesis-related diseases using the effect of inhibiting angiogenesis.
혈관신생은 정상 및 병리적 조건에서도 모두 일어나며, 기존의 혈관으로부터 새로운 혈관이 생성되는 것을 말한다. 배아 발달 및 상처 치유와 같은 생리적 조건과 암의 성장 및 망막질환 유발과 같은 병리적 조건에서 일어나는 모든 혈관신생은 혈관신생 촉진인자와 억제인자의 균형에 의해 조절된다. 그러나 병리적 조건에서 혈관신생 촉진인자의 과다한 생성 및 축적으로 인해 유발되는 비정상적인 혈관생성은 종양 성장 및 전이, 류마티스관절염, 당뇨망막병증, 노인성 황반병성을 포함한 여러 질환의 원인이 된다.Angiogenesis occurs in both normal and pathological conditions, and refers to the creation of new blood vessels from existing blood vessels. All angiogenesis that occurs in physiological conditions such as embryonic development and wound healing and pathological conditions such as cancer growth and retinal disease is regulated by the balance of angiogenesis promoters and inhibitors. However, abnormal angiogenesis induced by excessive production and accumulation of angiogenesis promoters in pathological conditions causes various diseases including tumor growth and metastasis, rheumatoid arthritis, diabetic retinopathy, and senile macular disease.
혈관신생은 다양한 혈관신생 촉진인자에 의해 유발되는 혈관내피세포의 활성화, 증식, 이동 및 관형성을 포함한 순차적 과정에 의해 유도되는 것이 일반적이다. 혈관신생 촉진인자 중 혈관내피성장인자(vascular endothelial growth factor, VEGF)는 다양한 신호전달 연쇄반응을 활성화시켜 내피세포 증식, 이동, 분화를 유도하는 역할을 한다. 병리적 조건에서 VEGF는 비정상적인 혈관신생을 유도해 종양세포 및 망막세포의 성장과 혈관누수를 촉진시켜 종양의 성장 및 전이, 당뇨망막병증, 노인성 황반변성 등을 야기한다. 따라서 VEGF의 중화항체와 신호억제제를 이용하여, VEGF의 생물학적 활성과 신호전달 연쇄반응을 방해함으로써, 암혈관과 망막혈관의 신생을 제어할 수 있다. VEGF나 VEGF의 수용체를 표적으로 하는 혈관신생 억제 약물은 병리적(비정상적) 혈관신생과 관련된 인간 질환을 효과적으로 제어하는 좋은 치료전략이다. 최근 몇몇 혈관신생억제 항체, 단백질 및 화학물질은 종양, 당뇨망막병증, 노인성 황반변성을 포함한 과다한 혈관신생관련 질병 치료용으로 개발되어 임상에 사용되었으나, 고혈압 및 출혈과 같은 부작용 발생되거나, 낮은 특이성과 생체이용률, 항원성 및 부적합한 약물 동태 등과 같은 치료적 한계점이 보고되고 있다. 일반적으로 작은 펩티드는 대량생산이 용이하고, 항원성이 없으며, 높은 용해도와 생체이용률 등의 장점이 있기 때문에 약제개발에 좋은 재료로 제안되고 있다.Angiogenesis is generally induced by sequential processes including activation, proliferation, migration, and tube formation of vascular endothelial cells induced by various angiogenesis-promoting factors. Among the angiogenesis promoting factors, vascular endothelial growth factor (VEGF) plays a role in inducing endothelial cell proliferation, migration, and differentiation by activating various signal transduction chain reactions. In pathological conditions, VEGF induces abnormal angiogenesis and promotes the growth of tumor cells and retinal cells and vascular leakage, leading to tumor growth and metastasis, diabetic retinopathy, and age-related macular degeneration. Therefore, it is possible to control neovascularization of cancer blood vessels and retinal blood vessels by interfering with VEGF biological activity and signal transduction chain reaction using VEGF neutralizing antibodies and signal inhibitors. Angiogenesis inhibitory drugs targeting VEGF or VEGF receptors are good therapeutic strategies to effectively control human diseases related to pathological (abnormal) angiogenesis. Recently, several anti-angiogenic antibodies, proteins and chemicals have been developed and used clinically for the treatment of excessive angiogenesis-related diseases, including tumors, diabetic retinopathy, and age-related macular degeneration. Therapeutic limitations such as bioavailability, antigenicity and inappropriate pharmacokinetics have been reported. In general, small peptides are proposed as good materials for drug development because they are easy to mass-produce, have no antigenicity, and have advantages such as high solubility and bioavailability.
이러한 맥락에서 본 발명자들은 이전에 항암 치료를 위한 VEGF 억제제로 다양한 헤파린과 담즙산 접합체를 평가했다. 그러나, 헤파린의 화학적 접합은 상기 헤파린의 분자 크기와 그 복잡성을 증가시켰다. 이러한 한계를 극복하기 위해 본 발명자들은 VEGF 억제에 더 유리하고 더 작은 헤파린 기반 접합체를 연구하였다.In this context, we previously evaluated various heparin and bile acid conjugates as VEGF inhibitors for anticancer therapy. However, the chemical conjugation of heparin increased the molecular size and complexity of the heparin. To overcome this limitation, the present inventors studied a smaller heparin-based conjugate that is more favorable for VEGF inhibition.
본 발명에서는 VEGF 의해 유도되는 혈관신생을 효과적으로 억제할 수 있는 저분자 화합물을 개발하기 위하여 다양한 연구를 시도하였으며, 그 결과 VEGF의 헤파린 결합자리에 결합 가능한 화합물을 개발할 수 있었다. 보다 개선된 제제를 개발하기위한 대안적인 접근 방식으로, 본 발명자들은 작은 크기의 합성 수라민과 디옥시콜산 (DOCA)의 새로운 접합체를 생성하여 헤파린과 유사한 수라민 단편(SF)에 결합 친화성을 부여할 수 있음을 확인하였다. 또한, VEGF의 HBD에 영향을 주어 종양에서 혈관 신생을 억제하고 SF에 대한 DOCA 접합은 VEGF에 대한 결합 친화도를 증가시키는 것을 확인하였다. 본 발명은 VEGF 억제를 위한 기능성 거대 분자의 사용과 관련된 신약 개발의 근본적인 문제를 극복하기위한 분자 기반을 제공할 것이다.In the present invention, various studies were attempted to develop a low molecular weight compound capable of effectively inhibiting angiogenesis induced by VEGF, and as a result, a compound capable of binding to the heparin binding site of VEGF could be developed. As an alternative approach to developing more improved formulations, we created a novel conjugate of small-sized synthetic suramin and deoxycholic acid (DOCA) that binds a heparin-like suramin fragment (SF) with binding affinity. It was confirmed that it can be given. In addition, it was confirmed that VEGF had an effect on HBD to inhibit angiogenesis in tumors and that DOCA conjugation to SF increased the binding affinity to VEGF. The present invention will provide a molecular basis for overcoming the fundamental problems of drug development associated with the use of functional macromolecules for VEGF inhibition.
본 발명에 따라 제조된 화합물은 VEGF의해 유도되는 혈관신생을 효과적으로 억제하는 활성을 나타내며, 이러한 활성은 과다한 혈관신생으로 인해 유발되는 질병, 특히 암의 치료제로 매우 유용하게 사용할 수 있는 것으로 확인된다.The compound prepared according to the present invention exhibits an activity of effectively inhibiting angiogenesis induced by VEGF, and this activity is confirmed to be very useful as a therapeutic agent for diseases caused by excessive angiogenesis, particularly cancer.
본 발명은 상기의 문제점을 해결하고 상기의 필요성에 의하여 안출된 것으로서, 수라민의 단편을 이용하여 혈관내피성장인자를 억제하는 저분자 화합물을 제공하는 것을 목적으로 한다. An object of the present invention is to provide a low molecular weight compound that inhibits vascular endothelial growth factor using a fragment of suramin, which has been devised in response to the above problems and needs.
본 발명은 또한, VEGF의 활성을 억제하여 혈관 신생 관련 질환의 치료, 예방, 개선을 위한 약학 조성물 또는 식품 조성물을 제공하는 것에 목적이 있다.Another object of the present invention is to provide a pharmaceutical composition or a food composition for the treatment, prevention, and improvement of angiogenesis-related diseases by inhibiting the activity of VEGF.
이하, 도면을 참조하여 본 발명을 상세히 설명한다. 본 발명의 이점 및 특징, 그리고 그것들을 달성하는 후술되어 있는 실시예들을 참조하면 명확해질 것이다. 그러나 본 발명은 이하에서 게시되는 실시예들에 한정되는 것이 아니라 서로 다른 다양한 형태로 구현될 수 있으며, 단지 본 실시예들은 본 발명의 게시가 완전하도록 하고, 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 발명의 범주를 완전하게 알려주기 위해 제공되는 것이며, 본 발명은 청구항의 범주에 의해 정의될 뿐이다. 명세서 전체에 걸쳐 동일 참조 부호는 동일 구성 요소를 지칭한다.Hereinafter, the present invention will be described in detail with reference to the drawings. Advantages and features of the present invention, as well as embodiments for achieving them, will become apparent with reference to the following embodiments. However, the present invention is not limited to the embodiments published below, but may be implemented in various different forms, and only these embodiments make the publication of the present invention complete, and common knowledge in the art to which the present invention pertains It is provided to fully inform those who have the scope of the invention, and the present invention is only defined by the scope of the claims. Like reference numerals refer to like elements throughout.
다른 정의가 없다면, 본 명세서에서 사용되는 모든 용어(기술 및 과학적 용어를 포함)는 본 발명이 속하는 기술분야에서 통상의 지식을 가진 자에게 공통적으로 이해될 수 있는 의미로 사용될 수 있을 것이다. 또 일반적으로 사용되는 사전에 정의되어 있는 용어들은 명백하게 특별히 정의되어 있지 않는 한 이상적으로 또는 과도하게 해석되지 않는다. 본 명세서에서 사용된 용어는 실시예들을 설명하기 위한 것이며 본 발명을 제한하고자 하는 것은 아니다. 본 명세서에서, 단수형은 문구에서 특별히 언급하지 않는 한 복수형도 포함한다.Unless otherwise defined, all terms (including technical and scientific terms) used herein may be used with the meaning commonly understood by those of ordinary skill in the art to which the present invention belongs. In addition, terms defined in a commonly used dictionary are not to be interpreted ideally or excessively unless clearly defined in particular. The terminology used herein is for the purpose of describing the embodiments and is not intended to limit the present invention. In this specification, the singular also includes the plural, unless specifically stated otherwise in the phrase.
본 발명자들은 처음 VEGF의 분자 구조를 연구하여 그 작용을 억제할 수 있는 효율적인 혈관형성억제제를 개발하였다. 그 후, VEGF의 헤파린 결합 부위의 명확한 구조를 얻었으며, 상기 헤파린 결합 부위는 비분획 헤파린의 분자 크기에 비해 작다는 것을 확인하였다. 이에 본 발명자들은 VEGF의 헤파린 결합 부위를 효과적으로 결합하고 억제하는 약물을 개발하기 위해 수라민 단편을 사용하여 접합체를 재설계하여 본 발명을 완성하였다.The present inventors first studied the molecular structure of VEGF and developed an effective angiogenesis inhibitor that can inhibit its action. Thereafter, a clear structure of the heparin-binding site of VEGF was obtained, and it was confirmed that the heparin-binding site was smaller than the molecular size of unfractionated heparin. Accordingly, the present inventors completed the present invention by redesigning the conjugate using a suramin fragment to develop a drug that effectively binds and inhibits the heparin binding site of VEGF.
본 발명에 따라 제조된 SFD는 VEGF의 헤파린 결합 부위에 결합하기위한 최적화된 합성 화합물이다. 헤파린 자체는 복잡성과 항응고 특성으로 인해 VEGF 표적 약물로 개발될 수 없기 때문에, 본 발명의 SFD는 헤파린 접합체의 문제점을 극복할 수 있는 VEGF-억제제로 사용될 수 있다.The SFD prepared according to the present invention is a synthetic compound optimized for binding to the heparin binding site of VEGF. Since heparin itself cannot be developed as a VEGF target drug due to its complexity and anticoagulant properties, the SFD of the present invention can be used as a VEGF-inhibitor that can overcome the problems of heparin conjugates.
본 발명에서 헤파린 및 SFD를 사용한 컴퓨터 시뮬레이션 및 SPR 결합 실험의 데이터는 SFD가 VEGF의 헤파린 결합 부위에 대해 효과적인 생체 분자임을 분명히 하였다. Data from computer simulations and SPR binding experiments using heparin and SFD in the present invention clarified that SFD is an effective biomolecule for the heparin binding site of VEGF.
본 발명에서는 일차 HUVEC에서 VEGF 매개 혈관 형성에 대한 SFD의 헤파린 모방 특성의 VEGF- 억제 효과를 평가했다. 처음에 고농도 (200 및 800 μM)의 SFD 또는 헤파린 처리는 HUVEC에 심각한 세포 독성 효과가 없었으나, SFD는 HUVEC에서 VEGF에 의한 혈관 형성을 억제하였다. 즉, 본 발명에 따르는 경우 SFD가 내피 세포의 혈관 형성 과정을 억제하고 VEGF를 억제함으로써 종양 모델에서 혈관 형성에 영향을 미친다는 것을 확인할 수 있다. 본 발명의 SFD는 다른 헤파린과 달리 명확한 분자 구조를 가지고 있어 VEGF에 대한 결합력을 향상시켜 다양한 질병에서 VEGF를 억제할 수 있다.In the present invention, we evaluated the VEGF-inhibitory effect of the heparin-mimicking properties of SFD on VEGF-mediated angiogenesis in primary HUVECs. Initially, high concentrations (200 and 800 μM) of SFD or heparin treatment had no significant cytotoxic effect on HUVECs, but SFD inhibited VEGF-induced angiogenesis in HUVECs. That is, according to the present invention, it can be confirmed that SFD affects angiogenesis in a tumor model by inhibiting the angiogenesis process of endothelial cells and inhibiting VEGF. The SFD of the present invention has a clear molecular structure unlike other heparin, and thus can inhibit VEGF in various diseases by improving binding to VEGF.
본 발명에서 "수라민(suramin)"이란, C51H34N6Na6O23S6의 화학식을 갖는 화합물로 안트폴-프리판블루의 유도체이며,"수라민 단편"이란, 상기 수라민의 일부 구조를 의미한다.In the present invention, "suramin" is a compound having a chemical formula of C 51 H 34 N 6 Na 6 O 23 S 6 and is a derivative of antpol-freepan blue, and "suramin fragment" means the suramin some structure of
본 발명의 일 실시예에 따르면, "수라민 단편"은, 하기 화학식 1의 구조로 표시될 수 있다.According to an embodiment of the present invention, the "suraamine fragment" may be represented by the structure of the following Chemical Formula 1.
[화학식 1][Formula 1]
본 발명에서 "담즙산(bile acid)"은, 빌산이라고도 하며, 주로 간의 콜레스테롤로부터 만들어져 생체 내의 콜레스테롤대사, 당대사, 핵산대사와 밀접한 관계를 갖는 C24 스테로이드계 카르복시산이다. 본 발명의 "담즙산"에는 콜산(cholic acid), 디옥시콜산(deoxycholic acid), 케노디옥시콜산(chenodeoxycholic acid), 리토콜산(lithocholic acid), 우르소콜산(ursocholic acid), 우르소디옥시콜산 (ursodeoxycholic acid), 이소우르소디옥시콜산(isoursodeoxycholic acid), 라고디옥시콜산(lagodeoxycholic acid), 글리코콜산(glycocholic acid), 타우로콜산(taurocholic acid), 글리코디옥시콜산(glycodeoxycholic acid), 글리코케노디옥시콜산(glycochenodeoxycholic acid), 디하이드로콜산(dehydrocholic acid), 히오콜산(hyocholic acid) 및 히오디옥시콜산(hyodeoxycholic acid)이 포함되나 이에 한정되는 것은 아니며, 바람직하게는 디옥시콜산이다.In the present invention, "bile acid", also called bilic acid, is a C 24 steroid-based carboxylic acid that is mainly made from liver cholesterol and has a close relationship with cholesterol metabolism, sugar metabolism, and nucleic acid metabolism in the living body. "Bile acids" of the present invention include cholic acid, deoxycholic acid, chenodeoxycholic acid, lithocholic acid, ursocholic acid, and ursodeoxycholic acid. (ursodeoxycholic acid), isoursodeoxycholic acid, lagodeoxycholic acid, glycocholic acid, taurocholic acid, glycodeoxycholic acid, glycoche Examples include, but are not limited to, glycochenodeoxycholic acid, dehydrocholic acid, hyocholic acid and hyodeoxycholic acid, and preferably deoxycholic acid.
본 발명에서 "SFD"란, 수라민 단편(또는 이의 유도체)과 담즙산(또는 이의 유도체 바람직하게는, 디옥시콜산)의 결합 화합물(SFD, suramin fragment and bile acid(deoxycholic acid) conjugate)을 의미한다. 이때 수라민 단편과 디옥시콜산의 결합은 공유 결합 형태로 연결될 수 있다.In the present invention, "SFD" means a binding compound (SFD, suramin fragment and bile acid (deoxycholic acid) conjugate) of a suramin fragment (or a derivative thereof) and a bile acid (or a derivative thereof, preferably, deoxycholic acid) . In this case, the bond between the suraamine fragment and deoxycholic acid may be connected in the form of a covalent bond.
본 발명의 "SFD"는, 이에 한정되는 것은 아니나 하기 화학식 2의 구조로 표시될 수 있고, 이의 유도체 및 입체 이성질체 등이 포함될 수 있다."SFD" of the present invention, but is not limited thereto, may be represented by the structure of Formula 2 below, and may include derivatives and stereoisomers thereof.
[화학식 2][Formula 2]
본 발명에서 "혈관내피성장인자 (VEGF, vascular endothelial growth factor)"는, 혈관내피세포에 특이적으로 작용하여 세포 증식이나 혈관신생을 촉진하는 당단백을 의미한다. In the present invention, "vascular endothelial growth factor (VEGF, vascular endothelial growth factor)" refers to a glycoprotein that specifically acts on vascular endothelial cells to promote cell proliferation or angiogenesis.
본 발명에서 상기 SFD는 VEGF의 헤파린 결합 부위(HBD, heparin-binding site)에 결합하고 VEGF의 활성을 억제하여, 혈관 신생 관련 질환의 개선, 치료 또는 예방에 사용될 수 있으며, 본 발명은 SFD 화합물을 유효성분으로 포함하는 혈관신생 관련 질환의 예방 또는 치료용 약학 조성물을 제공한다.In the present invention, the SFD binds to a heparin-binding site (HBD, heparin-binding site) of VEGF and inhibits the activity of VEGF, so that it can be used for improvement, treatment or prevention of angiogenesis-related diseases, and the present invention provides an SFD compound It provides a pharmaceutical composition for preventing or treating angiogenesis-related diseases, including as an active ingredient.
본 발명에서 "혈관 신생 관련 질환"이란, VEGF와 관련된 모든 질환을 포함할 수 있으며, 바람직하게는 암, 당뇨망막병증, 황반변성, 충혈, 류마티스성 관절염, 안구건조증 및 건선을 의미한다.In the present invention, "angiogenesis-related disease" may include all diseases related to VEGF, preferably cancer, diabetic retinopathy, macular degeneration, hyperemia, rheumatoid arthritis, dry eye syndrome and psoriasis.
본 발명에서 "예방"은 본 발명에 따른 조성물의 투여로 혈관 신생 관련 질환의 발병을 억제 또는 지연시키는 모든 행위를 말하며, "치료"는 상기 조성물에 의해 혈관 신생 관련 질환에 의한 증세가 호전되거나 이롭게 변경되는 모든 행위를 말한다.In the present invention, "prevention" refers to any action that suppresses or delays the onset of angiogenesis-related diseases by administration of the composition according to the present invention, and "treatment" means that symptoms caused by angiogenesis-related diseases are improved or advantageously by the composition Any action that changes.
본 발명에서 "개선"은 본 발명의 조성물을 이용하여 예방 또는 치료되는 혈관 신생 관련 질환의 의심 및 발병 개체의 증상이 호전되거나 이롭게 되는 모든 행위를 말한다.In the present invention, "improvement" refers to any action in which the symptoms of an angiogenesis-related disease and the symptoms of an angiogenesis-related disease that are prevented or treated using the composition of the present invention are improved or beneficial.
본 발명의 약학 조성물은 본 발명의 효과를 해치지 않는 범위 안에서 약학적으로 허용 가능한 희석제, 결합제, 붕해제, 윤활제, pH 조절제, 산화방지제, 용해보조제 등의 첨가제를 포함할 수 있다. The pharmaceutical composition of the present invention may contain additives such as pharmaceutically acceptable diluents, binders, disintegrants, lubricants, pH adjusters, antioxidants, solubilizers and the like within the scope not impairing the effects of the present invention.
상기 희석제는 슈가, 전분, 미결정셀룰로오스, 유당(유당수화물), 포도당, 디-만니톨, 알기네이트, 알칼리토금속류염, 클레이, 폴리에틸렌글리콜, 무수인산수소칼슘, 또는 이들의 혼합물 등을 사용할 수 있으며; 결합제는 전분, 미결정셀룰로오스, 고분산성 실리카, 만니톨, 디-만니톨, 자당, 유당수화물, 폴리에틸렌글리콜, 폴리비닐피롤리돈(포비돈), 폴리비닐피롤리돈 공중합체(코포비돈), 히프로멜로오스, 히드록시프로필셀룰로오스, 천연검, 합성검, 코포비돈, 젤라틴, 또는 이들의 혼합물 등을 사용할 수 있다. The diluent may be sugar, starch, microcrystalline cellulose, lactose (lactose hydrate), glucose, di-mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol, anhydrous calcium hydrogen phosphate, or mixtures thereof; The binder is starch, microcrystalline cellulose, highly dispersible silica, mannitol, di-mannitol, sucrose, lactose hydrate, polyethylene glycol, polyvinylpyrrolidone (povidone), polyvinylpyrrolidone copolymer (copovidone), hypromellose. , hydroxypropyl cellulose, natural gum, synthetic gum, copovidone, gelatin, or a mixture thereof may be used.
상기 붕해제는 전분글리콘산나트륨, 옥수수전분, 감자전분 또는 전호화전분 등의 전분 또는 변성전분; 벤토나이트, 몬모릴로나이트, 또는 비검(veegum) 등의 클레이; 미결정셀룰로오스, 히드록시프로필셀룰로오스 또는 카르복시메틸셀룰로오스 등의 셀룰로오스류; 알긴산나트륨 또는 알긴산 등의 알긴류; 크로스카멜로스(croscarmellose) 나트륨 등의 가교 셀룰로오스류; 구아검, 잔탄검 등의 검류; 가교 폴리비닐피롤리돈(crospovidone) 등의 가교 중합체; 중탄산나트륨, 시트르산 등의 비등성 제제, 또는 이들의 혼합물을 사용할 수 있다. The disintegrant is starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch; clays such as bentonite, montmorillonite, or veegum; celluloses such as microcrystalline cellulose, hydroxypropyl cellulose or carboxymethyl cellulose; algins such as sodium alginate or alginic acid; crosslinked celluloses such as croscarmellose sodium; gums such as guar gum and xanthan gum; crosslinked polymers such as crosslinked polyvinylpyrrolidone (crospovidone); Effervescent agents such as sodium bicarbonate, citric acid, or mixtures thereof may be used.
상기 윤활제는 탈크, 스테아린산, 스테아린산 마그네슘, 스테아린산 칼슘, 라우릴설페이트나트륨, 수소화식물성오일, 나트륨벤조에이트, 나트륨스테아릴푸마레이트, 글리세릴 베헤네이트, 글리세릴 모노레이트, 글리세릴모노스테아 레이트, 글리세릴 팔미토스테아레이트, 콜로이드성 이산화규소 또는 이들의 혼합물 등을 사용할 수 있다. The lubricant is talc, stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulfate, hydrogenated vegetable oil, sodium benzoate, sodium stearyl fumarate, glyceryl behenate, glyceryl monoate, glyceryl monostearate, glyceryl Palmitostearate, colloidal silicon dioxide, or a mixture thereof may be used.
상기 pH 조절제는 초산, 아디프산, 아스코르빈산, 아스코르빈산 나트륨, 에테르산 나트륨, 사과산, 숙신산, 주석산, 푸마르산, 구연산(시트르산)과 같은 산성화제와 침강 탄산 칼슘, 암모니아수, 메글루민, 탄산 나트륨, 산화 마 그네슘, 탄산 마그네슘, 구연산 나트륨, 삼염기칼슘인산염과 같은 염기성화제 등을 사용할 수 있다. The pH adjusting agent is an acidifying agent such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium etherate, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid) and precipitated calcium carbonate, aqueous ammonia, meglumine, A basifying agent such as sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate, or tribasic calcium phosphate may be used.
상기 산화방지제는 디부틸히드록시 톨루엔, 부틸레이티드 히드록시아니솔, 초산 토코페롤, 토코페롤, 프로필 갈레이트, 아황산수소나트륨, 피로아황산나트륨 등을 사용할 수 있다. 본 발명의 선방출성 구획에서, 용해보조제는 라우릴황산나트륨, 폴리소르베이트 등의 폴리옥시에틸렌 소르비탄 지방산 에스테류, 도큐세이트 나트륨, 폴록사머 (poloxamer) 등을 사용할 수 있다. The antioxidant may include dibutylhydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite, and the like. In the prior-release compartment of the present invention, the solubilizing agent may include polyoxyethylene sorbitan fatty acid esters such as sodium lauryl sulfate and polysorbate, sodium docusate, poloxamer, and the like.
또한, 본 발명의 약학 조성물은 지연방출성 제제를 만들기 위해 장용성 고분자, 수불용성 중합체, 소수성 화합물, 및 친수성 고분자를 포함할 수 있다. In addition, the pharmaceutical composition of the present invention may include an enteric polymer, a water-insoluble polymer, a hydrophobic compound, and a hydrophilic polymer to make a delayed-release preparation.
상기 장용성 고분자는 pH5 미만의 산성 조건하에서 불용성이거나 또는 안정한 것으로, pH5 이상인 특정 pH 조건 하에서 용해되거나 또는 분해되는 고분자를 말하며, 예를 들어, 히프로멜로오스아세테이트숙시네이트, 히프로멜 로오스프탈레이트(히드록시프로필메틸셀룰로오스 프탈레이트), 히드록시메틸에틸셀룰로오스프탈레이트, 셀룰로오 스아세테이트프탈레이트, 셀룰로오스아세테이트숙시네이트, 셀룰로오스아세테이트말레이트, 셀룰로오스벤조에이 트프탈레이트, 셀룰로오스프로피오네이트프탈레이트, 메틸셀룰로오스프탈레이트, 카르복시메틸에틸셀룰로오스 및 에틸히드록시에틸셀룰로오스프탈레이트, 메틸히드록시에틸셀룰로오스과 같은 장용성 셀룰로오스 유도체; 스티렌-아크릴산 공중합체, 아크릴산메틸-아크릴산 공중합체, 아크릴산메틸메타크릴산 공중합체(예컨대, 아크릴-이즈), 아크릴산부틸-스티렌-아크릴산 공중합체, 및 아크릴산메틸-메타크릴산-아크릴산옥틸공중합체과 같은 상기 장용성 아크릴산계 공중합체; 폴리(메타크릴산 메틸 메타크릴레이트) 공중합체(예컨대, 유드라짓 L, 유드라짓 S, 에보닉, 독일), 폴리 (메타크릴산 에틸아크릴레이트) 공중합체 (예컨대, 유드라짓 L100-55)와 같은 장용성 폴리메타크릴레이트 공중합체; 아세트산비닐-말레인산 무수물 공중합체, 스티렌-말레인산 무수물 공중합체, 스티렌-말레인산모노에스테를 공중합체, 비닐메틸에테르-말레인산 무수물 공중합체, 에틸렌-말레인산 무수물 공중합체, 비닐부틸에테르-말레인산 무수물 공중합체, 아크릴로니트릴-크릴산메틸ㆍ말레인산 무수물 공중합체, 및 아크릴산부틸-스티렌-말레인산 무수물 공중합체와 같은 장용성 말레인산계 공중합체; 및 폴리비닐알콜프탈레이 트, 폴리비닐아세탈프탈레이트, 폴리비닐부틸레이트프탈레이트 및 폴리비닐아세트아세탈프탈레이트와 같은 장용성 폴리비닐 유도체가 있다. The enteric polymer is insoluble or stable under acidic conditions of less than pH 5, and refers to a polymer that dissolves or decomposes under a specific pH condition of pH 5 or higher, for example, hypromellose acetate succinate, hypromellose phthalate (hydro hydroxypropylmethylcellulose phthalate), hydroxymethylethylcellulose phthalate, cellulose sacetate phthalate, cellulose acetate succinate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, methylcellulose phthalate, carboxymethylethyl cellulose and enteric cellulose derivatives such as ethylhydroxyethylcellulose phthalate and methylhydroxyethylcellulose; such as a styrene-acrylic acid copolymer, a methyl acrylate-acrylic acid copolymer, a methyl methacrylic acid acrylate copolymer (eg, acryl-ise), a butyl acrylate-styrene-acrylic acid copolymer, and a methyl acrylate-methacrylic acid-octyl acrylate copolymer the enteric acrylic acid-based copolymer; Poly(methyl methacrylate) copolymer (eg Eudragit L, Eudragit S, Evonik, Germany), poly (ethyl methacrylate) copolymer (eg Eudragit L100- 55) such as enteric polymethacrylate copolymers; Vinyl acetate-maleic anhydride copolymer, styrene-maleic anhydride copolymer, styrene-maleic acid monoester copolymer, vinylmethyl ether-maleic anhydride copolymer, ethylene-maleic anhydride copolymer, vinyl butyl ether-maleic anhydride copolymer, acrylic enteric maleic acid-based copolymers such as ronitrile-methyl acrylate/maleic anhydride copolymer and butyl acrylate-styrene-maleic anhydride copolymer; and enteric polyvinyl derivatives such as polyvinyl alcohol phthalate, polyvinyl acetal phthalate, polyvinyl butyrate phthalate and polyvinyl acetal phthalate.
상기 수불용성 중합체는 약물의 방출을 제어하는 약제학적으로 허용가능한 물에 용해되지 않는 고분자를 말한다. 예를 들어, 수불용성 중합체는 폴리비닐아세테이트(예컨대, 콜리코트 SR30D), 수불용성 폴리메타크릴레이트 공중합체[예컨대, 폴리(에틸아크릴레이트-메틸 메타크릴레이트) 공중합체(예컨대, 유드라짓 NE30D, 폴리 (에틸아크릴레이트-메틸 메타크릴레이트-트리메틸아미노에틸메타크릴레이트)공중합체(예컨대, 유드라짓 RSP O) 등], 에틸셀룰로오스, 셀룰로오스 에스테르, 셀룰로오스에테르, 셀룰로오스 아실레이트, 셀룰로오스 디아실레이트, 셀룰로오스 트리아실레이트, 셀룰로오스 아세테이트, 셀룰로오스 디아세테이트 및 셀룰로오스 트리아세테이트 등이 있다. The water-insoluble polymer refers to a pharmaceutically acceptable water-insoluble polymer that controls the release of the drug. For example, the water-insoluble polymer may be polyvinylacetate (eg, Colicotte SR30D), a water-insoluble polymethacrylate copolymer (eg, poly(ethylacrylate-methyl methacrylate) copolymer (eg, Eudragit NE30D) , poly (ethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate) copolymer (eg Eudragit RSP O), etc.], ethyl cellulose, cellulose ester, cellulose ether, cellulose acylate, cellulose diacylate , cellulose triacylate, cellulose acetate, cellulose diacetate and cellulose triacetate.
상기 소수성 화합물은 약물의 방출을 제어하는 약제학적으로 허용가능한 물에 용해되지 않는 물질을 말한다. 예를 들어, 글리세릴 팔미토스테아레이트, 글리세릴 스테아레이트, 글리세릴 비헤네이트, 세틸 팔미테이트, 글리세릴 모노 올레이트 및 스레아린산과 같은 지방산 및 지방산 에스테르류; 세토스테아릴 알코올, 세틸알코올 및 스테아릴알코올과 같은 지방산 알코올류; 카르나우바왁스, 밀납, 및 미결정왁스와 같은 왁스류; 탈크, 침강탄산 칼슘, 인산일수소칼슘, 산화아연, 산화티탄, 카올린, 벤토나이트, 몬모릴로나이트 및 비검과 같은 무기질 물질 등이 있다. The hydrophobic compound refers to a pharmaceutically acceptable water-insoluble substance that controls the release of the drug. For example, fatty acids and fatty acid esters such as glyceryl palmitostearate, glyceryl stearate, glyceryl bihenate, cetyl palmitate, glyceryl monooleate, and stearic acid; fatty acid alcohols such as cetostearyl alcohol, cetyl alcohol and stearyl alcohol; waxes such as carnauba wax, beeswax, and microcrystalline wax; and inorganic substances such as talc, precipitated calcium carbonate, calcium monohydrogen phosphate, zinc oxide, titanium oxide, kaolin, bentonite, montmorillonite, and veegum.
상기 친수성 고분자는 약물의 방출을 제어하는 약제학적으로 허용가능한 물에 용해되는 고분자 물질을 말한다. 예를 들어, 덱스트린, 폴리덱스트린, 덱스트란, 펙틴 및 펙틴 유도체, 알긴산염, 폴리갈락투론산, 자일란, 아라 비노자일란, 아라비노갈락탄, 전분, 히드록시프로필스타치, 아밀로오스, 및 아밀로펙틴와 같은 당류; 히프로멜 로오스, 히드록시프로필셀룰로오스, 히드록시메틸셀룰로오스, 히드록시에틸셀룰로오스, 메틸셀룰로오스 및 카르복시메틸셀룰로오스 나트륨과 같은 셀룰로오스 유도체; 구아검, 로커스트콩 검, 트라가칸타, 카라기난, 아카시아검, 아라비아검, 젤란검, 및 잔탄검과 같은 검류; 젤라틴, 카제인, 및 제인과 같은 단백질; 폴리비닐알코올, 폴리비닐피롤리돈, 및 폴리비닐아세탈디에틸아미노아세테이트과 같은 폴리비닐유도체; 폴리(부틸 메타크릴레이트-(2-디메틸아미노에틸)메타크릴레이트-메틸메타크릴레이트) 공중합체(예컨대, 유드라짓E100, 에보닉, 독일), 폴리(에틸 아크릴레이트-메틸 메타크릴레이드-트리에틸아미노에틸- 메타크릴레이트 클로라이드) 공중합체 (예컨대, 유드라짓 RL, RS, 에보닉, 독일)과 같은 친수성 폴리메타크릴레이트 공중합체; 폴리에틸렌 글리콜, 및 폴리에틸렌옥사이드와 같은 폴리에틸렌 유도체; 카보머 등이 있다. The hydrophilic polymer refers to a pharmaceutically acceptable water-soluble polymer that controls the release of a drug. For example, sugars such as dextrin, polydextrin, dextran, pectin and pectin derivatives, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropylstarch, amylose, and amylopectin ; cellulose derivatives such as hypromellose, hydroxypropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose and sodium carboxymethylcellulose; gums such as guar gum, locust bean gum, tragacantha, carrageenan, acacia gum, gum arabic, gellan gum, and xanthan gum; proteins such as gelatin, casein, and zein; polyvinyl derivatives such as polyvinyl alcohol, polyvinylpyrrolidone, and polyvinylacetaldiethylaminoacetate; Poly(butyl methacrylate-(2-dimethylaminoethyl)methacrylate-methylmethacrylate) copolymer (eg Eudragit E100, Evonik, Germany), poly(ethyl acrylate-methyl methacrylate- hydrophilic polymethacrylate copolymers such as triethylaminoethyl-methacrylate chloride) copolymers (eg Eudragit RL, RS, Evonik, Germany); polyethylene glycol, and polyethylene derivatives such as polyethylene oxide; Carbomer, etc.
이외에도 착색제, 향료 중에서 선택된 다양한 첨가제로서 약학적으로 허용 가능한 첨가제를 선택 사용하여 본 발명의 제제를 제제화할 수 있다. In addition, the formulation of the present invention may be formulated by selecting and using pharmaceutically acceptable additives as various additives selected from colorants and fragrances.
본 발명에서 첨가제의 범위가 상기 첨가제를 사용하는 것으로 한정되는 것은 아니며, 상기한 첨가제를 선택에 의하여 통상 범위의 용량을 함유하여 제제화할 수 있다.In the present invention, the scope of the additive is not limited to using the additive, and the additive may be formulated to contain a dose within a normal range by selecting the additive.
본 발명의 약학 조성물은"혈관 신생 관련 질환"의 치료, 예방, 개선 목적으로 개체에 투여될 수 있다.The pharmaceutical composition of the present invention may be administered to a subject for the purpose of treating, preventing, or improving an "angiogenesis-related disease".
본 발명에서 "투여"는 어떠한 적절한 방법으로 환자에게 본 발명의 약학 조성물을 도입하는 것을 의미하며, 본 발명의 조성물의 투여 경로는 목적 조직에 도달할 수 있는 한 어떠한 일반적인 경로를 통하여 투여될 수 있다. 본 발명의 조성물은 경구 투여, 복강 내 투여, 정맥내 투여, 근육내 투여, 피하 투여, 피내 투여, 비내 투여, 폐내 투여, 직장내 투여, 강내 투여, 복강내 투여, 경막내 투여될 수 있으나, 이에 제한되지는 않는다. 본 발명에 따른 약학 조성물은 일 회 투여될 수도 있고, 또는 일정한 시간 간격을 두고 2회, 3회 또는 그 이상으로 투여될 수도 있다. In the present invention, "administration" means introducing the pharmaceutical composition of the present invention to a patient by any suitable method, and the administration route of the composition of the present invention may be administered through any general route as long as it can reach the target tissue. . The composition of the present invention may be administered by oral administration, intraperitoneal administration, intravenous administration, intramuscular administration, subcutaneous administration, intradermal administration, intranasal administration, intrapulmonary administration, rectal administration, intraperitoneal administration, intraperitoneal administration, intrathecal administration, However, the present invention is not limited thereto. The pharmaceutical composition according to the present invention may be administered once, or may be administered twice, three times or more at regular time intervals.
혈관 신생 관련 환질의 종류나 투여 형태, 그리고 치료 효과 등을 고려하여 당업자에게 통상적으로 알려진 다양한 방법에 따라 본 발명에 따른 약학 조성물을 적절히 투여할 수 있으며, 바람직하게는 일일 1회 또는 일정한 시간 간격을 두고 일일 2회 이상 투여될 수 있다. The pharmaceutical composition according to the present invention may be appropriately administered according to various methods commonly known to those skilled in the art in consideration of the type or dosage form of the angiogenesis-related disease, the therapeutic effect, etc., preferably once a day or at a certain time interval. It can be administered twice or more per day.
본 발명의 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도 등에 따 라 그 범위가 다양할 수 있으나, 바람직하게는 0.1 내지 100mg/kg/day 이며, 보다 바람직하게는 10 내지 40mg/kg/day이다.The dosage of the composition of the present invention may vary depending on the patient's weight, age, sex, health status, diet, administration time, administration method, excretion rate and severity of disease, etc., but preferably 0.1 to 100 mg /kg/day, more preferably 10 to 40 mg/kg/day.
본 발명은 또한, SFD 화합물 또는 이의 유도체를 유효성분으로 포함하는 혈관신생 관련 질환의 개선 또는 예방용 건강 기능 식품 조성물을 제공한다.The present invention also provides a health functional food composition for improving or preventing angiogenesis-related diseases comprising an SFD compound or a derivative thereof as an active ingredient.
본 발명의 식품 조성물은 환제, 분말, 과립, 침제, 정제, 캡슐 또는 액제 등의 형태를 포함할 수 있으며, 본 발명의 식품 조성물에 첨가할 수 있는 식품의 종류에는 별다른 제한이 없으며, 예를 들어 각종 음료, 껌, 차, 비타민 복합제, 건강보조 식품류 등이 있다. The food composition of the present invention may include the form of pills, powders, granules, needles, tablets, capsules or liquids, and there is no particular limitation on the type of food that can be added to the food composition of the present invention, for example, Various beverages, chewing gum, tea, vitamin complexes, and health supplements are available.
상기 식품 조성물에는 본 발명의 SFD 화합물 또는 이의 유도체 이외에도 다른 성분을 추가할 수 있으며, 그 종류는 특별히 제한되지 않는다. 예를 들어, 통상의 식품과 같이 여러 가지 생약 추출물, 식품학 적으로 허용가능한 식품 보조첨가제 또는 천연 탄수화물 등을 추가 성분으로서 포함할 수 있으며, 이에 제한되지 않는다. In addition to the SFD compound or derivative thereof of the present invention, other ingredients may be added to the food composition, and the type thereof is not particularly limited. For example, it may include, as an additional ingredient, various herbal extracts, food pharmaceutically acceptable food supplements or natural carbohydrates, such as conventional food, but is not limited thereto.
상기 "식품보조첨가제"는 식품에 보조적으로 첨가될 수 있는 구성요소로서, 각 제형의 건강기능식품을 제조하는데 첨가될 수 있으며 당업자가 적절히 선택하여 사용할 수 있다. 식품보조첨가제의 예로는 여러 가지 영양제, 비타민, 광물(전해질), 합성 풍미제 및 천연 풍미제 등의 풍미제, 착색제 및 충진제, 펙트산 및 그의 염, 알긴산 및 그의 염, 유기산, 보호성 콜로이드 증점제, pH 조절제, 안정화제, 방부제, 글리세린, 알코올, 탄산음료에 사용되는 탄산화제 등이 포함되지만, 상기 예들에 의해 본 발명의 식품보조첨가제의 종류가 제한되는 것은 아니다. The "food supplement additive" is a component that can be added auxiliary to food, it can be added to the manufacture of health functional food of each formulation, and can be appropriately selected and used by those skilled in the art. Examples of food supplement additives include various nutrients, vitamins, minerals (electrolytes), synthetic flavoring agents and flavoring agents such as natural flavoring agents, coloring agents and fillers, pectic acid and salts thereof, alginic acid and salts thereof, organic acids, protective colloidal thickeners , pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonation agents used in carbonated beverages, etc., but the above examples are not limited to the types of food supplement additives of the present invention.
상기 "천연 탄수화물"의 예는 포도당, 과당 등의 단당류; 말토스, 수크로스 등의 이당류; 및 덱스트린, 시클로덱스트린 등의 다당류와, 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이 있으며, 상기한 것 이외의 향미제로서 천연 향미제(타우마틴 등), 스테비아 추출물(레바우디오시드 A, 글리시르히진 등) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다.Examples of the "natural carbohydrate" include monosaccharides such as glucose and fructose; disaccharides such as maltose and sucrose; and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol, and erythritol. hygin, etc.) and synthetic flavoring agents (saccharin, aspartame, etc.) may be used.
본 발명은, 수라민의 단편을 이용하여 혈관내피성장인자를 억제하는 새로운 화합물을 제시한다.The present invention provides a novel compound that inhibits vascular endothelial growth factor using a fragment of suramin.
본 발명의 화합물은 저분자의 형태로 혈관내피성장인자(VEGF)의 헤파린 결합자리와 유효하게 결합하여 VEGF의 활성을 억제하는 효과가 있다.The compound of the present invention has the effect of inhibiting the activity of VEGF by effectively binding to the heparin binding site of vascular endothelial growth factor (VEGF) in the form of a small molecule.
본 발명에 따라 제조된 조성물은 VEGF의 활성을 억제하여 혈관 신생 관련 질환의 치료, 예방, 개선에 효과적이다.The composition prepared according to the present invention is effective for the treatment, prevention, and improvement of angiogenesis-related diseases by inhibiting the activity of VEGF.
도 1은 본 발명의 일 실시예에 따른 수라민 단편과 디옥시콜산의 결합 화합물(SFD) 합성 이미지를 나타낸다. 도 1에서는 한 단계만으로 수라민 단편과 디옥시콜산(DOCA)이 결합될 수 있음을 나타낸다.
도 2는 본 발명의 일 실시예에 따라 SFD(용매로서 중수소 산화물), 수라민 단편(용매로서 중수소 산화물) 및 DOCA (용매로서 디메틸설폭사이드-d6)(500MHz)의 1H-NMR 스펙트럼을 확인한 이미지이다.
도 3의 a는 헤파린 단편 및 디옥시콜산의 결합 화합물(HFD)과 비교하여 수라민 단편 및 디옥시콜산 결합 화합물(SFD)의 혈관 상피 성장 인자(VEGF) 내 헤파린 결합 부위에 대한 결합을 나타낸 모식도이다. 도 3의 b는 SFD와 HFD의 표면 전하는 분자 결합에서 유사성을 나타낸 이미지이다.
도 4는 VEGF에서 헤파린 결합 부위의 분자 구조를 이용하여 결합 시뮬레이션을 나타낸 이미지이다. 도 4의 a는, 2 내지 16 범위의 상이한 중합도(DP, degrees of polymerization)를 갖는 선택된 헤파린 다당류에 대해 계산된 결합 친화도를 나타낸다. 도 4의 a를 참조하면, 더 작은(낮은 DP) 헤파린은 더 낮은 결합 에너지를 나타내는 경향이 있다. 도 4의 b는 VEGF의 헤파린 결합 부위에 대한 수라민 단편, DOCA 및 SFD의 결합 에너지 시뮬레이션 결과를 나타내며, 강화된 결합에너지는 SFD에서 특히 분명함을 나타낸다. 도 4의 b를 참조하면, SFD는 수라민 단편 (헤파린 모방 체)과 디옥시콜산 (DOCA)을 모두 가지고 있기 때문에 VEGF에 결합하는 데 적합함을 알 수 있다. 도 4의 c는 VEGF를 사용한 헤파린 단편(DP 2) 또는 SFD에 대한 결합 시뮬레이션을 나타내며, SFD가 결합에 적합한 적절한 분자 크기 및 구조를 가지고 있음을 알 수 있다. 특히, SFD의 수라민 단편은 HBD와 많은 수소 결합을 나타내는 반면 DOCA는 강한 소수성 상호 작용을 나타낸다. 도 4의 d는 HBD의 결합 부위에서 SFD의 에너지 최소화된 형태를 나타낸 구조도이다. SFD와 VEGF 사이에는 다양한 파이-파이 상호 작용이 있다. 특히 HBD에서 아르기닌을 포함한 친수성 펩타이드는 SFD와 다양한 상호 작용을 보인다. 도 4에서 SFD의 분자 결합 상호 작용은 BIOVIA Discovery Studio (2020)를 사용하여 계산되었다.
도 5는 저분자량 헤파린 (LMWH, 도 5의 a), 저분자량 헤파린 및 DOCA 접합체(LHD, 도 5의 b), 헤파린 단편 및 DOCA 접합체 (HFD, 도 5의 c) 및 CM5 칩 상에 VEGF로 고정된 HEPES(hydroxyethyl piperazineethanesulfonic acid)-완충 용액 내의 SFD(도 5의 d) 에 대한 상대 표면 플라스몬 공명 (SPR) 반응을 확인한 그래프이다. 도 5에서 친화도 곡선은 Biacore T100 평가 소프트웨어를 사용하여 그려졌다.
도 6은 인간 제대 정맥 내피 세포(HUVEC) 분석에서 헤파린 및 SFD에 의한 혈관 신생 억제를 확인한 이미지이다. 도 6의 a는 HUVEC의 시험관 내 관 형성을 Calcein-AM 처리 후 나타낸 이미지이다. 도 6의 b는 LMWH, LHD, HFD 또는 SFD (n = 4)의 존재 하에서 HUVEC의 혈관 수를 측정한 결과이다. 6의 c는 본 발명의 일 실시예에 따른 세포 독성 시험 (CCK 분석)의 결과이며, 헤파린 접합체와 SFD가 세포에 대한 세포 독성 효과가 없음을 확인하였다 n = 6). 도 6의 d는 본 발명의 일 실시예에 따른 VEGF 매개 상처 치유 분석 결과 이미지이며, SFD가 상처로의 내피 세포 이동을 억제할 수 있음을 보여준다. 도 6에서 상대적 치유된 상처 부위는 ImageJ 프로그램 (미국 국립 보건원)을 사용하여 톨루이딘블루로 처리한 후 측정되었다(n = 3).1 shows a composite image of a suramin fragment and deoxycholic acid binding compound (SFD) according to an embodiment of the present invention. 1 shows that the suramin fragment and deoxycholic acid (DOCA) can be combined with only one step.
2 is a 1 H-NMR spectrum of SFD (deuterium oxide as a solvent), a suraamine fragment (deuterium oxide as a solvent) and DOCA (dimethylsulfoxide-d6 as a solvent) (500 MHz) according to an embodiment of the present invention. It is an image.
3a is a schematic diagram showing the binding of suramin fragment and deoxycholic acid-binding compound (SFD) to heparin binding sites in vascular epithelial growth factor (VEGF) compared to heparin fragment and deoxycholic acid-binding compound (HFD); to be. Figure 3b is an image showing the similarity in the molecular bonding of the surface charges of SFD and HFD.
4 is an image showing a binding simulation using the molecular structure of the heparin binding site in VEGF. Figure 4a shows the calculated binding affinities for selected heparin polysaccharides with different degrees of polymerization (DP) ranging from 2 to 16. Referring to Figure 4a, smaller (lower DP) heparin tends to show lower binding energy. Figure 4b shows the binding energy simulation results of the suramin fragment, DOCA and SFD for the heparin binding site of VEGF, indicating that the enhanced binding energy is particularly clear in SFD. Referring to FIG. 4 b, it can be seen that SFD is suitable for binding to VEGF because it has both a suramin fragment (heparin mimic) and deoxycholic acid (DOCA). 4c shows a simulation of binding to a heparin fragment (DP 2) or SFD using VEGF, it can be seen that SFD has an appropriate molecular size and structure suitable for binding. In particular, the suramin fragment of SFD exhibits many hydrogen bonds with HBD whereas DOCA exhibits strong hydrophobic interactions. 4d is a structural diagram showing the energy-minimized form of SFD at the binding site of HBD. There are various pi-pi interactions between SFD and VEGF. In particular, hydrophilic peptides including arginine in HBD show various interactions with SFD. Molecular binding interactions of SFD in Fig. 4 were calculated using BIOVIA Discovery Studio (2020).
5 shows low molecular weight heparin (LMWH, FIG. 5 a), low molecular weight heparin and DOCA conjugate (LHD, FIG. 5 b), heparin fragment and DOCA conjugate (HFD, FIG. 5 c) and VEGF on CM5 chip. It is a graph confirming the relative surface plasmon resonance (SPR) response to SFD (FIG. 5 d) in immobilized hydroxyethyl piperazineethanesulfonic acid (HEPES)-buffered solution. Affinity curves in FIG. 5 were drawn using the Biacore T100 evaluation software.
6 is an image confirming the inhibition of angiogenesis by heparin and SFD in human umbilical vein endothelial cell (HUVEC) analysis. 6A is an image showing tube formation of HUVECs in vitro after Calcein-AM treatment. 6B is a result of measuring the number of blood vessels in HUVECs in the presence of LMWH, LHD, HFD, or SFD (n = 4). 6 c is the result of the cytotoxicity test (CCK analysis) according to an embodiment of the present invention, and it was confirmed that the heparin conjugate and SFD had no cytotoxic effect on cells (n = 6). 6 d is an image of a VEGF-mediated wound healing assay according to an embodiment of the present invention, showing that SFD can inhibit endothelial cell migration into a wound. In FIG. 6 , the relative healed wound area was measured after treatment with toluidine blue using the ImageJ program (National Institute of Health, USA) (n = 3).
이하 실시예를 참조하여 본 발명을 더욱 구체적으로 설명한다. 하기 실시예는 본 발명을 설명하기 위한 것일 뿐, 본 발명의 범위가 하기 실시예에 의해 한정되는 것은 아니다. The present invention will be described in more detail with reference to Examples below. The following examples are only for illustrating the present invention, and the scope of the present invention is not limited by the following examples.
[실시예 1][Example 1]
1-1. 재료 준비1-1. material preparation
수라민 단편(disodium 8-amino-1,3,6-naphthalenetrisulfonate)은 TCI (Tokyo, Japan)에서 구입했다. 디옥시콜산 (DOCA), 디메틸포름아미드 (DMF), 포름아미드, 미분획 헤파린(unfractionated heparin), 톨루이딘 블루 및 1-ethyl-3-(3-(dimethylaminopropyl) carbodiimide (EDAC)는 Sigma Aldrich (St. Louis, MO, USA)에서 구입하였다. 저분자량 헤파린 (Nadroparin)은 Nanjing King-Friend Biochemical Pharmaceutical Company Ltd. (중국 난징)에서 구입했으며 재조합 혈관 내피 성장 인자 165 (VEGF)는 Peprotech (미국 뉴저지 주 록키 힐)에서 구입하였다. 센서 칩과 러닝 버퍼는 GE 헬스 케어 (스웨덴 웁살라)에서, 내피 성장 배지-2 (EGM-2)는 Lonza (미국 메사추세츠 주 워커 스빌)에서 구입했으며 Matrigel은 BD Bioscience에서 구입하였다. 본 발명에서 모든 시약은 추가 정화없이 사용되었다.Suramin fragment (disodium 8-amino-1,3,6-naphthalenetrisulfonate) was purchased from TCI (Tokyo, Japan). Deoxycholic acid (DOCA), dimethylformamide (DMF), formamide, unfractionated heparin, toluidine blue and 1-ethyl-3-(3-(dimethylaminopropyl) carbodiimide (EDAC) were obtained from Sigma Aldrich (St. Louis, MO, USA) Low molecular weight heparin (Nadroparin) was purchased from Nanjing King-Friend Biochemical Pharmaceutical Company Ltd. (Nanjing, China) and recombinant vascular endothelial growth factor 165 (VEGF) was obtained from Peprotech (Rocky Hill, NJ, USA). The sensor chip and running buffer were purchased from GE Healthcare (Uppsala, Sweden), endothelial growth medium-2 (EGM-2) was purchased from Lonza (Walkersville, MA, USA), and Matrigel was purchased from BD Bioscience. All reagents in the present invention were used without further purification.
1-2. 세포 배양1-2. cell culture
인간 제대 정맥 내피 세포 (HUVEC)는 Promocell (독일 하이델베르그)에서 입수하였다. 상기 세포는 하이드로 코르티손, 아스코르브산, 2% 소 태아 혈청 (FBS) (GIBCO, NY, USA) 및 인간 표피 성장 인자, 혈관 내피 성장 인자 및 인간 섬유 아세포 성장 인자를 포함하여 다양한 성장 인자를 포함하는 SupplementMix (Promocell)와 함께 EGM-2에서 유지 및 배양하였다. 상기 세포는 37 ℃에서 5 % CO2 (95 % 공기)와 함께 CO2 배양기에서 배양되었다.Human umbilical vein endothelial cells (HUVEC) were obtained from Promocell (Heidelberg, Germany). The cells were prepared from a SupplementMix containing hydrocortisone, ascorbic acid, 2% fetal bovine serum (FBS) (GIBCO, NY, USA) and various growth factors including human epidermal growth factor, vascular endothelial growth factor and human fibroblast growth factor. (Promocell) was maintained and cultured in EGM-2. The cells were incubated in a CO 2 incubator with 5% CO 2 (95% air) at 37 °C.
[실시예 2][Example 2]
2-1. 수라민 단편 및 디옥시콜산(deoxycholic acid) 결합 화합물(SFD)의 합성 및 특성화2-1. Synthesis and characterization of suramin fragments and deoxycholic acid binding compounds (SFDs)
디옥시콜산(100 mg)을 실온에서 DMF(0.9 mL)로 제조하였다. 열처리된 포름 아미드 (2 mL)를 사용하여 친수성 수라민 단편 (20 mg)을 용해시켰다. 그 후, DMF와 포름아마이드 용액을 2 분 동안 함께 혼합하였다. 과량(45mg)의 EDAC를 용액에 첨가하여 아미드 형성 반응을 시작한 다음 실온에서 12 시간 동안 추가로 배양하였다. 이후, 여과하기 전 증류수 (10 mL)를 용액에 첨가하였다. 용액을 동결 건조하여 분말을 얻고 증류수에 녹였다. 해당 혼합물을 아세톤/에탄올 (1 : 2) 공용매에 침전시켜 미반응 물질을 제거하였다.Deoxycholic acid (100 mg) was prepared in DMF (0.9 mL) at room temperature. Heat-treated formamide (2 mL) was used to dissolve the hydrophilic suramin fragment (20 mg). Then, the DMF and formamide solution were mixed together for 2 minutes. An excess (45 mg) of EDAC was added to the solution to initiate the amide formation reaction, followed by further incubation at room temperature for 12 hours. Then, distilled water (10 mL) was added to the solution before filtration. The solution was freeze-dried to obtain a powder and dissolved in distilled water. The mixture was precipitated in acetone/ethanol (1:2) cosolvent to remove unreacted substances.
합성된 수라민 단편과 디옥시콜산 결합 화합물의 반응 및 순도를 박막 크로마토 그래피 (TLC)로 모니터링한 다음 TLC- 뷰잉 UV 캐비닛에서 UV 조사하였다. 최종 생성물의 분자 구조는 1H NMR 분광법으로 확인하였다. 1H NMR 스펙트럼은 중수소 산화물 (Sigma Aldrich) 또는 디메틸설폭사이드-d6 (Sigma Aldrich)를 용매로 사용하여 500MHz에서 기록되었다.The reaction and purity of the synthesized suramin fragment and the deoxycholic acid-binding compound were monitored by thin layer chromatography (TLC), followed by UV irradiation in a TLC-viewing UV cabinet. The molecular structure of the final product was confirmed by 1 H NMR spectroscopy. 1 H NMR spectra were recorded at 500 MHz using deuterium oxide (Sigma Aldrich) or dimethylsulfoxide-d6 (Sigma Aldrich) as solvents.
헤파린 단편과 헤파린 접합체는 앞서 설명한 방법으로 제조되었다.Heparin fragments and heparin conjugates were prepared by the method described above.
2-2. 수라민 단편 및 디옥시콜산(deoxycholic acid) 결합 화합물(SFD)의 설계 및 특성화2-2. Design and characterization of suramin fragments and deoxycholic acid binding compounds (SFDs)
종전의 연구에 따르면 일련의 헤파린-DOCA 접합체가 VEGF 활성의 강력한 억제제로 사용될 수 있다고 보고된다. 본 발명에서는 종양에서 혈관 신생 과정을 차단하기위한 저분자의 합성 VEGF 억제제(항암제)를 개발하였다. 헤파린은 생리학적 조건에서 VEGF의 헤파린 결합 부위에 결합할 수 있으므로 도 3에 나타난 바와 같이 수라민 단편을 사용하여 새로운 작은 헤파린 유사 혈관 신생 억제제를 설계하였다. 헤파린-DOCA의 치료 활성에 대한 기존의 이론들 개선하기 위해 본 발명자들은 VEGF의 헤파린 결합 부위에 결합할 수 있는 새로운 작은 접합체를 개발하여 헤파린의 복잡성을 제거하였다. SFD의 분자 길이는 약 19Å이고 VEGF의 HBD (15-25Å) 길이는 크기가 비슷하기 때문에 VEGF 결합에 최적인 것으로 간주된다. 수라민 단편과 DOCA를 사용하는 SFD의 합성은 한 단계로 간단하게 완료할 수 있으며 헤파린과 달리 거대 분자의 복잡성을 포함하지 않는다(도 1). 합성 및 정제 후 SFD 구조의 DOCA 모이어티는 1D 양성자 NMR 분석으로 확인하였다(도 2). 두 생체 분자의 분자 구조와 표면 전하는 SFD의 수라민 단편이 헤파린 모방체로서 VEGF의 헤파린 결합 부위와 결합할 수 있음을 보여준다. 소수성 DOCA는 그들 사이의 결합을 강화하는 역할을 한다(도 3의 b).Previous studies have reported that a series of heparin-DOCA conjugates can be used as potent inhibitors of VEGF activity. In the present invention, a low-molecular synthetic VEGF inhibitor (anticancer agent) was developed to block angiogenesis in tumors. Since heparin can bind to the heparin binding site of VEGF under physiological conditions, a novel small heparin-like angiogenesis inhibitor was designed using a suramin fragment as shown in FIG. 3 . In order to improve the existing theories on the therapeutic activity of heparin-DOCA, the present inventors developed a new small conjugate capable of binding to the heparin binding site of VEGF, thereby eliminating the complexity of heparin. The molecular length of SFD is about 19 Å and the length of HBD (15-25 Å) of VEGF is similar in size, so it is considered optimal for VEGF binding. The synthesis of SFD using suramin fragments and DOCA can be completed in one simple step and, unlike heparin, does not involve macromolecular complexity (Fig. 1). After synthesis and purification, the DOCA moiety of the SFD structure was confirmed by 1D proton NMR analysis ( FIG. 2 ). The molecular structure and surface charge of the two biomolecules show that the suramin fragment of SFD can bind to the heparin binding site of VEGF as a heparin mimic. The hydrophobic DOCA serves to strengthen the bond between them (Fig. 3b).
[실시예 3][Example 3]
3-1. In silico 분석3-1. In silico analysis
VEGF (PDB 코드: 2VGH)의 HBD 분자 구조는 이전 연구에서 보고되었다. 구조는 도킹 분석을 위해 AutoDockTools 패키지 프로그램에 의해 시각화되고 최적화되었다.The HBD molecular structure of VEGF (PDB code: 2VGH) was reported in a previous study. The structure was visualized and optimized by the AutoDockTools package program for docking analysis.
헤파린의 분자 구조의 경우, 저분자량 헤파린 (LMWH), LMWH- 디옥시콜산 접합체(LHD), 헤파린 단편-DOCA 접합체(HFD) 및 SFD는 ChemDraw Professional 15.1 (Cambridge Soft, CA, 미국)를 사용하여 나타냈다. 분자 구조는 Chem3D 15.1 (Cambridge Soft, CA, USA)에 의해 변환되고 추가로 안정화되었다.For the molecular structure of heparin, low molecular weight heparin (LMWH), LMWH-deoxycholic acid conjugate (LHD), heparin fragment-DOCA conjugate (HFD) and SFD were shown using ChemDraw Professional 15.1 (Cambridge Soft, CA, USA). . The molecular structure was transformed and further stabilized by Chem3D 15.1 (Cambridge Soft, CA, USA).
생체 분자와 VEGF 간의 분자 도킹 시뮬레이션은 AutoDock Vina 1.0.3을 사용하여 수행되었다. 도킹 설정에서 헤파린 또는 SFD의 모든 회전 가능한 결합은 자유로이 유지되는 반면 HBD는 단단하게 유지되고 그리드 치수 40 X 30 X 26 은 다음 좌표를 갖는다: x = - 4.3, y = 6.0 및 z = 6.6. 마지막으로 BIOVIA Discovery Studio 2020을 사용하여 SFD의 바인딩 포켓 캐비티의 부피를 계산하였다.Molecular docking simulations between biomolecules and VEGF were performed using AutoDock Vina 1.0.3. In a docking setup, all rotatable bonds of heparin or SFD remain free while the HBD remains rigid and grid dimensions 40 X 30 X 26 has the following coordinates: x = - 4.3, y = 6.0 and z = 6.6. Finally, the volume of the binding pocket cavity of the SFD was calculated using BIOVIA Discovery Studio 2020.
생체 분자 또는 VEGF의 3D 분자 구조는 BIOVIA Discovery Studio 및 PyMOL 프로그램 (PyMOL 분자 그래픽 버전 1.7.0.1; Schrφdinger, LLC)에 의해 시뮬레이션되었다.The 3D molecular structure of biomolecules or VEGF was simulated by BIOVIA Discovery Studio and the PyMOL program (PyMOL Molecular Graphics version 1.7.0.1; Schrφdinger, LLC).
3-2. VEGF의 헤파린 결합 부위에 대한 SFD의 결합 시뮬레이션3-2. Binding simulation of SFD to the heparin binding site of VEGF
VEGF에 결합하기위한 헤파린의 적절한 크기를 결정하기 위해 본 발명자들은 헤파린과 VEGF의 헤파린 결합 부위 간의 상호 작용에 대한 분자적 기초를 연구했다. 본 실험에서는 분자 도킹 시뮬레이션을 통해 크기가 다른 헤파린의 결합 에너지를 스크리닝하였다. 다양한 소형 헤파린의 도킹을 테스트한 결과 작은 헤파린 분자가 VEGF의 헤파린 결합 부위에 상대적으로 강한 결합을 나타내는 것으로 밝혀졌다 (도 4의 a). 가장 일반적으로 사용되는 헤파린인 LMWH는 대략적인 중합도(DP, degree of polymerization)가 16이지만 VEGF의 헤파린 결합 부위에 결합하는 경우 더 크게 나타난다. 분자 결합 연구에 따르면 작은 헤파린 (DP 2-5)은 LMWH (Ad3.8 kcal/mol)보다 VEGF(-5.6 ~ -6.8 kcal/mol)에 대해 더 높은 결합 친화성을 갖는다. 도 4의 a를 참조하면 헤파린 올리고당의 길이가 DP 16에서 DP 2로 감소함에 따라 결합 에너지가 감소하여 헤파린 결합 부위에 결합하도록 최적화(크기가 작게) 될 수 있음을 알 수 있다. 더욱이, 수라민 단편과 DOCA는 각각 헤파린과 유사한 특성과 강한 소수성 상호 작용으로 인해 낮은 결합 친화도(-6.0kcal/mol)를 나타냈다 (도 4의 b). 특히, SFD는 수라민 단편과 소수성 DOCA를 통해 VEGF의 헤파린 결합 자리에 결합하여 결합을 안정화시킬 수 있어 VEGF에 대한 상대적으로 강한 결합 (낮은 결합 에너지 값)을 보였다. 도 4의 c에 나타난 바와 같이, SFD는 VEGF 분자 구조에서 헤파린 결합 포켓에 결합하기에 적절한 크기이며, SFD와 VEGF의 결합은 다중 분자간 상호 작용을 나타냈다. 도킹 결과는 8-아미노-1,3,6-나프탈렌트리설포네이트(8-amino-1,3,6-naphthalenetrisulfonate) 그룹(수라민 단편)이 입체 충돌(steric conflicts)없이 DOCA의 소수성 상호 작용을 유지하면서 HBD의 포켓을 차지할 수 있음을 시사한다. 대부분의 상호 작용은 기존의 친수성 수소 결합이었지만 Arg46 및 Arg14 잔기는 파이-알킬 상호 작용을 나타냈다 (도 4의 d). 특히 HBD의 Arg31과 Arg14는 SFD와 분자간 수소 결합을 나타낸다. 종합하면, 시뮬레이션 결과는 작은 합성 SFD가 혈관 신생을 조절하기 위해 VEGF의 억제를 위해 구조적으로 설계된 약물 후보로 사용될 수 있음을 알 수 있다.To determine the appropriate size of heparin for binding to VEGF, we studied the molecular basis for the interaction between heparin and the heparin binding site of VEGF. In this experiment, the binding energies of heparin of different sizes were screened through molecular docking simulation. As a result of testing the docking of various small heparin, it was found that small heparin molecules exhibit relatively strong binding to the heparin binding site of VEGF (FIG. 4a). LMWH, the most commonly used heparin, has an approximate degree of polymerization (DP) of 16, but appears larger when it binds to the heparin binding site of VEGF. Molecular binding studies have shown that small heparin (DP 2-5) has a higher binding affinity for VEGF (-5.6 to -6.8 kcal/mol) than for LMWH (Ad3.8 kcal/mol). Referring to FIG. 4A , it can be seen that as the length of the heparin oligosaccharide decreases from DP 16 to
[실시예 4][Example 4]
4-1. 표면 플라즈몬 공명 (SPR) 분석4-1. Surface Plasmon Resonance (SPR) Analysis
SPR 결합 분석 방법은 VEGF와 생체 분자 간의 분자 상호 작용을 연구하는 데 사용되었다. 결합 친화도는 Biacore T100 기기(Biacore AB, Uppsala, Sweden)를 사용하여 측정되었다. 재조합 인간 VEGF165(Peprotech, Rocky Hill, NJ, USA)는 표준 EDC/NHS 커플링 반응에 의해 CM5 칩(Biacore carboxymethylated dextran 센서)의 금 표면에 고정되었다. The SPR binding assay method was used to study the molecular interactions between VEGF and biomolecules. Binding affinity was measured using a Biacore T100 instrument (Biacore AB, Uppsala, Sweden). Recombinant human VEGF165 (Peprotech, Rocky Hill, NJ, USA) was immobilized on the gold surface of a CM5 chip (Biacore carboxymethylated dextran sensor) by standard EDC/NHS coupling reaction.
SPR의 친화도 분석은 HEPES-EP running 버퍼 (HEPES 10 mM, sodium chloride 150 mM, EDTA 3 mM, 및 0.05% P-20)에서 0.001 ~ 1 uM 범위의 농도 (LMWH, 4500 Da; LHD, 6000 Da; HFD, 2500 Da; SFD, 802 Da)에서 헤파린, HFD 및 SFD에 대해 수행되었다. 결합 분석은 20 uL/min (37℃)의 유속으로 수행되었으며, VEGF 단백질은 NaOH 용액 (50mM)으로 5 초 동안 재생되었습니다. 결합 데이터는 Biacore T100 평가 소프트웨어를 사용하여 친화성 특성에 대해 분석되었다. 도 5의 곡선은 Biacore 소프트웨어를 사용하여 1:1 Langmuir 바인딩 모델에 따라 맞춰졌다.Affinity analysis of SPR was performed at concentrations ranging from 0.001 to 1 uM (LMWH, 4500 Da; LHD, 6000 Da) in HEPES-EP running buffer (
4-2. 표면 플라즈몬 공명(SPR) 방법을 통한 VEGF 결합 확인4-2. Confirmation of VEGF binding by surface plasmon resonance (SPR) method
VEGF에 대한 SFD의 특이성을 확인하기 위해 표면 플라즈몬 공명 분석을 통해 헤파린과 SFD의 결합 친화도를 평가하였다. 다양한 헤파린과 VEGF의 지배적인 분자 상호 작용은 VEGF에 대한 많은 구조 분석 연구에서 확인되었다. 본 발명자들은 새로운 헤파린 모방 DOCA 접합체(SFD)와 헤파린 단편 (HF) 또는 헤파린 단편과 DOCA 접합체(HFD)를 SFD와 비교했다. 처음에는 VEGF를 CM5 골드 SPR 칩에 결합한 다음 헤파린, HFs, HFD 또는 SFD를 흐르게하여 VEGF와의 실제 결합 에너지를 계산했다.To confirm the specificity of SFD to VEGF, the binding affinity of heparin and SFD was evaluated through surface plasmon resonance analysis. The dominant molecular interactions of various heparins with VEGF have been confirmed in many structural analysis studies of VEGF. We compared novel heparin-mimicking DOCA conjugates (SFD) and heparin fragments (HF) or heparin fragments and DOCA conjugates (HFD) to SFD. The actual binding energy with VEGF was calculated by first binding VEGF to a CM5 gold SPR chip and then flowing heparin, HFs, HFD or SFD.
결과적으로 저분자량 헤파린 (171.4 nM) 및 헤파린 단편 (157.6 nM)의 KD (해리 상수) 값은 VEGF165에 대해 높은 친화성을 보여 헤파린이 VEGF의 헤파린 결합 도메인에 결합할 수 있음을 나타낸다(도 5의 a 및 b). HFD는 DOCA 부분의 존재로 인해 저분자량 헤파린 또는 헤파린 단편보다 VEGF (KD = 25.6 nM)에 대해 더 높은 결합 친화성을 갖는다. 담즙산 접합(conjugation)은 일반적으로 VEGF에 대한 헤파린의 결합 친화성 또는 억제 효과를 향상시킨다 (도 5의 c). SFD의 경우 VEGF에 대해 가장 낮은 KD 값 (3.8 nM)을 보였으며 이는 혈관 신생 효과에 효과적인 VEGF 억제제가 될 수 있음을 나타낸다 (도 5의 d). SFD는 헤파린 단편과 유사하게 3 개의 술폰기(sulfone group)를 가지고 있으며, 이는 헤파린 결합 부위에 안정적으로 부착되고 VEGF에 지속적으로 결합할 수 있다.As a result, the K D (dissociation constant) values of the low molecular weight heparin (171.4 nM) and the heparin fragment (157.6 nM) show high affinity for VEGF 165 , indicating that heparin can bind to the heparin-binding domain of VEGF (Fig. 5 a and b). HFD has a higher binding affinity for VEGF (K D = 25.6 nM) than low molecular weight heparin or heparin fragments due to the presence of the DOCA moiety. Bile acid conjugation generally enhances the binding affinity or inhibitory effect of heparin to VEGF ( FIG. 5 c ). In the case of SFD, it showed the lowest K D value (3.8 nM) for VEGF, indicating that it can be an effective VEGF inhibitor for angiogenic effects (FIG. 5d). SFD has three sulfone groups similar to the heparin fragment, which is stably attached to the heparin binding site and can continuously bind to VEGF.
[실시예 5][Example 5]
5-1. 세포 생존력 테스트 (CCK 분석)5-1. Cell viability test (CCK assay)
SFD 및 기타 분자의 세포 독성을 평가하기 위해 HUVEC를 96-웰 플레이트에서 배양하였다. 96-웰 플레이트가 HUVEC와 합류할 때 배지는 성장 인자없이 LMWH, LHD, HFD 및 SFD의 다른 농도(200 및 800 ug/mL)를 포함하는 내피 성장 배지-2 (EGM-2)로 대체되었다. 37℃에서 12 시간 동안 배양한 후 EGM MV2 배지를 제거하고, 10 uL의 세포 계수 키트-8 (CCK-8) 용액이 포함된 EBM (내피 기저 배지) 배지를 플레이트에 첨가하여 1 시간 동안의 생존력을 분석하였다. HUVEC 생존력은 ELISA 판독기(n = 6)를 사용하여 흡광도 값(450 nm)에서 계산되었다.To evaluate the cytotoxicity of SFD and other molecules, HUVECs were cultured in 96-well plates. When the 96-well plate was confluent with HUVECs, the medium was replaced with endothelial growth medium-2 (EGM-2) containing different concentrations (200 and 800 ug/mL) of LMWH, LHD, HFD and SFD without growth factors. After incubation at 37°C for 12 hours, the EGM MV2 medium was removed, and EBM (endothelial basal medium) medium containing 10 uL of Cell Counting Kit-8 (CCK-8) solution was added to the plate to ensure viability for 1 hour. was analyzed. HUVEC viability was calculated from absorbance values (450 nm) using an ELISA reader (n = 6).
5-2. 내피 관(Endothelial Tubular) 형성 억제능 분석5-2. Endothelial Tubular Formation Inhibitory Analysis
HUVEC는 보충된 EGM MV2 배지와 함께 T-플라스크에서 4 일 동안 배양되었다. 그 후 EDTA/트립신 처리로 세포를 분리하고 마트리겔-코팅 (37 ℃에서 30 분 동안) 96-웰 플레이트(웰당 2 X 104개 세포)에 놓았다. 세포를 VEGF165 (60 ng / mL) 및 LMWH, LHD, HFD 또는 SFD (50 ug / mL)와 함께 5 % FBS를 포함하는 100 uL의 EGM MV2 배지에서 배양하였다. 37℃에서 6 시간 동안 배양한 후, Calcein AM (Sigma Aldrich)을 30분 동안 첨가하여 HUVEC의 내피 관 형성을 시각화하였다. 완성된 혈관의 수는 공 초점 레이저 스캐닝 현미경 (CLSM)을 통해 계산되었다(n = 4).HUVECs were cultured for 4 days in T-flasks with supplemented EGM MV2 medium. Cells were then dissociated by EDTA/trypsin treatment and placed in matrigel-coated (37° C. for 30 min) 96-well plates (2×10 4 cells per well). Cells were cultured in 100 uL of EGM MV2 medium containing 5% FBS with VEGF 165 (60 ng/mL) and LMWH, LHD, HFD or SFD (50 ug/mL). After incubation at 37° C. for 6 hours, Calcein AM (Sigma Aldrich) was added for 30 minutes to visualize the endothelial tube formation of HUVECs. The number of completed vessels was counted via confocal laser scanning microscopy (CLSM) (n = 4).
5-3. VEGF 기반 상처 치유 억제 능력 분석5-3. Analysis of VEGF-based wound healing inhibition ability
HUVEC는 EDTA/트립신 처리 후 24 웰 플레이트에 파종되었다. 세포가 합류(confluence)에 도달할 때까지 보충된 EGM MV2 배지에서 세포를 배양하였다. HUVEC의 상처는 각 웰의 중앙에 1 mL 팁으로 균일하게 만들었다. 세포 파편을 제거하기 위해 EBM 용액으로 3 회 세척한 후 나머지 세포를 EGM MV2 배지 (40 ng / mL VEGF 및 5 % FBS)에서 다른 농도(40 또는 400 ug/mL)의 SFD 존재 하에 24 시간 동안 배양하였다. 그 후, 상층 액을 제거하고 세포를 차가운 4 % 파라 포름 알데히드 용액으로 10분 동안 고정시켰다. 3 회 세척 후 이동된 세포를 0.001 % 톨루이딘 블루 (Sigma Aldrich) 처리로 시각화하고 ImageJ (미국 국립 보건원) (n = 3)를 사용하여 상처 치유 영역을 측정하였다.HUVECs were seeded in 24-well plates after EDTA/trypsin treatment. Cells were cultured in supplemented EGM MV2 medium until the cells reached confluence. Wounds of HUVECs were made uniformly with a 1 mL tip in the center of each well. After washing 3 times with EBM solution to remove cell debris, the remaining cells were cultured in EGM MV2 medium (40 ng/mL VEGF and 5% FBS) in the presence of SFD at different concentrations (40 or 400 ug/mL) for 24 h. did. After that, the supernatant was removed and the cells were fixed with cold 4% paraformaldehyde solution for 10 min. After three washes, the migrated cells were visualized with 0.001% toluidine blue (Sigma Aldrich) treatment and the wound healing area was measured using ImageJ (National Institute of Health) (n = 3).
5-4. HUVEC에 대한 SFD의 혈관형성억제 효과 평가5-4. Evaluation of the angiogenesis inhibitory effect of SFD on HUVECs
HUVEC는 SFD의 혈관형성억제 효과를 시험관 내에서 조사하는 데 사용되었다. 처음에는 HUVEC를 Matrigel에서 VEGF와 함께 또는 없이 배양하여 VEGF의 혈관 신생 특성과 관련된 메커니즘을 결정했다. 예상대로 VEGF는 혈관 신생 과정을 분명히 촉진하고 시험관 내에서 혈관 형성을 증가시켰다(도 6의 a). 헤파린, LHD, HFD 및 SFD의 억제 효과를 확인하기 위해 VEGF 와 HUVECs를 처리했다. 그 결과 HUVEC의 상대적 혈관 형성은 VEGF 처리 군(100 %)에 비해 68.5 % (LMWH), 41.9 % (LHD), 25.2 % (HFD), 32.2 % (SFD) 감소했다 (도 6의 b). VEGF를 처리하지 않은 경우 HUVEC에 의한 혈관 형성이 부족한 것으로 나타났다(1.4 %).HUVECs were used to investigate the angiogenesis inhibitory effect of SFD in vitro. Initially, HUVECs were cultured in Matrigel with or without VEGF to determine the mechanisms involved in the angiogenic properties of VEGF. As expected, VEGF clearly promoted the angiogenic process and increased angiogenesis in vitro (Fig. 6a). To determine the inhibitory effect of heparin, LHD, HFD and SFD, VEGF and HUVECs were treated. As a result, the relative angiogenesis of HUVECs was reduced by 68.5% (LMWH), 41.9% (LHD), 25.2% (HFD), and 32.2% (SFD) compared to the VEGF-treated group (100%) (Fig. 6b). When VEGF was not treated, HUVEC-induced angiogenesis was found to be insufficient (1.4%).
헤파린, LHD, HFD 및 SFD의 세포 독성은 CCK 분석 (세포 계수 키트 -8 분석, 생존력 테스트)에 의해 HUVEC로 테스트되었다. 저농도(200 μg/mL) 및 고농도 (800 μg/mL)에서 세포 독성이 관찰되지 않았으며, 이는 낮은 독성으로 혈관 형성 과정을 억제했음을 나타낸다(도 6의 c).The cytotoxicity of heparin, LHD, HFD and SFD was tested with HUVECs by CCK assay (Cell Counting Kit-8 assay, viability test). No cytotoxicity was observed at low (200 μg/mL) and high (800 μg/mL) concentrations, indicating that the angiogenesis process was inhibited with low toxicity (Fig. 6c).
마지막으로 SFD가 VEGF 매개 내피 세포 이동에 영향을 미치는 방식을 연구하기 위해 SFD가 VEGF 매개 상처 치유 분석에 미치는 혈관형성억제 효과를 평가했습니다. VEGF에 의해 유도된 상처 치유 과정에서 SFD는 저농도 (40μg/mL에서 63.5 %) 및 고농도 (400μg/mL에서 78.4 %)에서 억제 효과를 보였으며 현저한 혈관형성억제 효과를 입증했다 (도 6의 d). Finally, to study how SFD affects VEGF-mediated endothelial cell migration, we evaluated the antiangiogenic effect of SFD on VEGF-mediated wound healing assays. In the wound healing process induced by VEGF, SFD showed inhibitory effects at low concentrations (63.5% at 40 μg/mL) and high concentrations (78.4% at 400 μg/mL), demonstrating a significant angiogenesis inhibitory effect (Fig. 6d). .
통계 분석statistical analysis
모든 통계 분석은 SigmaPlot 13 Statistics (Systat Software Inc., San Jose, CA, USA)를 사용하여 수행되었다. 그룹 간의 차이는 일원 분산 분석에 이어 Bonferroni 테스트로 측정되었다.All statistical analyzes were performed using SigmaPlot 13 Statistics (Systat Software Inc., San Jose, CA, USA). Differences between groups were measured by one-way ANOVA followed by the Bonferroni test.
Claims (11)
상기 화합물은 혈관내피성장인자(vascular endothelial growth factor, VEGF)에 의해 유도되는 혈관신생을 억제하는 것을 특징으로 하는 혈관신생 억제용 조성물. The method of claim 1,
The compound is a composition for inhibiting angiogenesis, characterized in that it inhibits angiogenesis induced by vascular endothelial growth factor (VEGF).
상기 결합은 공유결합인, 혈관신생 억제용 조성물.The method of claim 1,
The bond is a covalent bond, composition for inhibiting angiogenesis.
상기 수라민 단편은 하기 화학식 1로 표시되는 것인, 혈관내피성장인자 억제용 조성물:
[화학식 1]
The method of claim 1,
The suramin fragment is a composition for inhibiting vascular endothelial growth factor, which is represented by the following formula (1):
[Formula 1]
상기 화합물은 하기 화학식 2로 표시되는 것인, 혈관내피성장인자 억제용 조성물:
[화학식 2]
The method of claim 1,
The compound is a composition for inhibiting vascular endothelial growth factor, which is represented by the following formula 2:
[Formula 2]
상기 화합물은 혈관내피성장인자의 헤파린 결합 자리(Heparin binding site)에 결합하는 것인, 혈관내피성장인자 억제용 조성물.The method of claim 1,
Wherein the compound binds to the heparin binding site of the vascular endothelial growth factor, the composition for inhibiting vascular endothelial growth factor.
상기 혈관신생 관련 질환은 암, 당뇨망막병증, 황반변성, 충혈, 류마티스성 관절염, 안구건조증 및 건선으로 이루어진 질환에서 선택된 적어도 어느 하나인, 혈관신생 관련 질환의 예방 또는 치료용 약학 조성물.9. The method of claim 8,
The angiogenesis-related disease is at least one selected from the group consisting of cancer, diabetic retinopathy, macular degeneration, hyperemia, rheumatoid arthritis, dry eye disease and psoriasis, a pharmaceutical composition for preventing or treating angiogenesis-related diseases.
상기 혈관신생 관련 질환은 암, 당뇨망막병증, 황반변성, 충혈, 류마티스성 관절염, 안구건조증 및 건선으로 이루어진 질환에서 선택된 적어도 어느 하나인, 혈관신생 관련 질환의 개선 또는 예방용 건강 기능 식품 조성물.11. The method of claim 10,
The angiogenesis-related disease is at least one selected from the group consisting of cancer, diabetic retinopathy, macular degeneration, hyperemia, rheumatoid arthritis, dry eye disease and psoriasis, angiogenesis-related disease improvement or prevention health functional food composition.
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