KR20090034239A - 골형성 촉진용 세포투과성 융합 단백질 및 그 용도 - Google Patents
골형성 촉진용 세포투과성 융합 단백질 및 그 용도 Download PDFInfo
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- KR20090034239A KR20090034239A KR1020070099510A KR20070099510A KR20090034239A KR 20090034239 A KR20090034239 A KR 20090034239A KR 1020070099510 A KR1020070099510 A KR 1020070099510A KR 20070099510 A KR20070099510 A KR 20070099510A KR 20090034239 A KR20090034239 A KR 20090034239A
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Abstract
골다공증, 골절 및 수술 등으로 인하여 손실된 뼈를 회복시키기 위한 골형성 촉진용 세포투과성 융합 단백질, 이를 유효성분으로 함유하는 골질환 치료용 약학 조성물 및 골질환용 건강 기능성 식품이 개시된다. 상기 골형성 촉진용 세포투과성 융합 단백질은 골조직으로의 분화에 관련하는 세포내 전사인자 단백질, 예를 들어 TAZ 또는 그 유사체 단백질의 아미노 말단에 세포 투과성 펩타이드가 공유결합된 것을 특징으로 한다. 상기 골형성 촉진용 세포투과성 융합 단백질은 골 형성을 유도함으로써 골다공증이나 골 형성 부전증, 치주질환 및 골절 등의 골질환 예방 및 치료에 사용될 수 있고, 지방세포를 억제해 골질환 예방 및 치료용 약학 조성물 및 건강기능성 식품의 용도로 유용하다.
골조직분화 전사인자 단백질, TAZ, 세포 투과성, 단백질 형질도입 부위, 골질환 예방, 비만 예방
Description
본 발명은 골형성 촉진용 세포투과성 융합 단백질에 관한 것으로서, 더욱 상세하게는 골다공증, 골절 및 수술 등으로 인하여 손실된 뼈를 회복시키기 위한 골형성 촉진용 융합 단백질, 이를 유효성분으로 함유하는 골질환 치료용 약학 조성물 및 골질환용 건강 기능성 식품에 관한 것이다.
중간엽 줄기세포(Mesenchymal Stem Cells)는 배아기에 골격계의 생성 및 성장에 관여하고 성장이 끝나면 골세포 외에 연골세포, 근육세포, 섬유세포 등 여러가지 종류의 골격계 세포들로 분화할 수 있는 능력을 가진 세포를 말하며, 골수기질간세포(Bone Marrow Stromal Stem Cells)라고도 한다. 중간엽 줄기세포에서 조골세포와 지방세포로 분화되는 결정적 전사인자는 Runx2와 표백작용 성장 활성화 수용체 PPAR gamma이다. 이들은 중간엽 줄기세포들로 하여금 뼈를 만드는 조골세포 또는 지방세포로 차별화 하도록 유도한다. Runx2는 자체적으로도 외부에서 주입시 뼈로의 이행이 관찰된 단백질이며, 이 외에 여러 전사단백질들이 세포의 골조직으로의 분화를 촉진시키는 것으로 알려져있다. 특히 Hong 등은 14-3-3 이라 불리 는 결속 단백질인, PDZ-결속을 유도하는 전사 활동자인 TAZ라는 유전자가 PPAR gamma 전사를 억제하고 Runx2를 활성화한다는 사실을 규명했다 (Hong J.H. et al., Science, 309:1074, 2005).
상기 Runx2(Runx Domain transcription factor)는 골분화에 깊은 관련이 있다는 것이 밝혀졌는데, 조골세포 분화의 초기 표현형질인 알칼라인포스파테이즈(ALP)와 후기 표현형질인 오스테오칼신(OC)의 발현을 조절하는 중요한 전사인자인 것으로 알려져 있다 (Ducy, P. et al., Cell , 89:747, 1997; Mundlos, S. et al., Cell , 89:773, 1997; Komori, T. et al., Cell , 89:755, 1997; Otto, F. et al., Cell , 89:765, 1997). 이와 더불어 LIM Mineralization protein-1 (LMP-1) 단백질 역시 세포내에서 골조직으로의 분화를 촉진시킴이 보고된 바 있다. 특히 본 발명자들은 이 단백질 중 특정의 아미노산 서열 (AADPPRYTFAPSVSLNKTARPPGAPPPADSAPQQNG, ADPPRYTFAP, KPQKASAPAADPPRYTFAP)이 골조직분화와 직접관련이 있음을 확인한 바 있다. 이러한 단백질 및 아미노산 서열은 세포질 내에서 골조직분화 유전자를 활성화시키는 작용을 한다. 그러나 이들이 특정 목적으로 세포질내로 혹은 조직내로 도입이 되기에는 분자량이 크기 때문에 세포내 도입 수송체의 활용이 절실한 상황이다.
최근 국내외에서 골다공증, 골절 및 수술 등으로 인하여 손실된 뼈를 회복하기 위한 골형성 촉진제의 개발이 요구되고 있다. 그러나, 현재까지 개발된 비스포스포네이츠(bisphosphonates), 칼시토닌(calcitonin), 에스트라디올(estradiol) 또는 비타민 D와 같은 골형성 촉진제는 골흡수의 억제에 주목적이 있고 이미 상실된 뼈의 재생에는 큰 효과가 없는 실정이다. 이에 골형성을 촉진할 수 있는 새로운 약제를 찾아내기 위하여 많은 노력을 기울이고 있으며, 따라서 많은 물질들을 짧은 시간 내에 대량 검색할 수 있는 검색 방법의 개발이 요구되고 있다. 한편, 최근 치료용 약물이나 단백질은 그 크기 또는 여러 생화학적 성질 때문에 세포막을 통과하기가 매우 힘들다. 일반적으로 분자량이 600 이상인 물질은 세포막을 통과하기가 거의 불가능한 것으로 알려져 있다.
최근 인간 면역결핍 바이러스(Human Immunodeficiency Virus type-1) 단백질의 일종인 Tat(Transactivator of transcription) 단백질은 효율적으로 세포막을 통과하여 세포질 내로 쉽게 이동한다는 것이 밝혀졌다. 이러한 기능은 Tat 단백질의 중간부위인 단백질 형질도입 부위(PTD, Protein Transduction Domain)의 특성 때문에 나타나며 아직 그 정확한 메카니즘은 알려지지 않은 상태이다 (Frankel, A.D. and Pabo, C.O., Cell , 55:1189, 1988; Green, M. and Loewenstein, P.M., Cell, 55:1179, 1988; Ma, M. and Nath, A., J. Virol., 71:2495, 1997; Vives, E. et al., B. J. Biol . Chem ., 272:16010, 1997). 그러나, Tat 단백질의 세포막에는 특정 수용체나 운반체가 관여하지 않는 것으로 보이며, Tat 단백질의 단백질 형질도입 부위가 직접 막의 지질 이중층과 작용함으로써 일어나는 것으로 이해되고 있다 (Vives, E. et al., J. Biol . Chem . 272:16010, 1997; Derossi, D. et al., J. Biol. Chem . 271:18188, 1996).
PTD로서의 효과가 확인된 다른 예로는 HSV-1(herpes simplex virus type 1)의 VP22 단백질의 267번째부터 300번째까지의 아미노산 서열을 가지는 펩타이 드(Elliott, G. et al., Cell , 88:223, 1997), HSV-2의 UL-56 단백질의 84번째부터 92번째까지의 아미노산 서열을 가지는 펩타이드(GeneBank code:D1047 [gi:221784])가 있다. 그러나, 상기 PTD들은 바이러스에서 유래된 단백질임으로 독성에 대한 염려가 있다. 또한, 드로소필라 속(Drosophila sp .)의 안테나페디아(antennapedia, ANTP) 단백질의 339번째부터 355번째까지의 아미노산 서열을 가지는 펩타이드(Schwarze, S.R. et al., Trends . Pharmacol . Sci., 21:45, 2000) 및 전기적으로 양성인 아미노산들을 나열한 인위적인 펩타이드의 경우도 그 효과가 확인되었다 (Laus, R. et al., Nature Biotechnol., 18:1269, 2000).
한편, 종래 PTD를 다른 펩타이드 또는 단백질과 연결시킨 경우, 이러한 융합 단백질의 세포 내 수송이 효율적이라는 것이 밝혀진 이후, PTD를 이용한 다양한 응용이 시도되었으나(대한민국 특허등록 제10-0568457호), 아직까지 중간엽 줄기세포에서 조골세포로 분화시키는 결정적 전사인자인 Runx2를 활성화하고, 지방세포로 분화시키는 전사인자인 PPAR gamma를 억제하는 TAZ 및 앞서 전술한 LMP-1 단백질 등의 조골세포 분화기능성 전사인자 단백질과 PTD를 결합하려는 시도는 한번도 없었다.
따라서, 당업계에서는 골 형성을 유도하여, 골질환 예방 및 치료에 사용될 수 있고, 지방세포를 억제하는 단백질을 세포 내로 효율적으로 운반되며, 합성이 용이하고, 독성에 대한 염려가 전혀 없는 융합 단백질의 개발이 절실한 실정이다.
이에, 본 발명자들은 질병 치료 물질을 세포 내로 효과적으로 전달할 수 있는 방법을 개발하고자 예의 노력한 결과, 중간엽 줄기세포에서 조골세포로 분화시키는 결정적 전사인자인 Runx2 및 이를 활성화시키는 TAZ나 기타 골조직분화 전사인자 단백질의 아미노 말단에 세포 투과성 펩타이드가 공유결합된 골형성 촉진용 세포투과성 융합 단백질이 세포 내에서 골 형성을 유도하고 지방 형성을 감소시키는 것을 확인하고, 본 발명을 완성하게 되었다.
결국 본 발명의 주된 목적은, 골 형성을 유도하여, 골질환 예방 및 치료에 사용될 수 있고, 지방세포를 억제하는 단백질을 세포 내로 효율적으로 운반할 수 있는 융합 단백질, 이를 함유하는 약학조성물 및 건강 기능성 식품을 제공하는데 있다.
상기 목적을 달성하기 위하여, 본 발명은 일 관점에서 골조직 분화기능성 전사인자 단백질의 아미노 말단에 세포 투과성 펩타이드가 공유결합된 골형성 촉진용 세포투과성 융합 단백질을 제공한다. 상기 골조직 분화기능성 전사인자 단백질은 TAZ, Runx2, LMP-1 및 LMP-1 유래 펩타이드로 구성된 군에서 선택되는 것을 특징으로 한다.
본 발명에 있어서, 상기 TAZ는 서열번호 1 또는 서열번호 2로 표시되는 것을 특징으로 하며, 지방세포로 분화시키는 전사인자인 PPAR gamma를 억제하고, 중간엽 줄기세포에서 조골세포로 분화시키는 결정적 전사인자인 Runx2를 활성화시킬 수 있다. 또한 본 발명에서 TAZ는 상기 TAZ 단백질을 코딩하는 유전자를 의미할 수도 있다.
또한 상기 Runx2는 서열번호 3 또는 4로 표시되는 것을 특징으로 하고, 상기 LMP-1는 서열번호 5 또는 6으로 표시되는 것을 특징으로 하며, 상기 LMP-1 유래 펩타이드는 서열번호 7 내지 9로 이루어진 군에서 선택되는 것을 특징으로 한다.
본 발명의 일실시예에 따른 상기 세포 투과성 펩타이드(Cell-Penetrating Peptide; CPP)는 양전하(+)를 띠는 펩타이드로서, (a) LMWP(Low Molecular Weight Protamine)(서열번호 10:VSRRRRRRGG RRRR), (b) TAT(Trans Activator of Transcription)(서열번호 11:CGRKKRRQRR RPPQC), (c) 페너트라틴(penetratin)(서열번호 12:RQIKIWFQNR RMKWKK), (d) 폴리아르기닌(polyarginine, 아르기닌 6개 이상), (e) 폴리라이신(polylysine, 라이신 6개 이상), (f) 프로타민(protamine) 절편, (g) 안테나페디아(antennapedia, ANTP) 및 (h)히스티딘, 아르기닌, 라이신 또는 이들의 혼합물을 70% 이상 함유하는 올리고펩타이드로 구성된 군에서 선택되는 것을 특징으로 할 수 있다. 또한 상기 세포 투과성 펩타이드(CPP)는 단백질 형질도입 부위(Protein Transduction Domain; PTD)를 포함하고 있으며, 상기 세포 투과성 펩타 이드는 세포 투과성 단백질일 수도 있다.
대부분의 세포내 약물 전달 기법은 세포 표면의 리셉터를 이용한 엔도사이토시스(endocytosis)에 의존하고 있으나 상기 펩타이드들은 기존의 세포내 물질 수송기전의 하나인 엔도사이토시스와는 전혀 다르게 (+) Charge를 띠고 있으므로 (-) Charge인 세포막의 전하에 의존하여 부착, 전달되는 과정을 거치며 세포내로 이동시키고자 하는 물질들을 직접적으로 단시간 내에 효율적인 도입을 시킬 수 있다는 장점을 가지고 있다.
본 발명에 따른 상기 골형성 촉진용 세포투과성 융합 단백질은 화학적 또는 생물학적으로 융합할 수 있으나, 부산물 등이 적게 발생하는 생물학적으로 융합시키는 것이 바람직하다. 화학적 융합방법은 상기 전사인자 단백질을 가교제로서 1,4-비스-말레이미도부탄(1,4-bis-maleimidobutane, BMB), 1,11-비스-말레이미도테트라에틸렌글리콜(1,11-bis-maleimidotetraethyleneglycol, BM[PEO]4), 1-에틸-3-[3-디메틸 아미노프로필] 카보디이미드 하이드로클로라이드(1-ethyl-3-[3-dimethyl aminopropyl] carbodiimide hydrochloride, EDC), 숙시니미딜-4-[N-말레이미도메틸시클로헥산-1-카복시-[6-아미도카프로에이트]](succinimidyl-4-[N-maleimidomethyl cyclohexane-1-carboxy-[6-amidocaproate]], SMCC) 및 그의 설폰화염(sulfo-SMCC), 숙시미딜 6-[3-(2-피리딜디티오)-로피오나미도] 헥사노에이트](succimidyl 6-[3-(2-pyridyldithio)-ropionamido] hexanoate, SPDP) 및 그의 설폰화염(sulfo-SPDP), m-말레이미도벤조일-N-하이드로시숙시니미드 에스터(m-maleimidobenzoyl-N-hydroxysuccinimide ester, MBS) 및 그의 설폰화염(sulfo-MBS), 숙시미딜[4-(p-말레이미도페닐) 부틸레이트](succimidyl[4-(p-maleimidophenyl) butyrate], SMPB) 및 그의 설폰화염(sulfo-SMPB) 등을 이용하여 아미노기와 세포내 투과 펩타이드와 S-S 결합을 유도하는 것인데, 단백질의 아미노기에 비선택적으로 펩타이드 결합이 이루어져 한 단백질에 다수의 펩타이드가 도입되는 부산물이 발생한다. 생물학적 방법에 의해서는 플라스미드 구성시 한 분자의 펩타이드가 도입되도록 설계되어 있으므로 부산물의 발생우려가 적다는 장점이 있다.
본 발명은 다른 관점에서 골조직 분화기능성 전사인자 단백질을 코딩하는 cDNA의 5' 말단에 세포 투과성 펩타이드를 코딩하는 DNA가 결합되어 있고, 상기 골형성 촉진용 세포투과성 융합 단백질을 코딩하는 재조합 폴리뉴클레오타이드를 제공한다(도10a ,10b 참조).
본 발명은 또 다른 관점에서 골조직 분화기능성 전사인자 단백질을 코딩하는 cDNA의 5' 말단에 세포 투과성 펩타이드를 코딩하는 DNA가 결합되어 상기 골형성 촉진용 세포투과성 융합 단백질을 코딩하는 재조합 폴리뉴클레오타이드를 함유하는 발현벡터를 제공한다(도 1a 및 1b 참조). 상기 벡터는 통상적인 TA 벡터 등을 사용할 수 있고, 상기 벡터의 발현은 T7 프로모터와 LacO-오퍼레이터의 조절하에 있다.
본 발명은 또 다른 관점에서 상기 발현벡터로 형질전환된 미생물을 제공한다. 상기 형질전환용 미생물은 통상적인 것을 사용할 수 있고, E· Coli 등을 예시할 수 있다.
본 발명은 또 다른 관점에서 (a) 상기 형질전환된 미생물을 배양하여 골형성 촉진용 세포투과성 융합 단백질을 발현시키는 단계; 및 (b) 상기 발현된 골형성 촉진용 세포투과성 융합 단백질을 정제하는 단계를 포함하는 골형성 촉진용 세포투과성 융합 단백질의 제조방법을 제공한다.
상기 발현된 골형성 촉진용 세포투과성 융합 단백질의 정제는 변성상태 또는 자연상태에서 금속 킬레이팅 친화 크로마토그래피(metal-chelating affinity chromatography)법으로 정제할 수 있다. 상기 변성상태의 정제는 상기 골형성 촉진용 세포투과성 융합 단백질을 4 내지 8M의 우레아로 변성시킨 후 정제하는 것을 특징으로 한다. 이때 상기 우레아가 4M 미만인 경우에는 유도가 되지 않는 문제가 있고, 8M을 초과할 경우 응집이 되는 문제가 있다.
본 발명은 또 다른 관점에서 상기 골형성 촉진용 세포투과성 융합 단백질을 유효성분으로 하고, 약학적으로 허용 가능한 담체를 포함하는 것을 특징으로 하는 골질환 치료용 약학 조성물을 제공한다. 여기서 골질환은 골다공증, 골형성 부전증, 치주질환, 골절 등을 예시할 수 있다.
상기 골질환 치료용 약학 조성물은 경구 투여 또는 비경구 투여(근육내, 피하, 정맥내, 좌약 등)에 의해 투여될 수 있다. 적당한 투여량은 환자의 상태, 예를 들어, 연령 및 증상의 정도 등에 따라 적절히 조절할 수 있지만, 통상 성인의 경우 100~500mg의 용량 범위에서 일반적으로 일회 또는 수 회로 나누어 1일당 100~1,000mg의 양으로, 바람직하게는 1일 300~1,000mg의 양으로 투여되는 것이 바람직하다.
본 발명에 따른 상기 골질환 치료용 약학 조성물을 경구용 제제로서 조제하는 경우에는 부형제, 필요에 따라서 결합제, 붕괴제, 활택제, 착색제, 교미교취제 등을 가한 후, 통상적인 방법에 따라 정제, 피복 정제, 과립제, 캡슐제 등으로 제조할 수 있다.
상기 골질환 치료용 약학 조성물에 포함될 수 있는 담체, 부형제 및 희석제로는 젖당, 옥수수 전분, 백당, 포도당, 솔비트, 결정 셀룰로스, 만니톨, 자일리톨, 에리스리톨, 말티톨, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등을 사용할 수 있고, 결합제로는 폴리비닐알콜, 폴리비닐에테르, 에틸셀룰로스, 메틸셀룰로스, 아라비아 고무, 젤라틴, 셸락(shellac), 하이드록시프로필셀룰로스, 하이드록시프로필스타치, 폴리비닐피리돈 등을 사용할 수 있다. 그리고, 붕괴제로는 전분, 한천, 젤라틴 분말, 결정 셀룰로스, 탄산칼슘, 탄산수소나트륨, 구연산칼슘, 덱스트란, 펙틴 등이, 활택제로는 스테아린산 마그네슘, 활석, 폴리에틸렌글리콜, 실리카, 경화 식물유 등을 사용할 수 있다. 또한, 착색제로는 의약품에 첨가하는 것이 허가된 것을 사용할 수 있고, 교미교취제로 코코아 분말, 박하뇌, 방향산, 박하유, 용뇌, 계피 분말 등을 사용할 수 있다.
또한 본 발명에 따른 골질환 치료용 약학 조성물을 주사제로 조제하는 경우에는 필요에 따라, pH 조절제, 완충제, 안정화제, 보존제 등을 첨가하고, 통상적인 방법에 따라 피하, 근육내, 정맥 주사제로 조제할 수 있다.
본 발명에 따른 골질환 치료용 약학 조성물은 쥐, 생쥐, 가축, 인간 등의 포유동물에 다양한 경로로 투여될 수 있다. 투여의 모든 방식은 예상될 수 있는데, 예를 들면, 경구, 직장 또는 정맥, 근육, 피하, 자궁 내 경막 또는 뇌혈관 내 (intracerebroventricular) 주사에 의해 투여될 수 있다.
본 발명은 또 다른 관점에서 골형성 촉진용 세포투과성 융합 단백질을 유효성분으로 하고, 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 것을 특징으로 하는 골질환용 건강 기능성 식품을 제공한다. 상기 골질환으로는 골다공증, 골형성 부전증, 치주질환, 골절 등을 예시할 수 있다.
본 명세서에서 '기능성 식품'이란, 일반 식품에 본 발명의 골형성 촉진용 세포투과성 융합 단백질(CPP-TAZ)을 첨가함으로써 일반 식품의 기능성을 향상시킨 식품을 의미한다. 기능성에는 물성 및 생리기능성으로 대별될 수 있는데, 본 발명의 골형성 촉진용 세포투과성 융합 단백질을 일반식품에 첨가할 경우, 일반 식품의 물성 및 생리기능성이 향상될 것이고, 본 발명은 이러한 향상된 기능의 식품을 포괄적으로 '기능성 식품'이라 정의한다.
본 발명에 따른 골질환용 건강 기능성 식품은 식품학적으로 허용 가능한 식품보조 첨가제로 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, 알콜, 탄산 음료에 사용되는 탄산화제 등을 함유할 수 있다. 그밖에 본 발명에 따른 골질환용 건강 기능성 식품은 천연 과일 쥬스, 과일 쥬스 음료 및 야채 음료 제조를 위한 과육 등을 함유할 수 있다. 이러한 성분은 독립적으로 또는 조합하여 사용할 수 있다. 이러한 첨가제의 비율은 특별히 제한되는 것은 아니지만, 본 발명의 골형성 촉진용 세포투과성 융합 단백질 100중량부 당 0.01~20중량부의 범위에서 선택되는 것이 일반적이다.
본 발명은 또 다른 관점에서, 골조직 분화기능성 전사인자 단백질의 아미노 말단에 세포 투과성 펩타이드가 공유결합된 비만 예방 또는 치료용 융합 단백질을 제공한다.
본 발명은 또한 상기 비만 치료용 융합 단백질을 유효성분으로 하고, 약학적으로 허용 가능한 담체를 포함하는 것을 특징으로 하는 비만 치료용 약학 조성물을 제공한다.
본 발명은 또한 상기 비만 예방용 융합 단백질을 유효성분으로 하고, 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 것을 특징으로 하는 비만 예방용 건강 기능성 식품을 제공한다.
이상 상세히 기술한 바와 같이, 본 발명에 따른 골 형성 촉진용 세포투과성융합 단백질은 골 형성을 유도함으로써 골다공증이나 골 형성 부전증, 치주지관 및 골절 등의 골질환 예방 및 치료에 사용될 수 있고, 지방세포를 억제해 골질환 예방 및 치료용 약학 조성물 및 건강기능성 식품의 용도로 유용하다.
이하, 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 이들 실시예는 단지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.
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사용되는 재료
제한 효소와 T4 DNA 리가아제(ligase)는 NEB(USA)에서 구입하였다. LMWP 올리고뉴클레오타이드(oligonucleotide)는 Bioneer custom primer(USA)에서 합성하였다. IPTG는 Sigma(USA)에서 구입하였다. pET-21b와 BL21(DE3) 플라스미드는 Novagen(USA)에서 구입하였고, Ni-니트릴로 트리아세틱 애시드 세파로즈 수퍼 플로우(Ni-nitrilo-triacetic acid sepharose superflow)는 Qiagen(Germany)에서 구입하였다.
인간 TAZ cDNA는 PCR(중합효소 연쇄반응방법)으로 pEF-BOS-TAZ에서 분리하였다. 또한, 본 발명의 실시예에서는 인간 TAZ를 사용하여 융합단백질을 제조하였으나, 본 발명의 범위가 인간 TAZ를 이용한 융합단백질 등에만 미치는 것은 아니며, 효모 유래, 박테리아 유래 효소 등을 이용하는 경우에도 본 발명의 효과를 얻을 수 있음은 당업자에게 자명한 것이다.
본
실시예의
웨스턴
블랏
분석 방법
본 발명의 실시예에서 웨스턴 블랏 분석은 다음과 같이 행하였다.
세포 분쇄액 내의 단백질을 10% SDS 폴리아크릴아미드 젤 전기이동법으로 분리한 다음 젤에 있는 단백질을 니트로셀룰로스 멤브레인(nitrocellulose membrane; Amersham, UK)으로 전기 이동시켰다. 단백질이 이동된 니트로셀룰로스멤브레인을 5% 우혈청 알부민 용액으로 처리하고, 인간 TAZ에 대한 단일클론항체(hTAZmAb-1.4)로 1시간 처리하였다. 세척 후 멤브레인을 horseradish peroxidase와 결합된 고우트 안티-마우스 IgG(goat anti-mouse IgG) 항체(Santa Cruz, 1:5,000 희석)와 1시간동안 반응시켰다. 최종적으로 ECL chemiluminescence reaction kit(Amersham, USA)를 처리하여 인간 TAZ 단일클론항체에 반응하는 단백질 밴드를 확인하였다.
실시예
1:
LMWP
-
TAZ
발현벡터의 제조 및 형질전환(
transformation
)
LMWP-TAZ 융합단백질을 과다 발현시키기 위하여 TAZ, CPP(Cell-Penetrating Peptide)의 한 종류인 LMWP의 PTD(단백질 형질 도입부위) 및 6개의 히스티딘에 대한 cDNA가 연속적으로 포함되어 있는 pET-CPP-TAZ 발현 벡터를 제조하였다 (도 1a). 도 1a는 pET-21b 벡터를 이용한 세포 투과성 펩타이드-TAZ 발현벡터(pCPP-TAZ)의 유전자 지도이다. 상기 융합단백질에 대한 대조 단백질인 TAZ를 과다 발현시키기 위하여 CPP(예:LMWP)의 형질 도입부위만 포함되지 않고 나머지 부위는 동일한 pET-TAZ 발현 벡터를 제조하였다.
먼저, LMWP-TAZ 융합단백질을 생산하기 위하여, HIV-1 LMWP의 기본 도메인(basic domain)이 포함된 pET-LMWP 발현벡터를 제조하였다. LMWP 기본 도메인에 해당하는 상위 쇄(top strand)(서열번호 13: AATTC GTGTCCCGACGTCGTCGCAGGAGAGGAGGCCGCAGGAGGCGTTA) 및 하위 쇄(bottom strand)(서열번호 14: AGCTTTAACGCCTCCTGCG GCCTCCTCTCCTGCGACGACGTCGGGACACCC) 두 종류의 올리고뉴클레오타이드를 EcoRI-Hind III 제한효소로 자른 pET21b에 결찰(ligation)하여 삽입한 다음, 인간 TAZ의 cDNA의 서열을 기본으로 하여 2종류의 올리고뉴클레오타이드를 합성하였다.
상기 올리고뉴클레오타이드의 합성에 사용된 정방향 프라이머(Forward primer)는 서열번호 15의 5'-AGCTTATGAATCCGTCCTCGGTG-3'로 Hind III 제한부위를 지니고 있으며, 역방향 프라이머(reverse primer)는 서열번호 16의 5'-TCGAGTTAGAAAGGGCTCGCTTTTG-3'로 Xho I 제한부위를 갖고 있다.
중합효소 연쇄반응(PCR)은 thermal cycler(Perkin-Elmer, model 9600)에서 수행하였으며, 반응 혼합액을 20㎕를 실리콘 튜브(siliconized reaction tube)에 넣고 94℃에서 5분간 가열하였다. PCR 반응은 94℃에서 40초간 30회의 연장(extension), 55℃에서 1분간 변성(denaturation), 72℃에서 3분간 어닐링(annealing) 및 72℃에서 10분간 최종 연장(final extension)을 유도하는 방법으로 수행하였다. PCR을 수행한 다음, 아가로즈 젤 전기이동으로 분리하여 반응물을 분리하고 이것을 TA 클로닝 벡터(Invitrogen, Sandiego, USA)에 결찰하였다. 다음으로 벡터를 형질전환용 세포(E. coli BL21(DE3)에 형질전환(transformation)시키고, 형질전환된 박테리아로부터 플라스미드를 알칼리 용균 방법(alkaline lysis method)으로 분리하였다(Sambrook, J., Fritsch, F.E. and Maniatis, T(1989) Molecular cloning, Cold spring harbor laboratory press, Cold spring harbor).
인간 TAZ cDNA가 포함된 TA 벡터를 Hind Ⅲ와 Xho I으로 절단한 다음 pET-15b 및 pET-21b-LMWP 발현 벡터에 삽입하였다 (도 1a). 상기 pET-TAZ와 pET-LMWP-TAZ로 형질전환된 E. coli BL21(DE3)의 콜로니(colony)를 100㎖의 LB 배지에 접종하고, IPTG 0.5 mM을 배지 내에 첨가하여, 재조합된 TAZ와 LMWP-TAZ의 과다 발현을 유도하였다. 발현된 융합 단백질 LMWP-TAZ와 대조 단백질로 사용한 TAZ의 모식도는 도 1b에 나타내었다. 또한 상기와 동일한 방법으로 TAT-TAZ 및 Pen-TAZ도 제조하였다.
IPTG로 융합단백질의 과다 발현을 유도한 대장균 세포를 4℃에서 초음파 처리(sonication)로 파쇄한 다음, 원심분리하여 상등액의 단백질을 10% SDS-폴리아크릴아미드 젤 전기이동방법으로 분리하였다. 도 2a는 투과성 단백질들의 더블 스트랜디드 DNA의 전기영동 결과를 나타낸 사진이다.
젤의 레인 2 (LMWP-TAZ)와 레인 3(TAZ)의 화살표 친 부분은 과다 발현된 융합단백질을 나타내며, 대조군인 레인 1(pET-15b 벡터)과 비교하여 매우 높은 농도의 융합단백질이 과다 발현되었음을 알 수 있었다. 도 2b는 TAZ의 cDNA의 전기영동 결과를 나타낸 사진이다.
실시예
2:
재조합
LMWP
-
TAZ
융합단백질의
정제
형질전환된 E· coli BL21을 앰피실린이 포함된 LB 배지에 넣고 37℃에서 200rpm으로 교반하며 배양하였다. 배양액 내의 박테리아 농도가 O.D 600=0.5~1.0를 나타낼 때 IPTG를 배지 내에 첨가하여 최종농도가 0.5mM가 되도록 한 다음 4시간을 더 배양하였다. 배양한 세포를 원심분리하여 모은 다음, 5㎖ 결합 완충용액(binding buffer; 5mM 이미다졸, 0.5M NaCl, 20mM Tris-HCl, pH 7.9)을 넣고 초음파처리(sonication)하였다. 본 실시예에서는 세포 내의 투과능력을 상호 비교하기 위하여 변성상태(denaturing condition)와 변성시키지 않은 자연상태(native condition)에서 융합단백질을 각각 정제하였다. 부분적으로 변성시킨 융합단백질(partially denatured fusion protein)을 얻기 위하여 세포를 6M 우레아가 함유된 결합 완충용액 내에서 초음파처리로 파쇄시키고, 즉시 정제과정에 들어갔다.
파쇄되어 얻은 세포액을 원심분리하여 상청액을 즉시 2.5㎖ Ni2 +-니트릴로트리아세틱 애시드 세파로즈 컬럼(nitrilotriacetic acid sepharose column)에 투입하고, 10배 부피의 결합 완충용액과 6배 부피의 세척 완충액(washing buffer; 60mM 이미다졸, 0.5M NaCl, 20mM Tris-HCl, pH 7.9)으로 세척한 다음, 용출 완충액(elution buffer; 500mM 이미다졸, 0.5M NaCl, 20mM Tris-HCl, pH 7.9)으로 융합단백질을 용출시켰다. 이어 세파덱스 G-15 컬럼 크로마토그래피를 이용하여 융합단백질이 포함된 분획물에 포함된 염분을 제거하였다. 융합단백질은 N-말단에 6개의 히스티딘을 포함하고 있기 때문에 고정 금속-킬레이트 친화 크로마토그래피(immobilized metal-chelate affinity chromatography) 단일 단계로 융합단백질을 거의 순수하게(순도 > 90%) 정제한 다음, 과다 발현된 TAZ와 LMWP-TAZ는 SDS-폴리아크릴아미드 젤 전기이동과 웨스턴 블랏 분석으로 확인하였다 (도 3). 도 3은 대장균에서 TAZ를 발현시킨 후 정제하는 과정 중 각 단계에서 회수된 단백질 분획을 10% SDS-PAGE로 분석한 결과를 쿠마시 블루로 염색한 것으로, 레인 1은 사이즈 마커, 레인 2: TAZ 벡터가 들어 있는 세포의 파쇄액, 레인 3: 세척완충액 처리 이후 TAZ 융합 단백질, 레인 4: 용출 완충액 처리 이후 TAZ 융합 단백질을 나타낸다.
대장균 100㎖ 배양으로부터 정제된 융합단백질의 단백질 농도는 우혈청 알부민을 표준물질로 사용하여 브래드포드(Bradford) 방법으로 측정하였다 (Bradford, M.A., Anal . Biochem. 72:248, 1976). 상기 방법으로 정제된 융합단백질을 웨스턴 블랏 분석으로 다시 한번 확인하였다 (도 4). 그 결과, 도 4에 나타난 바와 같이 TAZ 단일클론항체에 반응하는 LMWP-TAZ와 TAT-TAZ 밴드는 도 3의 단백질 밴드와 동일한 위치에서 각각 관찰되었으며 이는 TAZ 단백질의 밴드보다도 위에 존재함으로서 LMWP나 TAT이 융합되어 있음을 알 수 있었다.
실시예
3:
중간엽
줄기 세포배양 및 재조합
LMWP
-
TAZ
의 세포 내 투과
중간엽 줄기 세포(Mesenchymal Stem Cells, MSC)는 37℃에서 95% 공기와 5% CO2를 공급해주며 10% 우태혈청(FBS, fetal bovine serum) 및 항생제(스트렙토마이신 100㎍/㎖, 페니실린 100 U/㎖)가 포함된 Dulbecco's Modified Eagle's Medium에서 배양하였다.
LMWP-TAZ의 세포 내 투과를 관찰하기 위하여 중간엽 줄기세포(Mesenchymal Stem Cells, MSC)를 6-웰 플레이트에서 4~6시간 동안 배양한 다음, FBS가 포함되지 않은 1㎖의 신선한 배양액으로 교체하고 여러 농도의 재조합 LMWP-TAZ 5uM를 배양액 내에 처리하였다. 1시간 뒤 상기 세포를 트립신-EDTA(Gibco BRL)로 처리하고, 인산 완충액 생리식염수(phosphate buffered saline; PBS)로 충분히 세척하였다. 상기 세척한 세포를 분쇄한 다음, 세포 내로 투과된 TAZ의 양과 발현을 RT-PCR 및 웨스턴 블랏 분석으로 측정하였다.
그 결과, 도 5a 및 도 5b의 RT-PCR결과에 나타낸 바와 같이 변성상태의 LMWP-TAZ는 시간에 의존적으로 MSC 세포 내로 이동하였다. 그러나 대조단백질인 TAZ는 1시간까지 처리했을 때에도 세포 내로 투과된 융합단백질을 관찰할 수 없었다. LMWP-TAZ의 세포내 투과정도를 시간별로 관찰했을 때, 투여 10분 후에 투과된 융합단백질을 확인할 수 있었으며, 처리 시간에 비례하여 세포내 투과가 증가함을 관찰할 수 있었다 (도 5a 및 5b).
또한 세포내로 투과된 LMWP-TAZ의 양은 투여한 융합단백질의 농도 및 처리 시간에 비례하여 증가함을 웨스턴블랏으로 확인하였다(도 6). 도 6의 상단부 사진은 농도에 따른 LMWP-TAZ 융합 단백질의 MSC 투과 정도를 나타낸 사진이고, 하단부 사진은 시간에 따른 LMWP-TAZ 융합 단백질의 MSC 투과 정도를 나타낸 사진이다.
한편, 세포 내로 투과된 융합단백질이 그 고유한 활성을 유지해야만 이를 단백질 치료(protein therapy)에 응용할 수 있다. 따라서 세포 내로 투과된 융합단백질이 어느 정도 생물학적 활성을 지니는지는 매우 중요한 문제이다. 본 실험에서 발현시킨 LMWP-TAZ는 중간엽 줄기 세포 투과 이후 세포질 내에서 TAZ의 활성도를 관찰하였는 바, 도 5에서 보듯이 도입된 LMWP-TAZ의 양에 비례적으로 상응하는 세포질 내의 Runx2의 양이 증가하였다. 이로서 도입된 LMWP-TAZ가 Runx2를 활성화 시키고 있음을 알 수 있다.
LMWP-TAZ 융합단백질은 배양된 중간엽 줄기 세포에 시간 및 농도 의존적으로 세포에 운반되는 것을 역전사-중합효소 연쇄 반응(Reverse Transcriptase-Polymerase Chain Reaction; RT-PCR)과 웨스턴 블랏(Western blot)으로 확인하였 다. LMWP-TAZ 융합단백질을 처리한 세포에서 TAZ 효소의 활성은 세포 내로 운반된 단백질의 양에 비례하여 증가하였다.
이러한 결과는 HIV-1 LMWP 단백질이 TAZ를 세포 내로 이동시켜 세포 내 TAZ의 활성도를 인위적으로 증가시킬 수 있다는 것을 의미한다. 따라서 이러한 LMWP-TAZ 융합단백질의 세포 내로의 운반 기술은 연구 및 TAZ와 관련된 것으로 알려진 질환 치료분야에 다양하게 응용될 가능성을 제시해 준다.
도 7은 대조군 단백질과 LMWP-TAZ 융합단백질의 중간엽 줄기 세포 투과정도를 확인하기 위하여 유세포분리기로 분석한 결과를 나타낸 것이다. 그 결과 TAT-TAZ 및 LMWP-TAZ는 중간엽 줄기 세포로의 투과율이 대조군에 비하여 매우 높은 것을 알 수 있다.
실시예
4:
중간엽
줄기 세포배양에서 재조합
LMWP
-
TAZ
처리로 인한 석회화 결절 형성
중간엽 줄기 세포들을 아스코르빈 산(ascorbic acid) 50μg/㎖, β-글리세로포스페이트(β-glycerophosphate) 10mM 및 덱사메타손(Dexamethasone) 5μg을 함유한 DMEM 배양액에 pLMWP-TAZ 및 TAT-TAZ 융합 단백질과 함께 투여하면서 14일간 배양하였다. 배양 14일 후, PBS로 세 번 세척하고, 70% ethanol로 20분간 고정한 다음 0.1%NH4OH가 함유된 1% Alizalin Red-S(Sigma-Aldrich, St.Louis, Mo, USA) 용액 으로 5분간 염색하였다 (도 8). 그 결과, 도 8에 나타난 바와 같이, 대조군에 비해 처리군에서 석회화 결절 형성 증가를 관찰하였다. 도 8에서 CPP1-TAZ 및 CPP2-TAZ는 각각 LMWP-TAZ 및 TAT-TAZ를 의미한다.
실시예
5:
중간엽
줄기 세포배양에서 재조합
LMWP
-
TAZ
처리로 인한 지방형성감소
중간엽 줄기 세포를 3.5×105의 농도로 분화용 배지(고농도글루코스 DMEM, 1% FBS, 0.5mM 3-이소부틸-메틸잔틴(IBMX), 1μM 덱사메타손, 10μg/㎖ 인슐린, 100μM 인도메타신)가 들어있는 60mm 디쉬에서 배양하여 지방세포로의 분화를 유도하였다. 유도인자는 모두 Sigma(USA) 제품을 사용하였다. 배양 3일후, 배양액을 1% FBS 및 인슐린만 첨가한 DMEM에 넣어서 2일 동안 배양시켰다.
대조군과 융합 단백질을 1uM씩 함께 처리하여 배양하였다. 분화된 지방세포는 포르말칼슘으로 1시간 고정한 후에 60% 이소프로판올에 Oil red-O를 첨가하여 15분 염색하였다. 염색한 세포를 세척한 후에 Mayer's Hematoxylin 용액으로 세포핵을 염색하였다 (도 9). 도 9는 LMWP-TAZ 및 TAZ에 대한 중간엽 줄기 세포 투과실험 후 지방세포 분화를 나타낸 사진으로, 레인 1(NT); 분화되지 않은 세포, 레인 2(CON); 분화 유도된 세포, 레인 3(pET-TAZ); 분화 유도된 세포에 TAZ 처리한 군 및 레인 4(CPP-TAZ); 분화 유도된 세포에 pLMWP-TAZ처리한 군을 나타낸다. 도 9에 나타난 바와 같이, LMWP-TAZ 융합단백질을 처리한 세포에서 지방세포의 수가 감소 됨을 알 수 있었다.
이상으로 본 발명 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시 양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.
도 1a는 pET-21b 벡터를 이용한 세포 투과성 펩타이드-TAZ 발현벡터(pCPP-TAZ)의 유전자 지도이다.
도 1b는 발현된 융합단백질 CPP-TAZ들과 대조단백질로 사용한 TAZ의 모식도이다.
도 2a는 투과성 단백질들의 더블 스트랜디드 DNA의 전기영동 결과를 나타낸 사진이다.
도 2b는 TAZ의 cDNA의 전기영동 결과를 나타낸 사진이다.
도 3은 대장균에서 TAZ를 발현시킨 후 정제하는 과정 중 각 단계에서 회수된 단백질 분획을 10% SDS-PAGE로 분석한 결과를 나타낸 사진이다.
도 4는 정제된 LMWP-TAZ와 대조단백질에 His 단일클론항체를 이용한 웨스턴 블랏팅 결과를 나타낸 사진이다.
도 5a 및 도 5b는 CPP-TAZ가 시간에 따라 중간엽 줄기 세포로의 시간에 따라 투과하는 정도를 알아보기 위하여 LMWP-TAZ, Runx2, GAPDH 유전자를 역전사-중합효소 연쇄 반응 (Reverse Transcriptase-Polymerase Chain Reaction; RT-PCR)방법으로 분석한 결과를 나타낸 사진이다.
도 6은 인간 TAZ 단일클론항체를 이용한 웨스턴 블랏팅 결과를 나타낸 사진이다.
도 7은 대조군 단백질과 CPP-TAZ 단백질의 중간엽 줄기 세포 투과 정도를 알아보기 위하여 유세포분리기로 분석한 결과를 나타낸 그래프이다.
도 8은 CPP-TAZ 및 TAZ에 대한 중간엽 줄기 세포 투과실험 후 석회화 반응을 나타낸 사진이다.
도 9는 CPP-TAZ 및 TAZ에 대한 중간엽 줄기 세포 투과실험 후 지방세포 분화를 관찰한 사진이다.
도 10a 및 10b는 본 발명의 일 실시예에 따른 CPP-TAZ 융합단백질(pTAT-TAZ 및 pLMWP-TAZ)을 코딩하는 폴리뉴클리오타이드 서열을 나타낸 것이다.
<110> Seoul National University Industry Foundation
<120> Cell permeable fusion protein for facillitating ossification and
use thereof
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Asn Phe Leu Gln Glu Asp Cys Lys Lys Ala Leu Ala Phe Lys Trp Leu
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Ile Ser Ala Gly His Tyr Gln Pro Pro Arg Pro Thr Glu Ser Val Ser
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Leu Gln Pro Gly Lys Met Ser Asp Val Ser Pro Val Val Ala Ala Gln
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Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala Val
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Ala Asp His Pro Ala Glu Leu Val Arg Thr Asp Ser Pro Asn Phe Leu
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Cys Ser Val Leu Pro Ser His Trp Arg Cys Asn Lys Thr Leu Pro Val
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Ala Phe Lys Val Val Ala Leu Gly Glu Val Pro Asp Gly Thr Val Val
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Thr Val Met Ala Gly Asn Asp Glu Asn Tyr Ser Ala Glu Leu Arg Asn
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Ala Ser Ala Val Met Lys Asn Gln Val Ala Arg Phe Asn Asp Leu Arg
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Leu Asn Ser Ser Gly Arg Met Asp Glu Ser Val Trp Arg Pro Tyr
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Thr Val Leu Thr Arg His Ser Gln Pro Ala Thr Pro Thr Pro Leu Gln
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<211> 14
<212> PRT
<213> Artificial Sequence
<220>
<223> LMWP(Low Molecular Weight Protamine)
<400> 10
Val Ser Arg Arg Arg Arg Arg Arg Gly Gly Arg Arg Arg Arg
1 5 10
<210> 11
<211> 15
<212> PRT
<213> TAT(transactivator of transcription peptide from HIV type-1)
<400> 11
Cys Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Pro Pro Gln Cys
1 5 10 15
<210> 12
<211> 16
<212> PRT
<213> Unknown
<220>
<223> penetratin
<400> 12
Arg Gln Ile Lys Ile Trp Phe Gln Asn Arg Arg Met Lys Trp Lys Lys
1 5 10 15
<210> 13
<211> 49
<212> DNA
<213> top strand of HIV-1 LMWP
<400> 13
aattcgtgtc ccgacgtcgt cgcaggagag gaggccgcag gaggcgtta 49
<210> 14
<211> 51
<212> DNA
<213> bottom strand of HIV-1 LMWP
<400> 14
agctttaacg cctcctgcgg cctcctctcc tgcgacgacg tcgggacacc c 51
<210> 15
<211> 23
<212> DNA
<213> Artificial Sequence
<220>
<223> forward primer for synthesizing oligonucleotides
<400> 15
agcttatgaa tccgtcctcg gtg 23
<210> 16
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> reverse primer for synthesizing oligonucleotides
<400> 16
tcgagttaga aagggctcgc ttttg 25
Claims (19)
- 골조직 분화기능성 전사인자 단백질의 아미노 말단에 세포 투과성 펩타이드가 공유결합된 골형성 촉진용 세포투과성 융합 단백질.
- 제1항에 있어서 상기 골조직 분화기능성 전사인자 단백질은 TAZ, Runx2, LMP-1 및 LMP-1 유래 펩타이드로 구성된 군에서 선택되는 것을 특징으로 하는 골형성 촉진용 세포투과성 융합 단백질.
- 제2항에 있어서, 상기 TAZ는 서열번호 1 또는 서열번호 2로 표시되는 것을 특징으로 하는 골형성 촉진용 세포투과성 융합 단백질.
- 제2항에 있어서, 상기 Runx2는 서열번호 3 또는 4로 표시되는 것을 특징으로 하는 골형성 촉진용 세포투과성 융합 단백질.
- 제2항에 있어서, 상기 LMP-1는 서열번호 5 또는 6으로 표시되는 것을 특징으 로 하는 골형성 촉진용 세포투과성 융합 단백질.
- 제2항에 있어서, 상기 LMP-1 유래 펩타이드는 서열번호 7 내지 9로 이루어진 군에서 선택되는 것을 특징으로 하는 골형성 촉진용 세포투과성 융합 단백질.
- 제1항에 있어서, 상기 세포 투과성 펩타이드는 (a) LMWP(Low Molecular Weight Protamine), (b) TAT(Trans Activator of Transcription), (c) 페너트라틴(penetratin), (d) 폴리아르기닌(polyarginine, 아르기닌 6개 이상), (e) 폴리라이신(polylysine, 라이신 6개 이상), (f) 프로타민(protamine) 절편, (g) 안테나페디아(antennapedia, ANTP) 및 (h) 히스티딘, 아르기닌, 라이신 또는 이들의 혼합물을 70% 이상 함유하는 올리고펩타이드로 구성된 군에서 선택되는 것을 특징으로 하는 골형성 촉진용 세포투과성 융합 단백질.
- 골조직 분화기능성 전사인자 단백질을 코딩하는 cDNA의 5' 말단에 세포 투과성 펩타이드를 코딩하는 DNA가 결합되어 있고, 제1항의 골형성 촉진용 세포투과성 융합 단백질을 코딩하는 재조합 폴리뉴클레오타이드.
- 제8항의 재조합 폴리뉴클레오타이드를 함유하는 발현벡터.
- 제9항의 발현벡터로 형질전환된 미생물.
- 다음 단계를 포함하는 골형성 촉진용 세포투과성 융합 단백질의 제조방법:(a) 제10항의 형질전환된 미생물을 배양하여 골형성 촉진용 세포투과성 융합 단백질을 발현시키는 단계; 및(b) 상기 발현된 골형성 촉진용 세포투과성 융합 단백질을 정제하는 단계.
- 제11항에 있어서, 상기 정제 단계는 골형성 촉진용 세포투과성 융합 단백질을 4 내지 8M의 우레아로 변성시킨 후 정제하는 것을 특징으로 하는 골형성 촉진용 세포투과성 융합 단백질의 제조방법.
- 제1항의 골형성 촉진용 세포투과성 융합 단백질을 유효성분으로 하고, 약학적으로 허용 가능한 담체를 포함하는 것을 특징으로 하는 골질환 치료용 약학 조성 물.
- 제13항에 있어서, 상기 골질환은 골다공증, 골형성 부전증, 치주질환 및 골절로 구성된 군에서 선택되는 어느 하나인 것을 특징으로 하는 골질환 치료용 약학 조성물.
- 제1항의 골형성 촉진용 세포투과성 융합 단백질을 유효성분으로 하고, 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 것을 특징으로 하는 골질환용 건강 기능성 식품.
- 제15항에 있어서, 상기 골질환은 골다공증, 골형성 부전증, 치주질환 및 골절로 구성된 군에서 선택되는 어느 하나인 것을 특징으로 하는 골질환용 건강기능성 식품.
- 골조직 분화기능성 전사인자 단백질의 아미노 말단에 세포 투과성 펩타이드가 공유결합된 비만 예방 또는 치료용 융합 단백질.
- 제17항의 비만 치료용 융합 단백질을 유효성분으로 하고, 약학적으로 허용 가능한 담체를 포함하는 것을 특징으로 하는 비만 치료용 약학 조성물.
- 제17항의 비만 예방용 융합 단백질을 유효성분으로 하고, 식품학적으로 허용 가능한 식품보조 첨가제를 포함하는 것을 특징으로 하는 비만 예방용 건강 기능성 식품.
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KR1020070099510A KR20090034239A (ko) | 2007-10-02 | 2007-10-02 | 골형성 촉진용 세포투과성 융합 단백질 및 그 용도 |
PCT/KR2008/005814 WO2009045062A1 (en) | 2007-10-02 | 2008-10-02 | Cell permeable fusion protein for facilitating ossification and use thereof |
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WO2013032210A2 (ko) * | 2011-08-31 | 2013-03-07 | (주)아모레퍼시픽 | 생체막 투과성 조성물 |
WO2017159911A1 (ko) * | 2016-03-17 | 2017-09-21 | 서강대학교 산학협력단 | 줄기세포 분화 제어를 위한 바이오몰레트론 |
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KR101529634B1 (ko) * | 2013-08-28 | 2015-06-30 | 서울대학교산학협력단 | 역분화 유도를 위한 세포투과성 융합 단백질 및 그 용도 |
WO2015061856A1 (en) * | 2013-10-30 | 2015-05-07 | University Of Western Australia | Neuroprotective peptides |
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US7892532B2 (en) * | 1999-04-30 | 2011-02-22 | Warsaw Orthopedic, In Emory University | Intracellular delivery of osteoinductive proteins and peptides |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2013032210A2 (ko) * | 2011-08-31 | 2013-03-07 | (주)아모레퍼시픽 | 생체막 투과성 조성물 |
WO2013032210A3 (ko) * | 2011-08-31 | 2013-05-10 | (주)아모레퍼시픽 | 생체막 투과성 조성물 |
WO2017159911A1 (ko) * | 2016-03-17 | 2017-09-21 | 서강대학교 산학협력단 | 줄기세포 분화 제어를 위한 바이오몰레트론 |
US11718687B2 (en) | 2016-03-17 | 2023-08-08 | Sogangn University Research Foundation | Biomoletron for regulation stem cell differentiation |
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