KR20140001198A - 신규 시알로올리고당 유도체들의 합성 - Google Patents
신규 시알로올리고당 유도체들의 합성 Download PDFInfo
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- KR20140001198A KR20140001198A KR20137003908A KR20137003908A KR20140001198A KR 20140001198 A KR20140001198 A KR 20140001198A KR 20137003908 A KR20137003908 A KR 20137003908A KR 20137003908 A KR20137003908 A KR 20137003908A KR 20140001198 A KR20140001198 A KR 20140001198A
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- 238000003786 synthesis reaction Methods 0.000 title description 17
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- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
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Abstract
본 발명은 트랜스시알화 반응에 의하여 일반 화학식 1A의 화합물들 및 그의 염들의 합성 방법에 관한 것으로서, 일반 화학식 1A에서 R 기들 중의 하나는 α-시알릴 모이어티, 다른 하나는 H이고, X1은 탄수화물 링커를 나타내고, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, R1은 가수소분해에 의해 제거될 수 있는 보호기이고, m은 0 또는 1의 정수이다.
Description
본 발명은 시알로올리고당 배당체(glycoside)들의 효소적 합성, 및 상기 합성에 관여하는 신규한 전구체 및 결과물에 관한 것이다.
시알산(sialic acid)들은 9탄당 뉴라민산(neuraminic acid)의 유도체들이고, C-4, C-7, C-8 및 C-9이 다양한 모이어티(moiety)들로 치환될 수 있는 3 가지 모분자(parent molecule)들, N-아세틸-(Neu5Ac)(N-acetyl-(Neu5Ac)), N-글라이콜릴-(Neu5Gc)(N-glycolyl-(Neu5Gc)) 및 데아미노-뉴라민산(deamino-neuraminic acid)(3-deoxy-D-glycero-D-galacto-nonulosonic acid, KDN)을 망라한다. 그것들은 배발생(embryogenesis)에서부터 병원체 상호작용(pathogen interactions)에 대한 신경 가소성(neural plasticity)에 이르는 많은 주요한 생물학적 역할들을 가진다. 비록 그것들이 좀처럼 유리된 형태(free from)로 나타나지는 않지만, 그것들은 항상 당단백질(glycoprotein)들 및 당지질(glycolipid)들의 올리고당 측쇄의 비-환원 말단(non-reducing terminus) 또는 내부 위치에 있는 화학적 공유 결합(covalent linkage)들에서 발견된다. 갈락토스(galactose,), N-아세틸-갈락토사민(N-acetyl-galactosamine) 및 N-아세틸-글루코사민(N-acetyl-glucosamine)과 같은 끝에서 두 번째 당들에 결합된 시알산의 상기 결합들은 대부분 α-2,3- 및 α-2,6-케토사이드 결합(ketosidic bond)이다.
시알로글라이코 결합체(sialoglycoconjugate)들 중에서, 항박테리아성, 항바이러스성, 면역계 및 인지발달(cognitive development) 향상 활성과 같은 독특한 생물학적 활성과 직접적으로 연관되어 있는 시알릴화 된 인유 올리고당(human milk oligosaccharide, HMO)들은 매우 중요하다. 시알릴화 된 인유 올리고당들은 인간 내장계(intestinal system)에서 장내세균총(intestinal flora)의 발달과 유지를 돕는 프리바이오틱스(prebiotics)와 같이 작용하는 것으로 밝혀졌다. 더욱이, 그것들은 또한 항-염증성을 가지고, 따라서 이러한 화합물들은 합성적으로 구성되거나 자연적으로 발생한 화합물들 및 그의 염들 모두, 예를 들어, 영아용 제조분유(infant formulas), 영아용 씨리얼(infant cereals), 임상적 영아용 영양 제품(clinical infant nutritional product), 유아용 제조분유(toddler formulas), 또는 어린이, 성인, 노령 또는 수유 중의 여성을 위한 식이보충제(dietary supplements)나 건강 기능성 식품(health functional food)의 생산을 위한 영양 산업에서 매력적인 성분이다. 마찬가지로, 상기 화합물들은 또한 치료제의 생산을 위한 제약 산업에서도 관심거리이다. 상기 인유 올리고당에서, 상기 시알산 잔기는 항상 D-갈락토스의 말단 3-O- 및/또는 6-O- 위치(들)에 α-글라이코사이드 결합(α-glycosidic linkage)을 통해 연결되어 있다.
자연적으로 발생하는 시알릴화 된 인유 올리고당의 입수가능성은 제한적이다. 성숙 인유(mature human milk)는 가장 높은 농도(12-14 g/l)의 유 올리고당(milk oligosaccharide)들을 함유하는 자연적인 유원(milk source)이고, 다른 유원들은 소의 젖(0.01 g/l), 염소의 젖 및 다른 포유동물들에서 유래한 젖이 있다. 이러한 낮은 자연적 입수가능성과 어려운 분리 방법들은 이러한 매력적인 화합물들의 생산을 위한 생물공학적 및 화학적 방법론들의 발전에 중요한 동기가 된다.
HPLC Chip/MS(microchip liquid chromatography mass spectrometry) 및 MALDI-FT ICR MS(matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance mass spectrometry)를 포함하는 기술들의 조합에 의하여 인유로부터 약 200개의 HMO들이 검출되었고(Ninonuevo et al. J. Agric. Food Chem. 54, 7471 (2006)), 지금까지 적어도 115개의 올리고당들이 구조적으로 결정되었다(Urashima et al.: Milk Oligosaccharides, Nova Medical Books, NY, 2011). 상기와 같은 인유 올리고당들은 13개의 코어 단위들로 그룹화될 수 있다(표 1). 올리고당들의 약 1/4이 시알산을 포함한다.
| 인유 올리고당( HMO )들의 13개의 다른 코어 구조들 | ||
| No | Core name | Core structure |
| 1 | 락토스 (lactose, Lac) | Galβ1-4Glc |
| 2 | 락토-N-테트라오스 (lacto-N-tetraose, LNT) |
Galβ1-3GlcNAcβ1-3Galβ1-4Glc |
| 3 | 락토-N-네오테트라오스 (lacto-N-neotetraose, LNnT) | Galβ1-4GlcNAcβ1-3Galβ1-4Glc |
| 4 | 락토-N-헥사오스 (lacto-N-hexaose, LNH) |
Galβ1-3GlcNAcβ1-3(Galβ1-4GlcNAcβ1-6)Galβ1-4Glc |
| 5 | 락토-N-네오헥사오스 (lacto-N-neohexaose, LNnH) |
Galβ1-4GlcNAcβ1-3(Galβ1-4GlcNAcβ1-6)Galβ1-4Glc |
| 6 | 파라-락토-N-헥사오스 (para-lacto-N-hexaose, para-LNH) |
Galβ1-3GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc |
| 7 | 파라-락토-N-네오헥사오스 (para-lacto-N-neohexaose, para-LNnH) |
Galβ1-4GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc |
| 8 | 락토-N-옥타오스 (lacto-N-octaose, LNO) |
Galβ1-3GlcNAcβ1-3(Galβ1-4GlcNAcβ1-3Galβ1-4GlcNAcβ1-6)Galβ1-4Glc |
| 9 | 락토-N-네오옥타오스 (lacto-N-neooctaose, LNnO) |
Galβ1-4GlcNAcβ1-3(Galβ1-3GlcNAcβ1-3Galβ1-4GlcNAcβ1-6)Galβ1-4Glc |
| 10 | 아이소-락토-N-옥타오스 (Iso-lacto-N-octaose, iso-LNO) |
Galβ1-3GlcNAcβ1-3(Galβ1-3GlcNAcβ1-3Galβ1-4GlcNAcβ1-6)Galβ1-4Glc |
| 11 | 파라-락토-N-옥타오스 (para-lacto-N-octaose, para-LNO) |
Galβ1-3GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc |
| 12 | 락토-N-네오데카오스 (Lacto-N-neodecaose, LNnD) |
Galβ1-3GlcNAcβ1-3[Galβ1-4GlcNAcβ1-3(Galβ1-4GlcNAcβ1-6)Galβ1-4GlcNAcβ1-6]Galβ1-4Glc |
| 13 | 락토-N-데카오스 (Lacto-N-decaose, LND) |
Galβ1-3GlcNAcβ1-3[Galβ1-3GlcNAcβ1-3(Galβ1-4GlcNAcβ1-6)Galβ1-4GlcNAcβ1-6]Galβ1-4Glc |
많은 수의 유사 올리고당들이 존재하기 때문에 인간 및 다른 포유동물들의 젖으로부터 심지어는 밀리그람 양의 시알로올리고당들을 분리하는 것조차 상당히 어렵다. 지금까지, 오직 분석용 HPLC 방법론들만이 자연적인 원천으로부터 일부 시알로올리고당들의 분리를 위해 개발되어 왔다.
복잡한 시알로올리고당들의 합성은 보호(protection) 및 탈보호(deprotection) 전략들을 활용하는 다단계 합성 경로를 따른다. 입체선택성(stereoselective) 화학적 합성 과정들은 보호기(protecting group)들의 광범위한 사용으로 인하여 매우 복잡해질 수 있다. 이러한 전략들은 글라이코할라이드(glycosylhalide), 싸이오글라이코사이드(thioglycoside) 또는 아인산 다이에틸(diethyl phosphite) 공여체(donor) 활성화(activations)를 이용한 적절한 보호된 글라이코실(glycosyl) 수용체(acceptor)들의 입체선택성 O-시알릴화(O-sialylation)를 통하여 시알릴화 된 올리고당들을 생성한다. 사이안화 수은(mercury cyanide), 브롬화 수은(mercury bromide) 및 탄산 은(silver carbonate)과 같은, 시알릴화를 위한 매우 비싸거나 또는 매우 유독한 화학약품들은 이러한 방법론들이 매력적이지 않게 하는 이유들 중의 하나이다. 마찬가지로, 비효율적인 입체조절(stereocontrol) 및/또는 낮은 수율도 상기 전략들을 추가로 개발하는 것이 적합하지 않게 한다. 추가적으로, 이러한 전략들은 심각한 정제(purification) 상의 곤란성으로 특징지어진다.
시알로올리고당들의 효소적 생산의 경우에, 시알릴트랜스퍼라아제(sialyltransferase)들과 시알리다아제(sialidase)들이 선호되는 효소들로서 이용되어 왔다. 이러한 복잡한 효소적 체계들은 대량 생산(scale-up production)에 매우 돈이 많이 드는 방법론들 중 대표적인 것이고, 어려운 정제 프로토콜들 또한 마찬가지로 추가적인 기술 발전에 장애가 된다. 시알리다아제들은 낮은 수율과 위치- 및 입체선택성의 결여로 인해, 양산 방법론으로서 성공적으로 이용될 수 없다. 비록, 일부의 경우들에서, 시알릴트랜스퍼라아제 효소들이 복합한 시알로올리고당들(예, 3'-O-(N-아세틸-뉴라미노실)-락토스 나트륨(3'-O-(N-acetyl-neuraminosyl)-lactose sodium) 염의 1-O-β-벤질 배당체(1-O-β-benzyl glycoside)의 합성: WO 96/32492; 3'-O-(N-아세틸-뉴라미노실)-락토스 나트륨(3'-O-(N-acetyl-neuraminosyl)-lactose sodium) 염의 1-O-β-(4,5-다이메톡시-2-나이트로)-벤질 배당체(1-O-β-(4,5-dimethoxy-2-nitro)-benzyl glycoside)의 합성: Cohen et al. J. Org. Chem. 65, 6145 (2000))의 합성에 효율적인 것으로 밝혀졌지만, 시알산 부분을 수용체 올리고당으로 전이시키기 위한 시알릴 공여체로서 CMP-활성화된 시알산(사이티딘 5'-모노포스포시알산(cytidine 5'-monophosphosialic acid))-사실, 입수가능성이 상당히 제한적이지만-의 필요가 그것들의 유용성을 제한한다.
트랜스시알리다아제 반응에서 기질로서 작용하는 T. 크루지(T. cruzi) 유래 뮤신(mucin) 올리고당들의 N-아세틸-락토사민 벤질 배당체(N-acetyl-lactosamine benzyl glycoside) 및 벤질 배당체들이 연구되어 왔다(Lubineau et al. Carbohydr. Res. 300, 161 (1997); Agustㅽ et al. Bioorg. Med. Chem. 15, 2611 (2007)).
시알리다아제에 의하여 보호되지 않았거나 또는 아노머성으로 치환된 갈락토스, 락토스 또는 N-아세틸-락토사민(N-acetyl-lactosamine) 유도체들이 낮은 수율로 위치선택적 시알화됨이 보고되어 왔다(Thiem et al. Angew. Chem. Int. Ed. Eng. 30, 1503 (1991); Schmidt et al. Chem. Comm. 1919 (2000); Schmidt et al. J. Org. Chem. 65, 8518 (2000)).
유전학적으로 조작된 박테리아, 효모 또는 다른 미생물들을 이용하는 일부 생물공학적 방법론들 또한 보고되고 있다. 그러한 방법들은 제한된 상품화 기회로 인해 조절 과정(regulatory processes)에서 심각한 문제점을 가진다.
시알로글라이코 결합체들은 산 및 염기와 같은 특정 반응 조건 하에서 불안정한 것으로 알려져 있다. 실제로, 그것들은 자가-가수분해될 수 있다. 따라서, 이러한 화합물의 제조와 정제를 위한 조건들은 신중하게 선택되어야 한다.
요컨대, 자연적인 원천의 풀, 예, 인유에 존재하는 많은 수의 올리고당들로 인하여, 분리 기술들은 대량의 시알로올리고당들을 제공할 수 없었다. 또한, 극히 유사한 구조로 특징화되는 구조이성질체(regioisomer)들의 존재는 분리 기술들이 성공하기 더욱 힘들게 한다. 효소적 방법론들은 유전학적으로 조작된 미생물들에서 생산된 효소들을 사용하기 때문에, 효소의 낮은 입수가능성, 매우 높은 당 뉴클레오타이드 공여체 가격 및 조절 상의 어려움들이 있다. 생물공학을 통한 올리고당들의 제조는 몇몇의 비자연적인 글라이코실화(glycosylation) 산물의 잠재적인 형성으로 인하여 조절 상의 큰 장애가 있다. 일반적으로, 시알로올리고당들을 합성하기 위해 개발된 모든 화학적 방법들은 심지어는 수 그람(multigram) 양의 표적 화합물들을 제조하는 것조차 방해하는 몇몇의 문제점들이 있다(예, 대응하는 벤질 배당체를 통한 3'-O- 및 6'-O-(N-아세틸-뉴라미노실)-락토스(6'-O-(N-acetyl-neuraminosyl)-lactose)의 합성: Rencurosi et al. Carbohydr. Res. 337, 473 (2002) 참조).
과거 수십년 동안, 시알릴화 된 인유 올리고당의 제조 및 상업화에 대한 관심은 점점 증대되고 있다. 제조를 단순화하고, 선행 기술의 방법들에서 맞닥뜨렸던 정제 문제들을 극복 또는 회피할 수 있는 신규한 방법론들에 대한 필요는 여전히 존재한다.
일 측면에서, 본 발명은 트랜스시알리다아제(transsialidase) 활성을 가지는 효소의 촉매 작용 하에서, 화학식 SA-OR2 및 그의 염들의 시알릴 공여체(sialyl donor)가 일반 화학식 2A 및 그의 염들의 시알릴 수용체(sialyl acceptor)와 반응되는 것을 특징으로 하는 일반 화학식 1A의 화합물 및 그의 염들의 합성 방법에 관한 것이고,
화학식 SA-OR2에서, R2는 단-(mono-), 이-(di-) 또는 올리고당(oligosaccharide), 당지질(glycolipid), 당단백질(glycoprotein) 또는 당펩티드(glycopeptide), 고리형(cyclic) 또는 비고리형(acyclic) 지방족 기(aliphatic group), 또는 아릴 잔기(residue)이고, SA는 α-시알릴 모이어티(α-sialyl moiety)이고,
일반 화학식 1A에서, R 기들 중의 하나는 α-시알릴 모이어티, 다른 하나는 H이고, X1은 탄수화물 링커를 나타내고, A는 선택적으로 푸코실(fucosyl)로 치환된 D-글루코피라노실 단위(D-glucopyranosyl unit)이고, R1은 가수소분해(hydrogenolysis)에 의해 제거될 수 있는 보호기(protecting group)이고, m은 0 또는 1의 정수이며,
일반 화학식 2A에서, X1, A, m 및 R1은 상기에서 정의한 바와 같다.
다른 측면에서, 본 발명은 일반 화학식 1A'의 화합물 및 그의 염들을 제공하고,
일반 화학식 1A'에서, R 기들 중의 하나는 α-시알릴 모이어티, 다른 하나는 H이고, R1은 가수소분해에 의해 제거될 수 있는 보호기이고, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, m은 0 또는 1의 정수이고, X1은 탄수화물 링커를 나타내며,
단, 3'-O-(N-아세틸-뉴라미노실)-락토스((3'-O-(N-acetyl-neuraminosyl)-lactose)) 나트륨 염의 1-O-β-벤질(1-O-β-benzyl) 및 1-O-β-(4,5-다이메톡시-2-나이트로)-벤질(1-O-β-(4,5-dimethoxy-2-nitro)-benzyl) 배당체들, 및 6'-O-(N-아세틸-뉴라미노실)-락토스(6'-O-(N-acetyl-neuraminosyl)-lactose) 나트륨 염의 1-O-β-벤질(1-O-β-benzyl) 배당체는 제외된다.
본 발명은 아노머성 위치에서 보호된 신규 시알로올리고당들 및 그의 생산에 적합한 방법론을 제공한다.
본 발명은 트랜스시알화 반응에서 수용성 1-O-보호된 올리고당 중간체(1-O-protected oligosaccharide intermediates)의 활용에 기반하고, 상기 1-O-보호기는 가수소분해에 의하여 제거될 수 있다. 바람직하게, 상기 1-O-보호기는 또한 상기 올리고당 중간체에 강력한 정제 과정을 돕는 물리적 및 화학적 특성들을 제공한다. 예를 들어, 소수성 모이어티로서 벤질 또는 치환된 벤질 기와 같은 상기 방향족 기(aromatic group)는 유도체들이 그들의 수용성도(water solubility)는 그대로 두면서, 알콜과 같은 유기 양성자성 용매에 용해될 수 있도록 한다. 이는 광범위한 물/알콜 비율을 갖는 이동상(mobile phases)의 이용 가능성을 연다. 또한, 상기 방향족 기에 치환기들의 신중한 설계함으로써, 일부 경우들에서 생성물 정제에 결정화만을 이용하는 강력한 생산 절차의 개발을 가능하게 하는 결정성 화합물(crystalline compound)들을 수득할 수 있다. 더욱이, 상기 벤질 기를 포함하는 1-O-보호기는 부산물의 생성을 막는 온화하고 정교한 조건 하에서의 최종 단계에서 촉매적 환원(가수소분해)에 의해 제거될 수 있고, 이는 표적 올리고당에 적어도 하나의 시알릴 기(sialyl group)가 존재하는 경우에 확실히 유리하다. 상기 촉매적 환원은 수용액 상에서 일어날 수 있다.
본 발명은 하기에서, 본 발명에 따른 3'''-O-시알릴-β-LNnT(3'''-O-sialyl-β-LNnT)의 400 MHz 1H-NMR 스펙트럼을 나타내는 도 1을 참조하여 보다 상세히 설명될 것이다.
올리고당을 합성하기 위해 취해지는 경로에 관계없이, 최종 표적인 비보호된 올리고당은 오직 물에만 용해되는데, 이는 상기 합성의 후속 단계들을 위한 과제(challenge)들을 제공한다. 합성적 생산 과정들에서 흔히 이용되는 유기 용매들은 상기 올리고당 합성의 최종 단계의 반응들에 적합하지 않다.
본 발명은 아노머성 위치에서 보호된 신규 시알로올리고당들 및 그의 생산에 적합한 방법론을 제공한다. 본 발명은 트랜스시알화 반응에서 수용성 1-O-보호된 올리고당 중간체의 활용에 기반하고, 상기 1-O-보호기는 가수소분해에 의하여 제거될 수 있다. 바람직하게, 상기 1-O-보호기는 또한 상기 올리고당 중간체에 강력한 정제 과정을 돕는 물리적 및 화학적 특성들을 제공한다. 예를 들어, 소수성 모이어티로서 벤질 또는 치환된 벤질 기와 같은 상기 방향족 기는 유도체들이 그들의 수용성도는 그대로 두면서, 알콜과 같은 유기 양성자성 용매에 용해될 수 있도록 한다. 이는 광범위한 물/알콜 비율을 갖는 이동상의 이용 가능성을 연다. 또한, 상기 방향족 기에 치환기들의 신중한 설계함으로써, 일부 경우들에서 생성물 정제에 결정화만을 이용하는 강력한 생산 절차의 개발을 가능하게 하는 결정성 화합물들을 수득할 수 있다. 더욱이, 상기 벤질 기를 포함하는 1-O-보호기는 부산물의 생성을 막는 온화하고 정교한 조건 하에서의 최종 단계에서 촉매적 환원(가수소분해)에 의해 제거될 수 있고, 이는 표적 올리고당에 적어도 하나의 시알릴 기가 존재하는 경우에 확실히 유리하다. 상기 촉매적 환원은 수용액 상에서 일어날 수 있다.
일반적인 용어들
본 출원의 전체에 걸쳐, 시알릴 공여체들과 일반 화학식 1의 화합물에 존재하는 "α-시알릴 모이어티" 또는 "시알릴 모이어티(sialyl moiety)" 용어는 식(scheme) 1의 N-아세틸 뉴라민산(N-acetyl neuraminic acid)의 예로 도시되는 바와 같이, α-글라이코사이드 결합(α-glycosidic linkage)을 갖는, 모든 자연적으로 발생하거나 또는 변형된 뉴라민산 또는 시알산 유도체들의 글라이코실 모이어티(glycosyl moiety) 및 그의 유사체(analogue)들을 일컫는다. 바람직한 뉴라민산들은 N-아세틸- (N-acetyl-, Neu5Ac), N-글라이콜릴- (N-glycolyl-, Neu5Gc) 및 데아미노-뉴라민산(deamino-neuraminic acid) (3-deoxy-D-glycero-D-galacto-nonulosonic acid, KDN)이다. 또한, 링커들, 반응성 기능기들, 검출가능한 라벨들 또는 표적 모이어티들과 함께 유도되거나/유도되고, C-4, C-7-, C-8 및/또는 C-9가 아실옥시(acyloxy), 알콕시(alkoxy), 할로젠(halogen) 또는 아지도(azido)로 치환된 Neu5Ac, Neu5Gc 및 KDN 유도체들도 포함된다. 더욱 바람직한 O-치환기(O-substituent)들은 아세틸(C-4, C-7-, C-8 및/또는 C-9에), 락틸(C-9에), 메틸(C-8에), 황산(sulphate)(C-8에) 또는 인산(phosphate)(C-8에)이다. 아미노 기(amino group) 상의 상기 바람직한 치환기들은 글라이콜릴(glycolyl) 및 아세토아세틸(acetoacetyl)을 포함하는 아실들이다.
식(scheme) 1
상기 "가수소분해에 의해 제거되는 보호기"는 1-산소의 C-O 결합이 촉매량의 팔라듐(palladium), 라니 니켈(Raney nickel) 또는 가수소분해에 이용되는 것으로 알려진 다른 적절한 금속 촉매들의 존재 하에서 수소의 첨가에 의하여 갈라져 OH 기의 재생성을 야기하는 기들을 일컫는다. 상기와 같은 보호기들은 당업자에게 잘 알려져 있고, Protective Groups in Organic Synthesis, PGM Wuts and TW Greene, John Wiley & Sons 2007에 논의되어 있다. 적절한 보호기들은 벤질(benzyl), 다이페닐메틸(벤즈하이드릴)(diphenylmethyl (benzhydryl)), 1-나프틸메틸(1-naphthylmethyl), 2-나프틸메틸(2-naphthylmethyl) 또는 트라이페닐메틸(triphenylmethyl, trityl) 기들을 포함하고, 이들 각각은 알킬, 알콕시, 페닐, 아미노, 아실아미노, 알킬아미노, 다이알킬아미노, 나이트로, 카복실, 알콕시카보닐, 카바모일(carbamoyl), N-알킬카바모일(N-alkylcarbamoyl), N,N-다이알킬카바모일(N,N-dialkylcarbamoyl), 아지도, 할로젠알킬(halogenalkyl) 또는 할로젠으로부터 선택된 하나 이상의 기들에 의하여 선택적으로 치환될 수 있다. 바람직하게, 상기 치환이 존재한다면, 그러한 치환은 방향족 고리(들)상에 있다. 특히 바람직한 보호기들은 페닐, 알킬 또는 할로젠으로부터 선택된 하나 이상의 기들로 선택적으로 치환된 벤질(benzyl) 또는 2-나프틸메틸(2-naphthylmethyl) 기들이다. 더욱 바람직하게, 상기 보호기는 비치환된 벤질, 비치환된 2-나프틸메틸, 4-클로로벤질(4-chlorobenzyl), 3-페닐벤질(3-phenylbenzyl) 및 4-메틸벤질(4-methylbenzyl)이다. 이러한 특히 바람직하고 더욱 바람직한 보호기들은 상기 가수소분해의 부산물들이 각각 배타적으로 톨루엔(toluene), 2-메틸나프탈렌(2-methylnaphthalene), 또는 치환된 톨루엔 또는 2-메틸나프탈렌 유도체들이라는 이점을 갖는다. 그러한 부산물들은 수용성 올리고당 생성물들로부터 심지어는 수 톤 규모라 할지라도 증발(evaporation) 및/또는 추출 과정들을 통해 용이하게 제거될 수 있다.
본 명세서의 전체에 걸쳐, 용어 "알킬(alkyl)"은 메틸(methyl), 에틸(ethyl), n-프로필(n-propyl), i-프로필(i-propyl), n-뷰틸(n-butyl), i-뷰틸(i-butyl), s-뷰틸(s-butyl), t-뷰틸(t-butyl), n-헥실(n-hexyl) 등과 같이 탄화수소(hydrocarbon) 기가 1-6 탄소 원자들로 포화된 선형 또는 분지형의 사슬을 의미한다.
용어 "아릴(aryl)"은 페닐 또는 나프틸과 같은 유사방향족(homoaromatic) 기를 일컫는다.
본 명세서에서, 용어 "아실(acyl)"은 포밀(formyl), 아세틸(acetyl), 프로피오닐(propionyl), 뷰티릴(butyryl), 피발로일(pivaloyl), 벤조일(benzoyl) 등과 같은 R'-C(=O)-기, 여기서 R'은 H, 알킬(상기 참조) 또는 아릴(상기 참조)을 나타낸다. 상기 알킬 또는 아릴 잔기는 비치환되거나, 또는 알킬(오직 아릴 잔기들의 경우에만), 할로젠, 나이트로, 아릴, 알콕시, 아미노, 알킬아미노, 다이알킬아미노, 카복실, 알콕시카보닐, 카바모일, N-알킬카바모일, N,N-다이알킬카바모일, 아지도, 할로젠알킬 또는 하이드록시알킬(hydroxyalkyl)로부터 선택되는 하나 이상의 기로 치환되어 클로로아세틸(chloroacetyl), 트라이클로로아세틸(trichloroacetyl), 4-클로로벤조일(4-chlorobenzoyl), 4-나이트로벤조일(4-nitrobenzoyl), 4-페닐벤조일(4-phenylbenzoyl), 4-벤자미도벤조일(4-benzamidobenzoyl), 4-(페닐카바모일)-벤조일(4-(phenylcarbamoyl)-benzoyl), 글라이콜릴(glycolyl), 아세토아세틸(acetoacetyl) 등과 같은 아세틸 기들을 생성할 수 있다.
용어 "알킬옥시(alkyloxy)" 또는 "알콕시(alkoxy)"는 메톡시(methoxy), 에톡시(ethoxy), t-뷰톡시(t-butoxy) 등과 같이 산소 원자를 통해 모 분자 모이어티에 부착된 알킬 기(상기 참조)를 의미한다.
"할로젠(halogen)"은 플루오로(fluoro), 클로로(chloro), 브로모(bromo) 또는 아이오도(iodo))를 의미한다.
"아미노(amino)"는 -NH2 기를 일컫는다.
"알킬아미노(alkylamino)"는 메틸아미노(methylamino), 에틸아미노(ethylamino) 등과 같이 -NH-기를 통해 모 분자 모이어티에 부착된 알킬 기(상기 참조)를 의미한다.
"다이알킬아미노(dialkylamino)"는 다이메틸아미노(dimethylamino), 다이에틸아미노(diethylamino) 등과 같이 질소 원자를 통해 모 분자 모이어티에 부착된 동일 또는 상이한 두 개의 알킬 기(상기 참조)들을 의미한다.
"아실아미노(acylamino)"는 아세틸아미노(acetylamino, acetamido), 벤조일아미노(benzoylamino, benzamido) 등과 같이 -NH-기를 통해 모 분자 모이어티에 부착된 아실 기(상기 참조)를 일컫는다.
"카복실(carboxyl)"은 -COOH 기를 나타낸다.
"알킬옥시카보닐(alkyloxycarbonyl)"은 메톡시카보닐(methoxycarbonyl), t-뷰톡시카보닐(t-butoxycarbonyl) 등과 같이 -C(=O)-기를 통해 모 분자 모이어티에 부착된 알킬옥시 기(상기 참조)를 의미한다.
"카바모일(carbamoyl)"은 H2N-C(=O)-기이다.
"N-알킬카바모일(N-Alkylcarbamoyl)"은 N-메틸카바모일(N-methylcarbamoyl) 등과 같이 -HN-C(=O)-기를 통해 모 분자 모이어티에 부착된 알킬 기(상기 참조)를 의미한다.
"N,N-다이알킬카바모일(N,N-dialkylcarbamoyl)"은 N,N-메틸카바모일(N,N-methylcarbamoyl) 등과 같이 >N-C(=O)-기를 통해 모 분자 모이어티에 부착된 동일 또는 상이한 두 개의 알킬 기(상기 참조)들을 의미한다.
본 명세서에서, 적어도 하나의 시알릴 잔기를 포함하는 일반 화학식 1 및 2와 화학식 SA-OR2와 관련된 용어 "염(salt)"은 음전하를 띠는 산 잔기(acid residue)와 비화학량적 비율에 맞는 하나 이상의 양이온들로 구성되는 조합된 이온 쌍(associated ion pair)을 의미한다. 본 명세서에서 의미하는 양이온들은 양 전하를 띠는 원자들 또는 분자들이다. 상기 양이온은 유기 또는 무기 양이온일 수 있다. 바람직한 무기 양이온들은 암모늄(ammonium) 이온, 알칼리 금속(alkali metal), 알칼리 토금속(alkali earth metal) 및 전이 금속 이온들(transition metal ions)이고, 더욱 바람직하게 Na+, K+, Ca2+, Mg2+, Ba2+, Fe2+, Zn2+, Mn2+ 및 Cu2+, 가장 바람직하게 K+, Ca2+, Mg2+, Ba2+, Fe2+ 및 Zn2+이다. 양전하를 띠는 형태의 염기성 유기 화합물들은 유기 양이온과 관련이 있을 수 있다. 바람직한 양전하를 띠는 대응물들은, 모두 양성자화된 형태인, 다이에틸 아민(diethyl amine), 트라이에틸 아민(triethyl amine), 다이아이소프로필 에틸 아민(diisopropyl ethyl amine), 에탄올아민(ethanolamine), 다이에탄올아민(diethanolamine), 트라이에탄올아민(triethanolamine), 이미다졸(imidazol), 피페리딘(piperidine), 피페라진(piperazine), 모폴린(morpholin), 벤질 아민(benzyl amine), 에틸렌 디아민(ethylene diamine), 메글루민(meglumin), 피롤리딘(pyrrolidine), 콜린(choline), 트리스-(하이드록시메틸)-메일 아민(tris-(hydroxymethyl)-methyl amine), N-(2-하이드록시에틸)-피롤리딘(N-(2-hydroxyethyl)-pyrrolidine), N-(2-하이드록시에틸)-피페리딘(N-(2-hydroxyethyl)-piperidine), N-(2-하이드록시에틸)-피페라진(N-(2-hydroxyethyl)-piperazine), N-(2-하이드록시에틸)-모폴린(N-(2-hydroxyethyl)-morpholine), L-아르지닌(L-arginine), L-라이신(L-lysine), L-아르지닌 또는 L-라이신 단위를 갖는 올리고펩타이드들 또는 N-말단에 유리 아미노 기를 갖는 올리고펩타이드들 등이다. 상기와 같은 염 형성물(salt formation)들은 복잡한 분자의 안정성, 부형제(excipient)들에 대한 호환성(compatibility), 용해도 및 결정 형성능 등과 같은 특성을 전체적으로 변형하는데 이용될 수 있다.
트랜스시알화
반응들(
Transsialidation
reactions
)
본 발명에 따르면, 트랜스시알리다아제(transsialidase) 활성을 가지는 효소의 촉매 작용 하에서, 화학식 SA-OR2 및 그의 염들의 시알릴 공여체(sialyl donor)가 일반 화학식 2 및 그의 염들의 시알릴 수용체(sialyl acceptor)와 반응되는 것을 특징으로 하는 일반 화학식 1의 화합물 및 그의 염들의 합성 방법이 제공되고, 화학식 SA-OR2에서, R2는 단-(mono-), 이-(di-) 또는 올리고당, 당지질, 당단백질 또는 당펩티드, 고리형(cyclic) 또는 비고리형(acyclic) 지방족 기(aliphatic group), 또는 아릴 잔기이고, SA는 α-시알릴 모이어티이고, 일반 화학식 1에서, R 기들 중의 하나는 α-시알릴 모이어티), 다른 하나는 H이고, X는 탄수화물 링커를 나타내고, R1은 가수소분해에 의해 제거될 수 있는 보호기이고, n은 0 또는 1의 정수이다. 상기 과정은 식(scheme) 2에 도시된다.
식(scheme) 2
일반 화학식 1의 화합물을 제공하는 것의 이점은 비글라이코실화 된 시알로올리고당들에 비하여 시알릴화된 올리고당 1-O-보호된 배당체들의 보다 간단한 정제이다. 부산물로서 유리 시알산의 형성이 없고, 반응 화합물들의 다른 극성 때문에, 역상 도는 크기 배제 크로마토그래피에 의한 생성물의 분리가 가능하다. 역상 크로마토그래피의 경우, 물이 이용될 때, 일반 화학식 1의 화합물은 반응 혼합물 내에 존재하는 극성 화합물들보다 훨씬 더 느리게 이동하고, 따라서 상기 극성 화합물들은 원활하게 용출될 수 있다. 그런 다음, 일반 화학식 1의 화합물들은 예를 들어 알콜로 칼럼으로부터 세척될 수 있다.
트랜스시알리다아제
활성을 갖는 효소(
Enzymes
having
transsialidase
activity
)
트랜스시알리다아제 활성을 갖고 본 출원에서 청구되는 시알로올리고당들의 제조 방법의 목적에 적합한 효소들은 시알리다아제 및 트랜스시알리다아제 효소들로부터 선택될 수 있다.
GH33 족으로 분류되는 시알리다아제들(EC 3.2.1.18)은 다양한 시알로글라이코 결합체들의 말단 시알산의 α-결합, 주로 갈락토스에 α-2-3 또는 α-2-6 결합으로 결합된 것들을 가수분해하는 능력을 갖는 유지 효소(retaining enzyme)이다. 그것들은 특히 다양한 바이러스 족들과 박테리아에서 발견되고, 또한, 원생동물(protozoa), 일부 무척추동물(invertebrates) 및 포유동물(mammal)에서도 발견된다. 일부 박테리아의 시알리다아제는 박테리아 세포 성장을 위한 영양분으로서 시알릴화된 당단백질, 당지질 또는 다른 당-결합체(glycoconjugate)들로부터 시알산들을 제거하는데 이용될 수 있다.
비록 시알리다아제들이 그것들의 가수분해 활성에 의해 특징화되지만, 적절한 반응 조건들 하에서 그것들은 시알로글라이코-결합체들의 형성을 야기시키는 트랜스시알화 반응에 의하여 아시알로 수용체(asialo acceptor)로 시알산 단위의 전이를 촉매할 수 있다. 박테로이데스 프라질리스(Bacteroides fragilis), 클로스트리듐(Clostridium) 종들(예, C. 퍼프린젠스(C. perfringens)), 코리네박테리움 디프테라아(Corynebacterium diphtheriae), 해모필러스 파라수이스(Haemophilus parasuis), 파스튜렐라 물토시다(Pasteurella multocida), 슈도모나스 애루지노사(Pseudomonas aeruginosa), 살모넬라 티피뮤리움(Salmonella typhimurium), 스트렙토코커스 뉴모니아(Streptococcus pneumoniae), 타네렐라 포시티아(Tannerella forsythia), 비브리오 콜레라(Vibrio cholerae) 또는 뉴캐슬병 바이러스(Newcastle disease virus)와 같은 병원성 박테리아 또는 바이러스들, 및
악티노마이세스 비스코서스(Actinomyces viscosus), 아스로박터(Arthrobacter) 종들 또는 마이크로모노스포라 비기디파시엔스(Micromonospora viridifaciens)와 같은 비병원성 박테리아 또는 바이러스들로부터 유래한 시알리다아제들은 그것들의 α-2-3 및/또는 α-2-6 선택성을 갖는 트랜스시알리다아제 활성으로 인하여 시알릴화 반응(sialylation reaction)을 위한 촉매로서 작용할 수 있다. 상기 위치선택성(regioselectivity)에 관하여, α-2-3- 및 α-2-6-결합된 생성물들 간의 비율은 효소들 및/또는 수용체들에 따라 달라진다. 예를 들어, A. 우레아파시엔스(A. ureafaciens), C. 퍼프린젠스(C. perfringens) 및 V. 콜레라(V. cholerae)로부터 유래된 시알리다아제들은 좋은 α-2-6 선택성을 갖는 반면, S. 티피뷰리움(S. typhimurium) 및 뉴캐슬병 바이러스(Newcastle disease virus)로부터 유래한 것들은 α-2-3 결합의 형성에 높은 선호도(preference)를 가진다.
최근, 비피도박테리움 비피둠(Bifidobacterium bifidum) 및 비피도박테리움 롱검 아종. 인판티스(Bifidobacterium longum subsp. infantis)과 같은 비피도박테리움(Bifidobacterium) 종들에서 유래한 시알리다아제들이 동정, 클로닝되고 특성이 밝혀졌다. 상기 시알리다아제들은 α-2,3- 및 α-2,6-결합된 시알로사이드(sialoside)들을 모두 분해하고 인식할 수 있다. 비피도박테리움 롱검 아종. 인판티스(Bifidobacterium longum subsp. infantis)에서 유래한 시알리다아제들은 α-2,6-결합에 일관된 선호도를 가지는 반면, 비피도박테리움 비피둠(Bifidobacterium bifidum)은 α-2,3-결합에 일관된 선호도를 가진다.
위치선택성 및/또는 트랜스시알화 반응을 향상시키기 위해서, 상기 시알리다아제들은 다양한 조작 기술들에 의하여 변형될 수 있다.
적절한 조작으로, 점 돌연변이(point mutatiion)에 의하여 신규 변형 효소들(돌연변이체들)이 생성되었다. 상기 돌연변이는 유전학적으로 상기 효소의 활성 부위에 영향을 미친다. 촉매적 친핵체(catalytic nucleophile)의 비-친핵성 잔기로의 대체는 비활성 돌연변이의 형성 또는 트랜스글라이코실화(transglycosylation)를 위한 반응성 주-객 복합체(reactive host-guest complex)의 형성을 위한 적절한 환경의 결핍으로 인하여 감소된 트랜스글라이코실화 활성을 갖는 변형된 효소를 야기한다. 그러나, 천연형보다 더욱 높은 활성을 갖는 시알릴 공여체의 존재하에서, 상기 돌연변이된 효소는 상기 시알릴 잔기를 적합한 수용체에 효율적으로 전이시킬 수 있다. 효소의 적절한 조작은 일반적으로 정지된 상태의 3D 단백질 구조에 의존한다. 상기의 변형된 효소들은 생성물 가수분해 활성이 전혀 없을 수도 있다.
유도 진화(directed evolution) 전략라고 불리는 두 번째 기술은 선별된 천연형 시알리다아제 효소의 무작위적인 돌연변이 유발(mutagenesis)을 포함하여, 각각의 변이체들이 단일 또는 복수의 위치들에서 변형이 일어난 효소 변이체들의 라이브러리를 생성한다. 그것들은 약간 변형된 특성들을 갖는 재조합 변이체들을 생산하기 위하여 E. 콜라이(E. coli) 또는 S. 세레비시아(S. cerevisiae)와 같은 적합한 미생물들에 삽입될 수 있다. 그런 다음, 빠르고 신뢰성 있는 스크리닝 방법으로 향상된 효소를 발현하는 클론들이 동정되고, 선별되어, 돌연변이 과정의 다음 차례로 진행된다. 원하는 활성 및/또는 특이성을 가진 돌연변이(들)이 진화될 때까지 돌연변이, 재조합 및 선별의 반복되는 순환들이 계속된다.
트랜스시알리다아제들에 관하여, 가장 먼저 개시된 트랜스시알리다아제 효소는 샤가스 병(Chagas disease)을 일으키는 원생동물인 트리파노소마 크루지(Trypanosoma cruzi)에서 발견되었다. 그 이후로, 트랜스시알리다아제는 트리파노소마 브루세이 감비언스(Trypanosoma brucei gambiense), 트리파노소마 브루세이 로데시언스(Trypanosoma brucei rhodesiense), 트리파노소마 브루세이 브루세이(Trypanosoma brucei brucei) 및 프리파노소마 콩골렌스(Trypanosoma congolense)와 같은 몇몇의 다른 트리파노솜 유형들에서 발견되어 왔다. 더욱이, 트랜스시알리다아제들의 존재는 엔도트리파눔(Endotrypanum) 유형, 코리네박테리움 디프테리아(Corynebacterium diphtheriae) 및 심지어는 인간 혈장(plasma)에서도 밝혀졌다.
트랜스시알리다아제들은 시알리다아제의 시알산에 대한 가수분해 활성에 더하여 더욱 중요한 시알산 전이 활성(sialic acid transfer activity)을 가진다는 점에서 시알리다아제들과는 다르다. 트랜스시알리다아제들은 공여체 분자로부터 시알산들, 바람직하게는 α-2,3-결합된 시알산들을 수용체 유도체, 바람직하게는 β-인터글라이코사이드 결합(β-interglycosidic linkage)을 갖는 말단 갈락토스 모이어티로 전이시킬 수 있다. 상기의 전이의 결과로서, 상기 시알산과 상기 수용체 간에 α-글라이코사이드 결합이 형성된다. 그러나, 적합한 수용체가 없다면, 상기 트랜스시알리다아제는 상기 시알산을 가수분해한다.
트랜스시알리다아제 작용에 대하여, 예를 들어 아미노산 서열을 변경시킴으로써 상기 가수분해 활성이 제거된 유도된 트랜스시알리다아제 효소 돌연변이체들이 생산될 수 있다. 돌연변이 유발 및/또는 재조합에 의하여 변형된 유전자들의 라이브러리를 생성한 다음, 그것들은 약간 변형된 특성들을 갖는 재조합 변이체들을 생산하기 위해 E. 콜라이(E. coli) 또는 S. 세레비시아(S. cerevisiae)와 같은 적합한 미생물들에 삽입될 수 있다. 그런 다음, 효소를 발현하는 클론들이 동정되고, 분리되어 원하는 목적을 위해 이용될 수 있다. 예를 들어, 서열과 구조 비교에 기반하여, 트리파노소마 랑겔리(Trypanosoma rangeli)로부터 유래된 시알리다아제는 6개의 위치들에서 돌연변이될 수 있고, 상기 변형된 돌연변이체는 현저한 수준의 트랜스시알리다아제 활성을 나타낼 수 있다(Paris et al. J. Mol. Biol. 345, 923 (2005)).
바람직하게, 상기 트랜스시알리다아제 활성을 갖는 효소는 비도박테리움 롱검 아종. 인판티스(Bifidobacterium longum subsp. infantis) ATCC 15697, 비도박테리움 비피둠(Bifidobacterium bifidum) JCM1254, 비도박테리움 비피둠(Bifidobacterium bifidum) S17, 비도박테리움 비피둠(Bifidobacterium bifidum) PRL2010, 비도박테리움 비피둠(Bifidobacterium bifidum) NCIMB 41171, 트리바노소마 크루지(Trypanosoma cruzi) 등에서 유래된 시알리다아제들 또는 트랜스시알리다아제들로부터 선택될 수 있다.
보다 바람직하게, 상기 트랜스시알리다아제 활성을 갖는 효소는 하기의 기탁 번호에 따라 정의되는 시알리다아제들 또는 트랜스시알리다아제들로부터 선택될 수 있다: gi|213524659 (비도박테리움 롱검 아종. 인판티스 ATCC 15697, SEQ ID NO: 1), gi|213523006 비도박테리움 롱검 아종. 인판티스 ATCC 15697, SEQ ID NO: 2), gi|309252191 (비도박테리움 비피둠 S17, SEQ ID NO: 3), gi|309252190 (비도박테리움 비피둠 S17, SEQ ID NO: 4), gi|310867437 (비도박테리움 비피둠 PRL2010, SEQ ID NO: 5), gi|310867438 (비도박테리움 비피둠 PRL2010, SEQ ID NO: 6), gi|224283484 (비도박테리움 비피둠 NCIMB 41171, SEQ ID NO: 7), gi|224283485 (비도박테리움 비피둠 NCIMB 41171, SEQ ID NO: 8), gi|334283443 gi|47252690 (비도박테리움 비피둠 JCM1254, SEQ ID NO: 9), gi|47252690 (T. cruzi, SEQ ID NO: 10), gi|432485 (T. 크루지, SEQ ID NO: 11). 트랜스시알리다아제 활성을 갖는 특히 바람직한 시알리다아제들/트랜스시알리다아제들은 하기 표 2에 열거된다:
| 바람직한 시알리다아제들 / 트랜스시알리다아제들 | ||
|
GenBank
데이터베이스의 GI 번호 |
생물체(Organism) | 서열번호: |
| gi|213524659 | Bifidobacterium longum subsp. infantis ATCC 15697 | 1 |
| gi|213523006 | Bifidobacterium longum subsp. infantis ATCC 15697 | 2 |
| gi|309252191 | Bifidobacterium bifidum S17 | 3 |
| gi|309252190 | Bifidobacterium bifidum S17 | 4 |
| gi|310867437 | Bifidobacterium bifidum PRL2010 | 5 |
| gi|310867438 | Bifidobacterium bifidum PRL2010 | 6 |
| gi|224283484 | Bifidobacterium bifidum NCIMB 41171 | 7 |
| gi|224283485 | Bifidobacterium bifidum NCIMB 41171 | 8 |
| gi|334283443 | Bifidobacterium bifidum JCM1254 | 9 |
| gi|47252690 | Trypanosoma cruzi | 10 |
| gi|432485 | Trypanosoma cruzi | 11 |
트랜스시알리다아제 활성을 유지하고 상기 언급된 트랜스시알리다아제 활성을 갖는 효소 서열들의 서열에 대하여, 아미노산 수준 상의 전체 야생형 서열에 비해 적어도 70%, 보다 바람직하게는 적어도 80%, 보다 더욱 바람직하게는 적어도 85%, 보다 더욱 바람직하게는 적어도 90%, 그리고 가장 바람직하게는 적어도 95%, 또는 심지어 97%, 98% 또는 99%의 서열 유사성/상동성을 갖는 시알리다아제들/트랜스시알리다아제들 효소 돌연변이체들이 설계된다.
바람직하게는, 상기 서열 유사성이 적어도 90%, 보다 바람직하게는 95%, 97%, 98% 또는 가장 바람직하게 99%이다. 바람직하게는, 상기 트랜스시알리다아제 활성이 상기 효소의 천연형의 활성의 적어도 75%, 보다 바람직하게는 적어도 90% 및 보다 더욱 바람직하게는 적어도 100%이다.
시알리다아제들 및 트랜스시알리다아제들은 선행 기술에서 이용된 시알릴트랜스퍼라아제보다 광범위한 공여체와 수용체 특이성을 가지며, 특히 다양한 반응들에 이용될 수 있다. 따라서, 시알리다아제들/트랜스시알리다아제들은 종래 이용되던 시알릴트랜스퍼라아제보다 산업적 활용에 더욱 유리하다.
시알리다아제들 / 트랜스시알리다아제들의 공여체들(Donors for sialidases / transsialidases )
T. 크루지로 생물체를 감염시키면, T. 크루지 내의 트랜스시알리다아제가 숙주 생물체의 시알로올리고-결합체들로부터 시알산들을 제거하고, 자신의 에피토프(epitope)를 감추기 위하여 자신의 표면 뮤신을 효율적으로 시알릴화시킨다.
수많은 집중적인 연구 결과, 시알화 반응들에서 시알릴 공여체들로서 작용할 수 있는 유도체들을 포함하는 다수의 천연 및 합성의 시알산이 발견되었다. 따라서, 상기에서 정의된 일반 화학식 SA-OR2의 시알릴 공여체 화합물들은 트랜스시알리다아제들에 의하여 상기 수용체로 전이될 기질을 제공할 수 있다. 트랜스시알리다아제들은 상기 수용체로 순수한 시알산이나 CMP-시알산(실제로, β-시알라이드(β-sialide))를 전이시키는 것이 아니라, α-아노머성 아글리콘(α-anomeric aglycon) 또는 α-아노머성 치환기를 갖는 시알산의 존재가 트랜스-시알라다아제 반응들을 위한 필요조건이다. 전형적인 천연 시알릴 공여체들은 말단 β-갈락토사이드(β-galactoside) 잔기에 α-2,3-결합된 시알산 또는 α-2,8-결합을 갖는 폴리시알산을 포함하는 3'-O-시알릴-락토스(3'-O-sialyl-lactose), 페투인(fetuin), 강글리오사이드(ganglioside)들, O- 또는 N-결합된 당단백질들로부터 선택될 수 있으나, 이에 한정되지 아니한다. 합성 시알로사이드(sialoside)들 중에 2-O-(4-메틸움벨리페릴)- (2-O-(4-methylumbelliferyl)-) 또는 2-O-(선택적으로 치환도니 페닐)-α-D-시알로사이드(sialoside)들, 더욱 흔하게는 2-O-(p-나이트로페닐)-α-D-시알로사이드(2-O-(p-nitrophenyl)-α-D-sialoside)가 선호된다.
시알리다아제들
/
트랜스시알리다아제들의
수용체들(
Acceptors
for
sialidases
/
transsialidases
)
상기 개시된 트랜스시알화 반응에 이용되는 트랜스시알리다아제 수용체들은 R1-갈락토피라노사이드(R1-galactopyranosides)들(n이 0일 때) 또는 비-환원 말단 상의 말단 당 모이어티가 갈락토피라노스(galactopyranose)인 올리고당 R1-배당체들(n이 1일 때)인 일반 화학식 2 및 그의 염들에 의하여 특징화된다. 상기 말단 갈락토피라노실 단위는 바람직하게 β-글라이코사이드 결합에 의하여 결합된다.
일반 화학식 2의 화합물의 상기 아노머성 하이드록실 기는 가수소화반응에 의하여 제거될 수 있는 R1 기들로 보호된다. 상기에서 설명한 바와 같이, 그러한 기들은 선택적으로 치환된 벤질 및 나프틸메틸 기들을 포함한다. 페닐, 알킬 또는 할로젠으로 선택적으로 치환된 벤질 또는 2-나프틸메틸 기들은 바람직한 R1-기들이고, 그 중에서도 비치환된 벤질, 비치환된 2-나프틸메틸, 4-클로로벤질, 3-페닐벤질 또는 4-메틸벤질 기들이 특히 바람직하다.
n이 1일 때, 상기 구조적 성분 X는 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-(tri-), 사-(tetra-), 오-(penta-) 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류(monosaccharide) 구성 단위(building unit)들은 가장 흔히 발생되는 단위들인 글루코스(glucose), N-아세틸 글루코사민(N-acetyl glucosamine), 갈락토스, 푸코스(fucose) 및 시알산를 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다.
바람직한 방법에서, n은 1이고, 링커 X는 일반 화학식 2A 또는 그의 염들의 수용체들을 형성하는 화학식 -(X1)m-A-에 대응되고,
일반 화학식 2A에서, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, X1은 탄수화물 링커를 나타내며, m은 0 또는 1의 정수이다. -OR1 기는 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향(β orientation)으로 연결된다.
m이 0일 때, 상기 말단 D-글루코피라노실 단위는 인터글라이코사이드 결합(interglycosidic linkage)을 통해 A 기에 직접 결합된다. 바람직하게, 상기 인터글라이코사이드 결합은 1-4 결합이고, 따라서 일반 화학식 2B의 화합물을 형성하고,
화학식 2B에서 R3는 푸코실 또는 H이다. 보다 바람직하게는, 상기 갈락토스와 상기 글루코스 부분 사이의 상기 인터글라이코사이드 결합은 β이고, 따라서 락토스 유도체를 생성한다. 보다 더욱 바람직한 구현예에서는, 아글리콘 -OR1 또한 β 배향이다.
m이 1일 때, 상기 구조적 성분 X1은 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다.
바람직하게, 링커 X1은 일반 화학식 2C의 화합물들 또는 그의 염들을 형성하는 화학식 -B-X2-로 표현되고,
일반 화학식 2C에서, B 기는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위(N-acetyl-glucosaminopyranosyl unit)이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. -OR1 기는 상기 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다. 바람직하게는, 말단 갈락토실 기가 1-3 또는 1-4 인터글라이코사이드 결합을 통해 B 기에 부착되어, 각각 락토-N-바이오실(lacto-N-biosyl) 또는 N-아세틸-락토사미닐(N-acetyl-lactosaminyl) 말단 이당류(disaccharide) 모이어티들을 형성한다. 보다 더 바람직한 방법에서는, 푸코실 치환기가 단위 B의 3-OH 기 또는 4-OH 기, 및/또는 단위 A의 3-OH 기에 결합될 수 있고/있거나, 시알릴이 단위 B의 6-OH에 연결될 수 있다.
보다 바람직한 방법에서, X2 기는 시알릴 또는 N-아세틸-락토사민, 락토-N-바이오스(lacto-N-biose), 푸코스 및 시알산으로부터 선택되는 당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 올리고당으로 선택적으로 치환된 갈락토스이므로, 일반 화학식 2D 또는 그의 염들로 표현되는 인유 올리고당 유도체들을 형성하고,
일반 화학식 2D에서, R1은 가수소분해에 의해 제거될 수 있는 기이고, R3는 H 또는 푸코실 단위이고, Y는 서로에 관계없이, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 서로에 관계없이 0, 1 또는 2의 정수이고, R8은 일반 화학식 5 및 6에 의하여 특징화되는 기들로부터 선택되고, R9는 H, α-시알릴 모이어티, 일반 화학식 5의 기 및 일반 화학식 6의 기로부터 선택되며,
일반 화학식 5 또는 6에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이다.
보다 바람직한 방법에 따라, 상기에서 정의된 바와 같은 일반 화학식 2D의 화합물 및 그의 염들은 그것의 결합부 및 부착된 모이어티들로 특징지을 수 있으며, 이때에
- Y 기의 N-아세틸-락토사미닐 기는, 또 다른 N-아세틸-락토사미닐 기(p = 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 5의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 6의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 푸코실 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 1-3 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 N-아세틸-글루코사민에 연결되고,
- α-시알릴 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 2-6 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 갈락토스에 연결된다.
추가적인 측면에서, 상기에서 정의된 바와 같은 일반 화학식 2B, 2C 또는 2D의 화합물 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/또는 푸코실 잔기로 치환되고, 비치환된 말단 갈락토실(galactosyl) 잔기를 갖는 락토스(lactose), 락토-N-네오테트라오스(lacto-N-neotetraose), 파라-락토-N-헥사오스(para-lacto-N-hexaose), 파라-락토-N-네오헥사오스(para-lacto-N-neohexaose), 락토-N-네오헥사오스(lacto-N-neohexaose), 파라-락토-N-옥타오스(para-lacto-N-octaose), 락토-N-네오옥타오스(lacto-N-neooctaose), 락토-N-테트라오스(lacto-N-tetraose), 락토-N-헥사오스(lacto-N-hexaose), 락토-N-옥타오스(lacto-N-octaose), 아이소-락토-N-옥타오스(iso-lacto-N-octaose), 락토-N-데카오스(lacto-N-decaose) 및 락토-N-네오데카오스(lacto-N-neodecaose)의 R1-배당체들을 나타낸다. 바람직하게, 상기 시알릴 치환기는 N-아세틸 뉴라미닐(N-acetyl neuraminy) 기이다.
특히 바람직하게, 상기에서 정의된 바와 같은 일반 화학식 2B, 2C 또는 2D의 화합물 및 그의 염들은 Galβ1-4Glc (락토스(lactose)), Galβ1-4(Fucα1-3)Glc (3-O-푸코실락토스(3-O-fucosyllactose)), Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LNT), Galβ1-4GlcNAcβ1-3Galβ1-4Glc (LNnT), Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (LNFP II), Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc (LNFP III), Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-4)Glc (LNFP V), Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNDFH II), Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (LSTb), Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNDFH III)의 R1-배당체들의 군, 또는 그들의 염들로부터 선택된다. 상기 R1-배당체들은 α- 또는 β-아노머들일 수 있다. 바람직하게, 상기 R1-배당체들은 β-아노머들이다.
일반 화학식 2의 화합물들의 전형적인 합성은 갈락토스, 또는 비환원 말단에 갈락토시파노실 단위(galactopyranosyl unit)를 갖는 올리고당들을 50-125 ℃에서 아세트산 무수물(acetic anhydride) 및 아세트산 나트륨(sodium acetate)으로 처리한 다음, DCM 톨루엔(toluene), THF 등과 같은 유기 용매 내에서 R1-OH, 바람직하게는 벤질/치환된 벤질 알콜들을 이용하여 루이스 산 촉매된 글라이코실화(Lewis acid catalyzed glycosylation)시키는 것을 포함한다. 뒤이어, 상기 글라이코실화된 생성물들의 최종 젬플렌 탈보호(Zemplen deprotection)를 통해 일반 화학식 2의 화합물들이 수득된다.
다른 전형적인 아노머성 O-보호 과정에 따르면, DMF, DMSO, N-메틸피롤리돈(N-methylpyrrolidone), 헥사메틸포스포라마이드(hexamethylphosphoramide, HMPA), N,N'-다이메틸헥사하이드로피리미딘-2-온(N,N'-dimethylhexahydropyrimidine-2-one, DMPU), THF, 다이옥세인(dioxane), 아세토나이트릴(acetonitrile) 등 또는 그들의 혼합물과 같은 쌍극성 비양성자성 용매(dipolar aprotic solvent) 내에서 유리 아노머성 OH로 전부 또는 일부가 보호된 갈락토스 또는 비환원 말단에 갈락토피라노실 단위(galactopyranosyl unit)을 갖는 올리고당들은 강 염기 및 R1-X의 존재하에서 O-알킬화되고, R1-X에서 X는 할로젠(halogen), 메실(mesyl), 트라이플릴(triflyl) 등과 같은 알킬설포닐옥시(alkylsulfonyloxy) 및 벤젠설포닐(benzenesulfonyl), 토실(tosyl) 등과 같은 아릴설포닐(arylsulfonyl)로부터 선택되는 이탈기(leaving group)이다. 바람직한 알킬화제(alkylating agent)들은 선택적으로 페닐, 알킬 또는 할로젠으로부터 선택된 하나 이상의 기들로 치환된 벤질 또는 1- 또는 2-나프틸메틸 할로제나이드(1- or 2-naphthylmethyl halogenide)들이다. 상기 강 염기는 동등량 또는 약간 초과량(1 내지 1.5 equiv)의 염기가 이용되었을 때, 아노머성 OH의 보다 강한 산성 특성으로 인하여 아노머성 OH를 화학선택적으로 탈양성자화할 수 있다. 상기 아노머성 OH를 활성화시키는데 적합한 강 염기는 일반적으로 NaH, KH, CaH2, NaOMe, NaOtBu, KOtBu, 무기 하이드록사이드(inorganic hydroxide)들, 탄산 칼륨(potassium carbonate) 등과 같은 알칼리 금속(alkali metal) 또는 알칼라인 토금속 하이드라이드(alkaline earth metal hydride)들 또는 알콕사이드(alkoxide)들의 군으로부터 취해진다. 상기 알킬화제는 동응량 또는 약간 초과량(1 내지 1.5 equiv)으로 첨가된다. 상기 반응은 -10 내지 80 ℃ 사이, 바람직하게는 반응의 전 과정 동안 낮은 온도에서, 또는 시약/반응물들의 첨가하는 동안에는 낮은 온도, 상기 반응 과정의 후속 단계들에서 상승된 온도에서 수행된다. 통상적인 마무리(work-up) 후에 일반 화학식 2의 벤질/치환된 벤질 배당체들이 수득된다.
추가적인 측면에서, 본 발명은 일반 화학식 2A'의 화합물 및 그의 염들을 제공하는 것과 관련되고,
일반 화학식 2A'에서, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, X1은 탄수화물 링커를 나타내고, m은 0 또는 1의 정수이고, 단, a) m이 0일 때, 상기 A는 푸코실로 치환되고, b) 상기 화합물은 1-O-β-벤질-LNT(1-O-β-benzyl-LNT), 1-O-β-(4-하이드록시메틸벤질)-LNnT(1-O-β-(4-hydroxymethylbenzyl)-LNnT) 및 1-O-β-벤질-LNnT(1-O-β-benzyl-LNnT)와는 상이하다. -OR1 기는 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다.
m이 0일 때, 상기 말단 D-글루코피라노실 단위는 인터글라이코사이드 결합을 통해 A 기에 직접 결합된다. 바람직하게, 상기 인터글라이코사이드 결합은 1-4 결합이고, 따라서 일반 화학식 2B'의 화합물들 및 그의 염들을 형성하고,
화학식 2B'에서 R3는 푸코실이다. 보다 바람직하게는, 상기 갈락토스와 상기 글루코스 부분 사이의 상기 인터글라이코사이드 결합은 β이고, 따라서 락토스 유도체를 생성한다. 보다 더욱 바람직한 구현예에서는, 아글리콘 -OR1 또한 β 배향이다.
m이 1일 때, 상기 구조적 성분 X1은 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다. 바람직하게, 링커 X1은 화학식 -B-X2-로 표현되어, 일반 화학식 2C'의 화합물들 및 그의 염들을 형성하고,
일반 화학식 2C에서, B 기는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. -OR1 기는 상기 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다. 바람직하게는, 말단 갈락토실 기가 1-3 또는 1-4 인터글라이코사이드 결합을 통해 B 기에 부착되어, 각각 락토-N-바이오실 또는 N-아세틸-락토사미닐 말단 이당류 모이어티들을 형성한다. 보다 더 바람직한 방법에서는, 푸코실 치환기가 단위 B의 3-OH 기 또는 4-OH 기, 및/또는 단위 A의 3-OH 기에 결합될 수 있고/있거나, 시알릴이 단위 B의 6-OH에 연결될 수 있다.
보다 바람직한 방법에서, X2 기는 시알릴 또는 N-아세틸-락토사민, 락토-N-바이오스, 푸코스 및 시알산으로부터 선택되는 당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 올리고당 잔기로 선택적으로 치환된 갈락토스이므로, 일반 화학식 2D' 또는 그의 염들로 표현되는 인유 올리고당 유도체들을 형성하고,
일반 화학식 2D'에서, R1은 가수소분해에 의해 제거될 수 있는 기이고, R3는 H 또는 푸코실 단위이고, Y는 서로에 관계없이, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 서로에 관계없이 0, 1 또는 2의 정수이고, R8은 일반 화학식 5 및 6에 의하여 특징화되는 기들로부터 선택되고, R9는 H, α-시알릴 모이어티, 일반 화학식 5의 기 및 일반 화학식 6의 기로부터 선택되며,
일반 화학식 5 또는 6에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이다.
보다 바람직한 구현예에 따라, 상기에서 정의된 바와 같은 일반 화학식 2D'의 화합물 및 그의 염들은 그것의 결합부 및 부착된 모이어티들로 특징지을 수 있으며, 이때에
- Y 기의 N-아세틸-락토사미닐 기는, 또 다른 N-아세틸-락토사미닐 기에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 5의 기는, Y에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 6의 기는, Y에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 푸코실 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 1-3 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 N-아세틸-글루코사민에 연결되고,
- α-시알릴 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 2-6 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 갈락토스에 연결된다.
추가적인 측면에서, 상기에서 정의된 바와 같은 일반 화학식 2 C' 또는 2 D'의 화합물 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/또는 푸코실 잔기로 치환되고, 비치환된 말단 갈락토실 잔기를 갖는 락토-N-네오테트라오스(lacto-N-neotetraose), 파라-락토-N-헥사오스(para-lacto-N-hexaose), 파라-락토-N-네오헥사오스(para-lacto-N-neohexaose), 락토-N-네오헥사오스(lacto-N-neohexaose), 파라-락토-N-옥타오스(para-lacto-N-octaose), 락토-N-네오옥타오스(lacto-N-neooctaose), 락토-N-테트라오스(lacto-N-tetraose), 락토-N-헥사오스(lacto-N-hexaose), 락토-N-옥타오스(lacto-N-octaose), 아이소-락토-N-옥타오스(iso-lacto-N-octaose), 락토-N-데카오스(lacto-N-decaose) 및 락토-N-네오데카오스(lacto-N-neodecaose)의 R1-배당체들을 나타낸다. 바람직하게, 상기 시알릴 치환기는 N-아세틸 뉴라미닐 기이다.
특히 바람직하게, 상기에서 정의된 바와 같은 일반 화학식 2 A'의 화합물 및 그의 염들은 Galβ1-4(Fucα1-3)Glc (3-O-푸코실락토스(3-O-fucosyllactose)), Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LNT), Galβ1-4GlcNAcβ1-3Galβ1-4Glc (LNnT), Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (LNFP II), Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc (LNFP III), Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-4)Glc (LNFP V), Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNDFH II), Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (LSTb), Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNDFH III)의 R1-배당체들의 군, 또는 그들의 염들로부터 선택된다. 상기 R1-배당체들은 α- 또는 β-아노머들일 수 있다. 바람직하게, 상기 R1-배당체들은 β-아노머들이다.
트랜스시알화
반응의 생성물들(
Products
of
transsialidation
reaction
)
상기에서 설명한 바와 같이, 본 출원에서 청구된 트랜스시알화 반응은 일반 화학식 2의 화합물 및 그의 염들로부터 일반 화학식 1의 화합물들 및 그의 염들을 생성하고,
일반 화학식 1에서 R 기들 중의 하나는 α-시알릴 모이어티, 다른 하나는 H이고, X는 탄수화물 링커를 나타내고, R1은 가수소분해에 의해 제거될 수 있는 보호기이고, n은 0 또는 1의 정수이다.
R1 기는 선택적으로 치환된 벤질 및 나프틸메틸 기들을 포함하고, 그 중에서 선택적으로 페닐, 알킬 또는 할로젠으로 치환된 벤질 또는 2-나프틸메틸 기들은 바람직한 R1-기들이고, 그 중에서 비치환된 벤질, 비치환된 2-나프틸메틸, 4-클로로벤질, 3-페닐벤질 또는 4-메틸벤질 기들이 특히 바람직하다.
n이 1일 때, 상기 구조적 성분 X는 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다.
바람직한 방법에서, n은 1이고, 링커 X는 일반 화학식 1A 또는 그의 염들의 시알릴화된 생성물들을 형성하는 화학식 -(X1)m-A-에 대응되고,
일반 화학식 1A에서, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, X1은 탄수화물 링커를 나타내며, m은 0 또는 1의 정수이다. -OR1 기는 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다.
m이 0일 때, 상기 D-글루코피라노실 단위는 인터글라이코사이드 결합을 통해 A 기에 직접 결합된다. 바람직하게, 상기 인터글라이코사이드 결합은 1-4 결합이고, 따라서 일반 화학식 1B의 화합물들 및 그의 염들을 형성하고,
화학식 1B에서 R3는 푸코실 또는 H이다. 보다 바람직하게, 상기 갈락토스와 상기 글루코스 부분 사이의 상기 인터글라이코사이드 결합은 β이고, 따라서 3'-O-시알릴-락토스(3'-O-sialyl-lactose) 유도체를 생성한다. 보다 더욱 바람직한 구현예에서는, 아글리콘 -OR1 또한 β 배향이다.
m이 1일 때, 상기 구조적 성분 X1은 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다. 바람직하게, 링커 X1은 화학식 -B-X2-로 표현되어, 일반 화학식 1C의 화합물들 및 그의 염들을 형성하고,
일반 화학식 1C에서, B 기는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 나타낸다. -OR1 기는 상기 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다. 바람직하게는, 상기 시알릴-갈락토실 기가 1-3 또는 1-4 인터글라이코사이드 결합을 통해 B 기에 부착되어, 각각 시알릴-락토-N-바이오실(sialyl-lacto-N-biosyl) 또는 시알릴-N-아세틸-락토사미닐(sialyl-N-acetyl-lactosaminyl) 말단 삼당류(trisaccharide) 모이어티들을 형성한다. 보다 더 바람직한 방법에서는, 푸코실 치환기가 단위 B의 3-OH 기 또는 4-OH 기, 및/또는 단위 A의 3-OH 기에 결합될 수 있고/있거나, 시알릴이 단위 B의 6-OH에 연결될 수 있다.
시알릴 올리고당 유도체들을 합성하는 보다 바람직한 방법에서, 일반 화학식 1C 및 그의 염들의 X2 기는 시알릴 또는 N-아세틸-락토사민, 락토-N-바이오스, 푸코스 및 시알산으로부터 선택되는 당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 올리고당으로 선택적으로 치환된 갈락토스이므로, 일반 화학식 1D 및 그의 염들로 표현되는 인유 올리고당 유도체들을 형성하고,
일반 화학식 1D에서, R1은 가수소분해에 의해 제거될 수 있는 기이고, R3는 H 또는 푸코실 단위이고, Y는 서로에 관계없이, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 서로에 관계없이 0, 1 또는 2의 정수이고, R4는 일반 화학식 3 및 4에 의하여 특징화되는 기들로부터 선택되고, R5는 H, α-시알릴 모이어티, 일반 화학식 3의 기 및 일반 화학식 4의 기로부터 선택되며,
일반 화학식 3 또는 4에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이고, R 기들 중의 하나는 α-시알릴 모이어티, 다른 하나는 H이다.
보다 바람직한 방법에 따라, 상기에서 정의된 바와 같은 일반 화학식 1D의 화합물 및 그의 염들은 그것의 결합부 및 부착된 모이어티들로 특징지을 수 있으며, 이때에
- Y 기(p = 2)의 N-아세틸-락토사미닐 기는, 또 다른 N-아세틸-락토사미닐 기에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 3의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 4의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 푸코실 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 1-3 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 N-아세틸-글루코사민에 연결되고,
- α-시알릴 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 2-6 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 갈락토스에 연결된다.
추가적인 측면에서, 상기에서 정의된 바와 같은 일반 화학식 1B, 1C 또는 1D의 화합물 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/ 또는 푸코실 잔기로 치환되고, 말단 갈락토실 잔기의 3-OH 또는 6-OH에 시알릴 치환기를 갖는 락토스, 락토-N-네오테트라오스, 파라-락토-N-헥사오스, 파라-락토-N-네오헥사오스, 락토-N-네오헥사오스, 파라-락토-N-옥타오스, 락토-N-네오옥타오스, 락토-N-테트라오스, 락토-N-헥사오스, 락토-N-옥타오스, 아이소-락토-N-옥타오스, 락토-N-데카오스 및 락토-N-네오데카오스의 R1-배당체들을 나타낸다. 바람직하게, 상기 시알릴 치환기는 N-아세틸 뉴라미닐 기이다.
특히 바람직하게, 상기에서 정의된 바와 같은 일반 화학식 2B, 2C 또는 2D의 화합물 및 그의 염들은 Neu5Acα2-3Galβ1-4Glc (3'-O-(N-아세틸-뉴라미노실)-락토스(3'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-6Galβ1-4Glc (6'-O-(N-아세틸-뉴라미노실)-락토스(6'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-3Galβ1-4(Fucα1-3)Glc (3-O-푸코실-3'-O-(N-아세틸-뉴라미노실)-락토스(3-O-fucosyl-3'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LST a), Neu5Acα2-6Galβ1-3GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-4GlcNAcβ1-3Galβ1-4Glc (LST c), Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FLST a), Neu5Acα2-6Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-4)Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (DSLNT), Neu5Acα2-6Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FDSLNT I), Neu5Acα2-6Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FDSLNT II), Neu5Acα2-6Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FLST c), Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc의 R1-배당체들의 군, 또는 그들의 염들로부터 선택된다. 상기 R1-배당체들은 α- 또는 β-아노머들일 수 있다. 바람직하게, 상기 R1-배당체들은 β-아노머들이다.
선택적 α-2-3 시알화의 경우에, 본 출원에서 청구된 상기 트랜스시알화 반응은 일반 화학식 2의 화합물 및 그의 염들로부터 일반 화학식 1-3의 화합물들 및 그의 염들을 생성하고,
일반 화학식 1-3에서, SA는 α-시알릴 모이어티이고, R1은 가수소분해에 의해 제거될 수 있는 보호기이고, n은 0 또는 1의 정수이다. R1 기는 선택적으로 치환된 벤질 및 나프틸메틸 기들을 포함하고, 그 중에서 선택적으로 페닐, 알킬 또는 할로젠으로 치환된 벤질 또는 2-나프틸메틸 기들은 바람직한 R1-기들이고, 그 중에서 비치환된 벤질, 비치환된 2-나프틸메틸, 4-클로로벤질, 3-페닐벤질 또는 4-메틸벤질 기들이 특히 바람직하다.
n이 1일 때, 상기 구조적 성분 X는 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다.
바람직한 방법에서, n은 1이고, 링커 X는 일반 화학식 1-3A 또는 그의 염들의 시알릴화된 생성물들을 형성하는 화학식 -(X1)m-A-에 대응되고,
일반 화학식 1-3A에서, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, X1은 탄수화물 링커를 나타내며, m은 0 또는 1의 정수이다. -OR1 기는 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다.
m이 0일 때, 상기 D-글루코피라노실 단위는 인터글라이코사이드 결합을 통해 A 기에 직접 결합된다. 바람직하게, 상기 인터글라이코사이드 결합은 1-4 결합이고, 따라서 일반 화학식 1-3B의 화합물 및 그의 염들을 형성하고,
화학식 1B에서 R3는 푸코실 또는 H이다. 보다 바람직하게, 상기 갈락토스와 상기 글루코스 부분 사이의 상기 인터글라이코사이드 결합은 β이고, 따라서 3'-O-시알릴-락토스(3'-O-sialyl-lactose) 유도체를 생성한다. 보다 더욱 바람직한 구현예에서는, 아글리콘 -OR1 또한 β 배향이다.
m이 1일 때, 상기 구조적 성분 X1은 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다. 바람직하게, 링커 X1은 화학식 -B-X2-로 표현되어, 일반 화학식 1-3C의 화합물들 및 그의 염들을 형성하고,
일반 화학식 1-3C에서, B 기는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. -OR1 기는 상기 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다. 바람직하게는, 상기 시알릴-갈락토실 기가 1-3 또는 1-4 인터글라이코사이드 결합을 통해 B 기에 부착되어, 각각 시알릴-락토-N-바이오실 또는 시알릴-N-아세틸-락토사미닐) 말단 삼당류 모이어티들을 형성한다. 보다 더 바람직한 방법에서는, 푸코실 치환기가 단위 B의 3-OH 기 또는 4-OH 기, 및/또는 단위 A의 3-OH 기에 결합될 수 있고/있거나, 시알릴이 단위 B의 6-OH에 연결될 수 있다.
시알릴 올리고당 유도체들을 합성하는 보다 바람직한 방법에서, 일반 화학식 1-3C의 X2 기는 시알릴 또는 N-아세틸-락토사민, 락토-N-바이오스, 푸코스 및 시알산으로부터 선택되는 당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 올리고당으로 선택적으로 치환된 갈락토스이므로, 일반 화학식 1-3D 및 그의 염들로 표현되는 인유 올리고당 유도체들을 형성하고,
일반 화학식 1-3D에서, R1은 가수소분해에 의해 제거될 수 있는 기이고, R3는 H 또는 푸코실 단위이고, Y는 서로에 관계없이, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 서로에 관계없이 0, 1 또는 2의 정수이고, R4'은 일반 화학식 3-3 및 4-3에 의하여 특징화되는 기들로부터 선택되고, R5'은 H, α-시알릴 모이어티, 일반 화학식 3-3의 기 및 일반 화학식 4-3의 기로부터 선택되며,
일반 화학식 3-3 또는 4-3에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이고, SA는 α-시알릴 모이어티이다.
보다 바람직한 구현예에 따라, 상기에서 정의된 바와 같은 일반 화학식 1-3D의 화합물 및 그의 염들은 그것의 결합부 및 부착된 모이어티들로 특징지을 수 있으며, 이때에
- Y 기(p = 2)의 N-아세틸-락토사미닐 기는, 또 다른 N-아세틸-락토사미닐 기에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 3-3의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 4-3의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 푸코실 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 1-3 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 N-아세틸-글루코사민에 연결되고,
- α-시알릴 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 2-6 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 갈락토스에 연결된다.
추가적인 측면에서, 상기에서 정의된 바와 같은 일반 화학식 1-3B, 1-3C 또는 1-3D의 화합물 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/ 또는 푸코실 잔기로 치환되고, 말단 갈락토실 잔기의 3-OH에 시알릴 치환기를 갖는 락토스, 락토-N-네오테트라오스, 파라-락토-N-헥사오스, 파라-락토-N-네오헥사오스, 락토-N-네오헥사오스, 파라-락토-N-옥타오스, 락토-N-네오옥타오스, 락토-N-테트라오스, 락토-N-헥사오스, 락토-N-옥타오스, 아이소-락토-N-옥타오스, 락토-N-데카오스 및 락토-N-네오데카오스의 R1-배당체들을 나타낸다. 바람직하게, 상기 시알릴 치환기(들)는 N-아세틸 뉴라미닐 기(들)이다.
특히 바람직하게, 상기에서 정의된 바와 같은 일반 화학식 1-3B, 1-3C 또는 1-3D의 화합물 또는 그의 염들은 Neu5Acα2-3Galβ1-4Glc (3'-O-(N-아세틸-뉴라미노실)-락토스(3'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-3Galβ1-4(Fucα1-3)Glc (3-O-푸코실-3'-O-(N-아세틸-뉴라미노실)-락토스(3-O-fucosyl-3'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LST a), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FLST a), Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (DSLNT), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FDSLNT I), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FDSLNT II), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc의 R1-배당체들의 군, 또는 그들의 염들로부터 선택된다. 상기 R1-배당체들은 α- 또는 β-아노머들일 수 있다. 바람직하게, 상기 R1-배당체들은 β-아노머들이다.
선택적 α-2-6 시알화의 경우에, 본 출원에서 청구된 상기 트랜스시알화 반응은 일반 화학식 2의 화합물 및 그의 염들로부터 일반 화학식 1-6의 화합물들 및 그의 염들을 생성하고,
일반 화학식 1-6에서, SA는 α-시알릴 모이어티이고, X는 탄수화물 링커를 나타내고, R1은 가수소분해에 의해 제거될 수 있는 보호기이고, n은 0 또는 1의 정수이다. R1 기는 선택적으로 치환된 벤질 및 나프틸메틸 기들을 포함하고, 그 중에서 선택적으로 페닐, 알킬 또는 할로젠으로 치환된 벤질 또는 2-나프틸메틸 기들은 바람직한 R1-기들이고, 그 중에서 비치환된 벤질, 비치환된 2-나프틸메틸, 4-클로로벤질, 3-페닐벤질 또는 4-메틸벤질 기들이 특히 바람직하다.
n이 1일 때, 상기 구조적 성분 X는 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다.
바람직한 방법에서, n은 1이고, 링커 X는 일반 화학식 1-6A 또는 그의 염들의 시알릴화된 생성물들을 형성하는 화학식 -(X1)m-A-에 대응되고,
일반 화학식 1-6A에서, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, X1은 탄수화물 링커를 나타내며, m은 0 또는 1의 정수이다. -OR1 기는 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다.
m이 0일 때, 상기 D-글루코피라노실 단위는 인터글라이코사이드 결합을 통해 A 기에 직접 결합된다. 바람직하게, 상기 인터글라이코사이드 결합은 1-4 결합이고, 따라서 일반 화학식 1-6B의 화합물들 및 그의 염들을 형성하고,
화학식 1-6B에서 R3는 푸코실 또는 H이다. 보다 바람직하게, 상기 갈락토스와 상기 글루코스 부분 사이의 상기 인터글라이코사이드 결합은 β이고, 따라서 3'-O-시알릴-락토스(3'-O-sialyl-lactose) 유도체를 생성한다. 보다 더욱 바람직한 구현예에서는, 아글리콘 -OR1 또한 β 배향이다.
m이 1일 때, 상기 구조적 성분 X1은 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다. 바람직하게, 링커 X1은 화학식 -B-X2-로 표현되어, 일반 화학식 1-6C의 화합물들 및 그의 염들을 형성하고,
일반 화학식 1-6C에서, B 기는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. -OR1 기는 상기 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다. 바람직하게는, 상기 시알릴-갈락토실 기가 1-3 또는 1-4 인터글라이코사이드 결합을 통해 B 기에 부착되어, 각각 시알릴-락토-N-바이오실 또는 시알릴-N-아세틸-락토사미닐) 말단 삼당류 모이어티들을 형성한다. 보다 더 바람직한 방법에서는, 푸코실 치환기가 단위 B의 3-OH 기 또는 4-OH 기, 및/또는 단위 A의 3-OH 기에 결합될 수 있고/있거나, 시알릴이 단위 B의 6-OH에 연결될 수 있다.
시알릴 올리고당 유도체들을 합성하는 보다 바람직한 방법에서, 일반 화학식 1-6C의 X2 기는 시알릴 또는 N-아세틸-락토사민, 락토-N-바이오스, 푸코스 및 시알산으로부터 선택되는 당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 올리고당으로 선택적으로 치환된 갈락토스이므로, 일반 화학식 1-3D 및 그의 염들로 표현되는 인유 올리고당 유도체들을 형성하고,
일반 화학식 1-6D에서, R1은 가수소분해에 의해 제거될 수 있는 기이고, R3는 H 또는 푸코실 단위이고, Y는 서로에 관계없이, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 서로에 관계없이 0, 1 또는 2의 정수이고, R4''은 일반 화학식 3-6 및 4-6에 의하여 특징화되는 기들로부터 선택되고, R5''은 H, α-시알릴 모이어티, 일반 화학식 3-6의 기 및 일반 화학식 4-6의 기로부터 선택되며,
일반 화학식 3-6 또는 4-6에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이고, SA는 α-시알릴 모이어티이다.
보다 바람직한 구현예에 따라, 상기에서 정의된 바와 같은 일반 화학식 1-6D의 화합물 및 그의 염들은 그것의 결합부 및 부착된 모이어티들로 특징지을 수 있으며, 이때에
- Y 기(p = 2)의 N-아세틸-락토사미닐 기는, 또 다른 N-아세틸-락토사미닐 기에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 3-6의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 4-6의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 푸코실 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 1-3 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 N-아세틸-글루코사민에 연결되고,
- α-시알릴 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 2-6 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 갈락토스에 연결된다.
추가적인 측면에서, 상기에서 정의된 바와 같은 일반 화학식 1-6B, 1-6C 또는 1-6D의 화합물 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/ 또는 푸코실 잔기로 치환되고, 말단 갈락토실 잔기의 6-OH에 시알릴 치환기를 갖는 락토스, 락토-N-네오테트라오스, 파라-락토-N-헥사오스, 파라-락토-N-네오헥사오스, 락토-N-네오헥사오스, 파라-락토-N-옥타오스, 락토-N-네오옥타오스, 락토-N-테트라오스, 락토-N-헥사오스, 락토-N-옥타오스, 아이소-락토-N-옥타오스, 락토-N-데카오스 및 락토-N-네오데카오스의 R1-배당체들을 나타낸다. 바람직하게, 상기 시알릴 치환기(들)는 N-아세틸 뉴라미닐 기(들)이다.
특히 바람직하게, 상기에서 정의된 바와 같은 일반 화학식 1-6B, 1-6C 또는 1-6D의 화합물 또는 그의 염들은 Neu5Acα2-6Galβ1-4Glc (6'-O-(N-아세틸-뉴라미노실)-락토스(6'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-6Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-3GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-4GlcNAcβ1-3Galβ1-4Glc (LST c), Neu5Acα2-6Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FLST c), Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc의 R1-배당체들의 군, 또는 그들의 염들로부터 선택된다. 상기 R1-배당체들은 α- 또는 β-아노머들일 수 있다. 바람직하게, 상기 R1-배당체들은 β-아노머들이다.
상기와 같이 정의되고 본 출원에 개시된 트랜스시알화 반응에서 수득될 수 있는 일반 화학식 1에 의해 표현되는 일부 화합물들 및 그의 염들은 신규하다. 따라서, 본 발명은 일반 화학식 1A'의 신규한 화합물들 및 그의 염들을 제공하는 것에 관한 것이고,
일반 화학식 1A'에서 R 기들 중의 하나는 α-시알릴 모이어티, 다른 하나는 H이고, R1은 가수소분해에 의해 제거될 수 있는 보호기이고, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, m은 0 또는 1의 정수이고, X1은 탄수화물 링커를 나타내며, 단, 3'-O-(N-아세틸-뉴라미노실)-락토스((3'-O-(N-acetyl-neuraminosyl)-lactose)) 나트륨 염의 1-O-β-벤질(1-O-β-benzyl) 및 1-O-β-(4,5-다이메톡시-2-나이트로)-벤질(1-O-β-(4,5-dimethoxy-2-nitro)-benzyl) 배당체들, 및 6'-O-(N-아세틸-뉴라미노실)-락토스(6'-O-(N-acetyl-neuraminosyl)-lactose) 나트륨 염의 1-O-β-벤질(1-O-β-benzyl) 배당체는 제외된다. -OR1 기는 상기 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다.
m이 0일 때, 상기 D-글루코피라노실 단위는 인터글라이코사이드 결합을 통해 A 기에 직접 결합된다. 바람직하게, 상기 인터글라이코사이드 결합은 1-4 결합이고, 따라서 일반 화학식 1B'의 화합물 및 그의 염들을 형성하고,
화학식 1B'에서 R3는 푸코실 또는 H이다. 보다 바람직하게, 상기 갈락토스와 상기 글루코스 부분 사이의 상기 인터글라이코사이드 결합은 β이고, 따라서 3'-O-시알릴-락토스(3'-O-sialyl-lactose) 유도체를 생성한다. 보다 더욱 바람직한 구현예에서는, 아글리콘 -OR1 또한 β 배향이다.
m이 1일 때, 상기 구조적 성분 X1은 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다. 바람직하게, 링커 X1은 화학식 -B-X2-로 표현되어, 일반 화학식 1C'의 화합물들 및 그의 염들을 형성하고,
일반 화학식 1C'에서, B 기는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. -OR1 기는 상기 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다. 바람직하게는, 상기 시알릴-갈락토실 기가 1-3 또는 1-4 인터글라이코사이드 결합을 통해 B 기에 부착되어, 각각 시알릴-락토-N-바이오실 또는 시알릴-N-아세틸-락토사미닐) 말단 삼당류 모이어티들을 형성한다. 보다 더 바람직한 방법에서는, 푸코실 치환기가 단위 B의 3-OH 기 또는 4-OH 기, 및/또는 단위 A의 3-OH 기에 결합될 수 있고/있거나, 시알릴이 단위 B의 6-OH에 연결될 수 있다.
보다 바람직한 구현예에서, 일반 화학식 1C'의 화합물들 및 그의 염들의 X2 기는 시알릴 또는 N-아세틸-락토사민, 락토-N-바이오스, 푸코스 및 시알산으로부터 선택되는 당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 올리고당으로 선택적으로 치환된 갈락토스이므로, 일반 화학식 1D' 및 그의 염들로 표현되는 인유 올리고당 유도체들을 형성하고,
일반 화학식 1D'에서, R1은 가수소분해에 의해 제거될 수 있는 기이고, R3는 H 또는 푸코실 단위이고, Y는 서로에 관계없이, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 서로에 관계없이 0, 1 또는 2의 정수이고, R4는 일반 화학식 3 및 4에 의하여 특징화되는 기들로부터 선택되고, R5는 H, α-시알릴 모이어티, 일반 화학식 3의 기 및 일반 화학식 4의 기로부터 선택되며,
일반 화학식 3 또는 4에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이고, R 기들 중의 하나는 α-시알릴 모이어티, 다른 하나는 H이다.
보다 바람직한 구현예에 따라, 상기에서 정의된 바와 같은 일반 화학식 1D'의 화합물 및 그의 염들은 그것의 결합부 및 부착된 모이어티들로 특징지을 수 있으며, 이때에
- Y 기(p = 2)의 N-아세틸-락토사미닐 기는, 또 다른 N-아세틸-락토사미닐 기에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 3의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 4의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 푸코실 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 1-3 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 N-아세틸-글루코사민에 연결되고,
- α-시알릴 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 2-6 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 갈락토스에 연결된다.
추가적인 측면에서, 상기에서 정의된 바와 같은 일반 화학식 1B', 1C' 또는 1D'의 화합물 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/ 또는 푸코실 잔기로 치환되고, 말단 갈락토실 잔기의 3-OH 또는 6-OH에 시알릴 치환기를 갖는 락토스, 락토-N-네오테트라오스, 파라-락토-N-헥사오스, 파라-락토-N-네오헥사오스, 락토-N-네오헥사오스, 파라-락토-N-옥타오스, 락토-N-네오옥타오스, 락토-N-테트라오스, 락토-N-헥사오스, 락토-N-옥타오스, 아이소-락토-N-옥타오스, 락토-N-데카오스 및 락토-N-네오데카오스의 R1-배당체들, 및 그의 염들로 구성된 군으로부터 선택된다. 바람직하게, 상기 시알릴 치환기(들)는 N-아세틸 뉴라미닐 기(들)이다.
특히 바람직하게, 상기에서 정의된 바와 같은 일반 화학식 1A'의 화합물 및 그의 염들은 Neu5Acα2-3Galβ1-4Glc (3'-O-(N-아세틸-뉴라미노실)-락토스(3'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-6Galβ1-4Glc (6'-O-(N-아세틸-뉴라미노실)-락토스(6'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-3Galβ1-4(Fucα1-3)Glc (3-O-푸코실-3'-O-(N-아세틸-뉴라미노실)-락토스(3-O-fucosyl-3'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LST a), Neu5Acα2-6Galβ1-3GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-4GlcNAcβ1-3Galβ1-4Glc (LST c), Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FLST a), Neu5Acα2-6Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-4)Glc, Neu5Acα2-6Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-4)Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (DSLNT), Neu5Acα2-6Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FDSLNT I), Neu5Acα2-6Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FDSLNT II), Neu5Acα2-6Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FLST c), Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc의 R1-배당체들의 군, 또는 그들의 염들로부터 선택된다. 상기 R1-배당체들은 α- 또는 β-아노머들일 수 있다. 바람직하게, 상기 R1-배당체들은 β-아노머들이다.
일반 화학식 1A'의 화합물들 및 그의 염들의 군 내의 일 구현예에서, 본 발명은 일반 화학식 1'-3A의 α-2-3 시알릴화된 화합물들 및 그의 염들에 관한 것이고,
일반 화학식 1'-3A에서, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, X1은 탄수화물 링커를 나타내며, m은 0 또는 1의 정수이다. -OR1 기는 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다.
m이 0일 때, 상기 D-글루코피라노실 단위는 인터글라이코사이드 결합을 통해 A 기에 직접 결합된다. 바람직하게, 상기 인터글라이코사이드 결합은 1-4 결합이고, 따라서 일반 화학식 1'-3B의 화합물 및 그의 염들을 형성하고,
화학식 1'-3B에서 R3는 푸코실 또는 H이다. 보다 바람직하게, 상기 갈락토스와 상기 글루코스 부분 사이의 상기 인터글라이코사이드 결합은 β이고, 따라서 3'-O-시알릴-락토스(3'-O-sialyl-lactose) 유도체를 생성한다. 보다 더욱 바람직한 구현예에서는, 아글리콘 -OR1 또한 β 배향이다.
m이 1일 때, 상기 구조적 성분 X1은 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다. 바람직하게, 링커 X1은 화학식 -B-X2-로 표현되어, 일반 화학식 1'-3C의 화합물들 및 그의 염들을 형성하고,
일반 화학식 1'-3C에서, B 기는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. -OR1 기는 상기 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다. 바람직하게는, 상기 시알릴-갈락토실 기가 1-3 또는 1-4 인터글라이코사이드 결합을 통해 B 기에 부착되어, 각각 시알릴-락토-N-바이오실 또는 시알릴-N-아세틸-락토사미닐) 말단 삼당류 모이어티들을 형성한다. 보다 더 바람직한 방법에서는, 푸코실 치환기가 단위 B의 3-OH 기 또는 4-OH 기, 및/또는 단위 A의 3-OH 기에 결합될 수 있고/있거나, 시알릴이 단위 B의 6-OH에 연결될 수 있다.
보다 바람직한 구현예에서, 일반 화학식 1'-3C의 X2 기는 시알릴 또는 N-아세틸-락토사민, 락토-N-바이오스, 푸코스 및 시알산으로부터 선택되는 당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 올리고당으로 선택적으로 치환된 갈락토스이므로, 일반 화학식 1'-3D 및 그의 염들로 표현되는 인유 올리고당 유도체들을 형성하고,
일반 화학식 1'-3D에서, R1은 가수소분해에 의해 제거될 수 있는 기이고, R3는 H 또는 푸코실 단위이고, Y는 서로에 관계없이, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 서로에 관계없이 0, 1 또는 2의 정수이고, R4'은 일반 화학식 3-3 및 4-3에 의하여 특징화되는 기들로부터 선택되고, R5'은 H, α-시알릴 모이어티, 일반 화학식 3-3의 기 및 일반 화학식 4-3의 기로부터 선택되며,
일반 화학식 3-3 또는 4-3에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이고, SA는 α-시알릴 모이어티이다.
보다 바람직한 구현예에 따라, 상기에서 정의된 바와 같은 일반 화학식 1'-3D의 화합물 및 그의 염들은 그것의 결합부 및 부착된 모이어티들로 특징지을 수 있으며, 이때에
- Y 기(p = 2)의 N-아세틸-락토사미닐 기는, 또 다른 N-아세틸-락토사미닐 기에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 3-3의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 4-3의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 푸코실 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 1-3 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 N-아세틸-글루코사민에 연결되고,
- α-시알릴 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 2-6 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 갈락토스에 연결된다.
추가적인 측면에서, 상기에서 정의된 바와 같은 일반 화학식 1'-3B, 1'-3C 또는 1'-3D의 화합물 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/ 또는 푸코실 잔기로 치환되고, 말단 갈락토실 잔기의 3-OH에 시알릴 치환기를 갖는 락토스, 락토-N-네오테트라오스, 파라-락토-N-헥사오스, 파라-락토-N-네오헥사오스, 락토-N-네오헥사오스, 파라-락토-N-옥타오스, 락토-N-네오옥타오스, 락토-N-테트라오스, 락토-N-헥사오스, 락토-N-옥타오스, 아이소-락토-N-옥타오스, 락토-N-데카오스 및 락토-N-네오데카오스의 R1-배당체들, 및 그의 염들로 구성된 군으로부터 선택된다. 바람직하게, 상기 시알릴 치환기(들)는 N-아세틸 뉴라미닐 기(들)이다.
특히 바람직하게, 상기에서 정의된 바와 같은 일반 화학식 1'-3B, 1'-3C 또는 1'-3D의 화합물 또는 그의 염들은 Neu5Acα2-3Galβ1-4Glc (3'-O-(N-아세틸-뉴라미노실)-락토스(3'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-3Galβ1-4(Fucα1-3)Glc (3-O-푸코실-3'-O-(N-아세틸-뉴라미노실)-락토스(3-O-fucosyl-3'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LST a), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FLST a), Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (DSLNT), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FDSLNT I), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FDSLNT II), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc의 R1-배당체들의 군, 또는 그들의 염들로부터 선택된다. 상기 R1-배당체들은 α- 또는 β-아노머들일 수 있다. 바람직하게, 상기 R1-배당체들은 β-아노머들이다.
일반 화학식 1A'의 화합물들 및 그의 염들의 군 내의 또 다른 구현예에서, 본 발명은 일반 화학식 1'-6A의 α-2-6 시알릴화된 화합물들 및 그의 염들에 관한 것이고,
일반 화학식 1'-6A에서, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, X1은 탄수화물 링커를 나타내며, m은 0 또는 1의 정수이다. -OR1 기는 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다.
m이 0일 때, 상기 D-글루코피라노실 단위는 인터글라이코사이드 결합을 통해 A 기에 직접 결합된다. 바람직하게, 상기 인터글라이코사이드 결합은 1-4 결합이고, 따라서 일반 화학식 1'-6B의 화합물 및 그의 염들을 형성하고,
일반 화학식 1'-6B에서 R3는 푸코실 또는 H이다. 보다 바람직하게, 상기 갈락토스와 상기 글루코스 부분 사이의 상기 인터글라이코사이드 결합은 β이고, 따라서 3'-O-시알릴-락토스(3'-O-sialyl-lactose) 유도체를 생성한다. 보다 더욱 바람직한 구현예에서는, 아글리콘 -OR1 또한 β 배향이다.
m이 1일 때, 상기 구조적 성분 X1은 탄수화물 링커로서, 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. 상기 탄수화물 링커의 단당류 구성 단위들은 가장 흔히 발생되는 단위들인 글루코스, N-아세틸 글루코사민, 갈락토스, 푸코스 및 시알산을 포함하여, 모든 자연적으로 발생하는 5-, 6-. 또는 9-탄소 함유 당 유도체들일 수 있다. 바람직하게, 링커 X1은 화학식 -B-X2-로 표현되어, 일반 화학식 1'-6C의 화합물들 및 그의 염들을 형성하고,
일반 화학식 1'-6C에서, B 기는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미한다. -OR1 기는 상기 D-글루코피라노실 고리의 아노머성 탄소(C1) 원자에, 바람직하게는 β 배향으로 연결된다. 바람직하게는, 상기 시알릴-갈락토실 기가 1-3 또는 1-4 인터글라이코사이드 결합을 통해 B 기에 부착되어, 각각 시알릴-락토-N-바이오실 또는 시알릴-N-아세틸-락토사미닐) 말단 삼당류 모이어티들을 형성한다. 보다 더 바람직한 방법에서는, 푸코실 치환기가 단위 B의 3-OH 기 또는 4-OH 기, 및/또는 단위 A의 3-OH 기에 결합될 수 있고/있거나, 시알릴이 단위 B의 6-OH에 연결될 수 있다.
보다 바람직한 구현예에서, 일반 화학식 1'-6C의 화합물 및 그의 염의 X2 기는 시알릴 또는 N-아세틸-락토사민, 락토-N-바이오스, 푸코스 및 시알산으로부터 선택되는 당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 올리고당으로 선택적으로 치환된 갈락토스이므로, 일반 화학식 1'-6D 및 그의 염들로 표현되는 인유 올리고당 유도체들을 형성하고,
일반 화학식 1'-6D에서, R1은 가수소분해에 의해 제거될 수 있는 기이고, R3는 H 또는 푸코실 단위이고, Y는 서로에 관계없이, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 서로에 관계없이 0, 1 또는 2의 정수이고, R4''은 일반 화학식 3-6 및 4-6에 의하여 특징화되는 기들로부터 선택되고, R5''은 H, α-시알릴 모이어티, 일반 화학식 3-6의 기 및 일반 화학식 4-6의 기로부터 선택되며,
일반 화학식 3-6 또는 4-6에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이고, SA는 α-시알릴 모이어티이다.
보다 바람직한 구현예에 따라, 상기에서 정의된 바와 같은 일반 화학식 1'-6D의 화합물 및 그의 염들은 그것의 결합부 및 부착된 모이어티들로 특징지을 수 있으며, 이때에
- Y 기(p = 2)의 N-아세틸-락토사미닐 기는, 또 다른 N-아세틸-락토사미닐 기에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 3-6의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 일반 화학식 4-6의 기는, Y(p = 1, 2)에 부착될 때, 1-3 인터글라이코사이드 결합으로 결합되고,
- 푸코실 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 1-3 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 N-아세틸-글루코사민에 연결되고,
- α-시알릴 잔기는, Y에 존재하는 N-아세틸-락토사미닐 기에 부착되는 경우, 2-6 인터글라이코사이드 결합으로 N-아세틸-락토사미닐 기의 갈락토스에 연결된다.
추가적인 측면에서, 상기에서 정의된 바와 같은 일반 화학식 1'-6B, 1'-6C 또는 1'-6D의 화합물 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/ 또는 푸코실 잔기로 치환되고, 말단 갈락토실 잔기의 6-OH에 시알릴 치환기를 갖는 락토스, 락토-N-네오테트라오스, 파라-락토-N-헥사오스, 파라-락토-N-네오헥사오스, 락토-N-네오헥사오스, 파라-락토-N-옥타오스, 락토-N-네오옥타오스, 락토-N-테트라오스, 락토-N-헥사오스, 락토-N-옥타오스, 아이소-락토-N-옥타오스, 락토-N-데카오스 및 락토-N-네오데카오스의 R1-배당체들, 및 그의 염들을 나타낸다. 바람직하게, 상기 시알릴 치환기(들)는 N-아세틸 뉴라미닐 기(들)이다.
특히 바람직하게, 상기에서 정의된 바와 같은 일반 화학식 1'-6B, 1'-6C 또는 1'-6D의 화합물 또는 그의 염들은 Neu5Acα2-6Galβ1-4Glc (6'-O-(N-아세틸-뉴라미노실)-락토스(6'-O-(N-acetyl-neuraminosyl)-lactose)), Neu5Acα2-6Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-3GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-4GlcNAcβ1-3Galβ1-4Glc (LST c), Neu5Acα2-6Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-6Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FLST c), Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-6Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc의 R1-배당체들의 군, 또는 그들의 염들로부터 선택된다. 상기 R1-배당체들은 α- 또는 β-아노머들일 수 있다. 바람직하게, 상기 R1-배당체들은 β-아노머들이다.
본 발명의 다른 특징들은 본 발명의 구체화를 위해 제공되는 하기의 실험예들의 개시에 의하여 명확해질 것이고, 이에 한정되지 아니한다.
실험예(
EXPERIMENTAL
)
1.
시알릴
수용체들의 합성(
Synthesis
of
sialyl
acceptors
)
A) 일반 과정: 실온에서 락토스(lactose)(5 g, 14.6 mmol) 및 TsOHㅇH2O(0.2 g, 1.05 mmol)가 DMF(20 ml)와 벤즈알데하이드 다이메틸 아세탈(benzaldehyde dimethyl acetal)(5.5 ml, 35.4 mmol, 2.4 eq.)의 혼합물에 일부 첨가되었다. 상기 반응 혼합물은 제습(exclusion of humidity) 하의 70 ℃에서 1시간 동안 강하게 교반되었다. 냉각된 트라이에틸 아민(triethyl amine)(0.15 ml)을 첨가한 다음, 휘발성 구성들(MeOH, 트라이에틸 아민(triethyl amine), 잔존하는 벤즈알데하이드 다이메틸 아세탈(benzaldehyde dimethyl acetal))을 진공에서 제거하였다. 상기 반응 혼합물에, 상기 브로민화 벤질 유도체(benzyl bromide derivative)(1.5 eq.)-만약 시약이 고체라면, 5-10 ml의 DMF에 선용해된-를 첨가하고, 상기 혼합물을 20분 동안 0℃로 냉각시켰다. 여전히 냉각시키면서, NaH(미네랄오일 상에서 55 % 분산된 것의 0.8 g, 1.3 eq.)가 일부로 첨가되었고, 상기 혼합물이 냉각 하에서 수소 형성이 멈출 때까지 실온에서 2-3 시간동안 교반되었다. 메탄올(methanol (2 ml))이 조심스럽게 첨가되었고, 상기 반응 혼합물이 추가 5분 동안 교반되었다. 상기 반응 혼합물은 100 ml의 DCM과 100 ml의 물 사이에서 나뉘어져, 추출되었다. 상기 물층은 100 ml의 DCM으로 2회 역추출(back-extraction)되었다. 상기 혼합된 유기 상들은 증발되었고, 상기 잔사들은 100 ml의 아세토나이트릴(acetonitrile)용해되어 100 ml의 헥산(hexane)으로 추출되었다. 상기 아세토나이트릴은 증류되어 제거되고, 상기 잔사는 50 ℃에서 아이소프로판올(isopropanol)(10 ml)과 아이소프로필 에테르(isopropyl ether)(50 ml)에 첨가되었다. 상기 투명 용액은 하룻밤(overnight) 동안 20 ℃로 냉각되었다. 상기 수득된 결정들은 TBME로 2회 여과 및 세척되고 건조되었다. 재결정화는 TBME(~50 ml)과 에탄올(~20 ml)의 혼합물로부터 수행될 수 있다.
4-클로로벤질 4',6'-O-벤질리덴-β-락토사이드(4-Chlorobenzyl 4',6'-O-benzylidene-β-lactoside)
수율: 1.71 g
4-메틸벤질 4',6'-O-벤질리덴-β-락토사이드(4-Methylbenzyl 4',6'-O-benzylidene-β-lactoside)
수율: 3.20 g
3-페닐벤질 4',6'-O-벤질리덴-β-락토사이드(3-Phenylbenzyl 4',6'-O-benzylidene-β-lactoside)
수율: 2.70 g
2-나프틸메틸 4',6'-O-벤질리덴-β-락토사이드(2-Naphthylmethyl 4',6'-O-benzylidene-β-lactoside)
수율: 1.77 g
B) 메탄올(10 ml)과 물(0.5 ml)에 혼합된 상기 벤질리덴 아세탈(benzylidene acetal)들(500 mg) 중 하나의 혼합물에, TFA가 실온에서 첨가되었고, 상기 반응 혼합물은 제습 하에서 2-4시간 동안 교반된 다음, 증발되었다. 상기 잔류 물질은 에탄올(ethanol)로 3-4회 동시증발되어, 건조된 후 메탄올(methanol)(~10-35 ml)과 물(~0-2 ml)의 혼합물로부터 재결정화될 수 있는 미가공의 고체를 생성하였다.
4-클로로벤질 β-락토사이드(4-Chlorobenzyl β-lactoside)
수율: 333 mg
13C-NMR (75.1 MHz, D2O): δ = 135.25, 133.67, 130.30, 128.70, 103.00, 101.13, 78.39, 75.44, 74.89, 74.49, 72.88, 72.58, 71.03, 70.83, 68.62, 61.11, 60.13.
4-메틸벤질 β-락토사이드(4-Methylbenzyl β-lactoside)
수율: 439 mg
13C-NMR (75.1 MHz, D2O): δ = 138.91, 133.50, 129.37, 129.07, 103.01, 100.96, 78.43, 75.44, 74.87, 74.52, 72.90, 72.59, 71.47, 71.03, 68.63, 61.11, 60.17, 20.34.
3-페닐벤질 β-락토사이드(3-Phenylbenzyl β-lactoside)
수율: 438 mg
13C-NMR (75.1 MHz, d6-DMSO/d4-MeOH/D2O 8:1:1): δ = 140.29, 140.24, 138.88, 129.13, 129.02, 127.66, 126.88, 126.83, 126.03, 125.90, 103.95, 102.03, 80.76, 75.65, 75.07, 75.00, 73.34, 73.28, 70.66, 69.81, 68.27, 60.56.
2-나프틸메틸 β-락토사이드(2-Naphthylmethyl β-lactoside)
수율: 378 mg
13C-NMR (75.1 MHz, D2O/d6-DMSO): δ = 134.96, 133.24, 133.12, 128.59, 128.31, 128.08, 127.46, 126.98, 126.90, 126.79, 103.26, 101.59, 78.89, 75.62, 75.09, 74.81, 73.14, 72.81, 71.33, 71.14, 68.75, 61.22, 60.39.
C)
10 g(8.13 mmol)의 벤질 2,3,6,2',6'-펜타-O-(4-클로로벤조일)-4'-O-벤조일-β-락토사이드(benzyl 2,3,6,2',6'-penta-O-(4-chlorobenzoyl)-4'-O-benzoyl-β-lactoside)와 10 g(1.6 equiv.)의 메틸 N-트라이클로로아세틸-3,6,2',3',4'6'-헥사-O-아세틸-1-싸이오-락토사미나이드(methyl N-trichloroacetyl-3,6,2',3',4'6'-hexa-O-acetyl-1-thio-lactosaminide)가 아르곤 하에서 35 ml의 건조 CHCl3에 용해되었다. 상기 용액에, 3.7 g의 NIS 및 4990 mg의 AgOTf가 실온에서 첨가되었고, 교반이 약 20분 동안 계속되었다. 트라이에틸 아민(triethyl amine)(5 ml)이 상기 슬러리에 첨가되고, CH2Cl2(500 ml)로 희석된 다음, 2X 싸이오황산 나트륨(sodium thiosulphate) 수용액(10 %)으로 추출되었고, 상기 유기 상은 분리되고, MgSO4로 건조되고, 농축되었고, 상기 시럽(syrup)은 CH2Cl2 : 아세톤(acetone) 98:2 → 95:5의 구배를 이용하여 실리카-겔의 컬럼(column)에서 크로마토그래피되었다. 수율: 12.7 g, 80 %. MS (ESP): 1972.1 [M+Na]+, 1988.1 [M+K]+, 1948.2 [M-H]-, 1984.0 [M+Cl]-. 13C NMR (CDCl3) δ: 101.2, 100.7, 100.0, 98.8 (아노머성 탄소들(anomeric carbons)).
상기와 같이 제조된 사당류 10 g(5.1 mmol)이 MeOH(110 ml)에 용해되었고, pH10이 될 때가지 NaOMe의 용액(MeOH 내 1 M)이 첨가되었다. 상기 용액은 40 ℃에서 5시간 동안 교반된 다음, 앰버라이트 IR 120 H+ 레진(Amberlite IR 120 H+ resin)을 첨가하여 중화되었고, 상기 레진은 여과되었고, 상기 여과물은 건조한 상태로 증발되었다. 상기 잔사는 따듯한 DMF(10 ml)에 용해되었고, iPr2O(150 ml)에 한방울씩 첨가되었고, 상기 현탁액은 추가적인 3시간 동안 교반되었다. 상기 침전물은 여과되었고, iPr2O (2x20 ml)로 세척되었고, 건조되어 생성물로서 4.2g의 황백색(off-white)의 분말을 생성하였다(91%). MS (ESP): 900.1 [M-H]-. 13C NMR (D2O) δ: 105.6, 105.5, 104.2, 103.7 (아노머성 탄소들(anomeric carbons)).
상기와 같이 제조된 4당류의 화합물 25 g이 110 ml의 MeOH 및 110 ml의 KOH(7.5 g) 수용액에 용해되었고, 상기 혼합물은 상온에서 1일 동안 교반되었다. 그런 다음, 상기 혼합물은 아이스-배스(ice-bath)로 냉각되었고, HCl-가스로 중화되었고, 건조한 상태로 농축되었다. 상기 생성되는 미가공의 갈색 유리는 피리딘(pyridine)(150 ml) 및 아세트산 무수물(acetic anhydride)(150 ml)로 실온에서 1일 동안 아세틸화된다. 상기 용액은 농축되고, 상기 시럽은 CH2Cl2에 용해되고, 상기 유기 상은 1M HCl-용액 및 sat. NaHCO3-용액으로 순차 추출되고, MgSO4로 건조되고, 여과된 후, 농축되어, CH2Cl2:아세톤(acetone) 8:2를 용리제로 이용하여 컬럼 크로마토그래피에 주입될 갈색 포말(foam) 4.3 g을 생성하였다. 13C NMR (CDCl3) δ: 101.2, 100.8, 100.4, 99.2 (아노머성 탄소들(anomeric carbons)).
상기와 같에 제조된 과아세틸화된 사당류(peracetylated tetrasaccharide) 140 g(107.5 mmol)이 1.5 L의 MeOH에 용해되었고, NaOMe-용액(1 M)이 pH 10이 될 때까지 첨가되고, 상기 혼합물은 50 ℃에서 하룻밤동안 교반되었다. 상기 생성물은 상기 반응 혼합물로부터 결정화되었다. 상기 혼합물은 실온으로 냉각될 수 있어서, 냉각 및 여과되었고, 상기 여과물은 차가운 EtOH로 세척된 다음, 건조되어 백색 분말의 벤질 β-LNnT(benzyl β-LNnT) 69 g를 생성하였다(86.5 mmol, 80 %). 13C NMR (D2O) δ: 105.6, 105.5, 105.4, 103.6 (아노머성 탄소들(anomeric carbons)). Mp. 284-286 ℃
D) 중성 HMO 벤질/치환된 벤질 배당체의 제조를 위한 일반 과정
선별된 중성 HMO(1 equiv.)이 1-10 부피(g/ml)의 DMF, DMSO 또는 그들의 혼합물에 용해/현탁되었다. 상기 반응 혼합물은 0 ℃로 냉각되고, 브로민화 벤질/치환된 브로민화 벤질(benzyl bromide/substituted benzyl bromide)(1.2-1.4 equiv.)이 첨가되었다. 수소화 나트륨(sodium hydride), 수소화 칼륨(potassium hydride), 수소화 칼슘(calcium hydride), 삼차-부톡시화 칼륨(potassium t-butoxide), 삼차-부톡시화 나트륨(sodium t-butoxide)과 같은 강 염기(1.2-1.4 equiv)가 0-40 ℃에서 첨가되었고, 상기 반응 혼합물이 0-60 ℃에서 6-24시간 동안 교반되었다. 그런 다음, 물이 첨가되어 상기 과량의 염기를 소거하고, 상기 반응 혼합물은 실온에서 30분 동안 교반되었다. 상기 생성되는 반응 혼합물은 농축되고, 역상 크로마토그래피(reverse phase chromatography), 실리카 겔 크로마토그래피(silica gel chromatography), 이온-교환 크로마토그래피(ion-exchange chromatography), 크기-배제 크로마토그래피(size-exclusion chromatography) 등으로 정제되거나 결정화되어 원하는 벤질화된/치환된 벤질화된 중성 HMO 화합물을 70-80 % 수율로 생성하였다.
1-O-β-(4-메틸벤질)-LNnT( 1-O-β-(4-methylbenzyl)-LNnT)
1H NMR (D2O): 7.3 (dd, 4H), 4.88 (d, 1H), 4.7 (m), 4.54 (d, 1H), 4.48 (d, 1H), 4.42 (d, 1H), 4.34 (d), 4.0-3.5 (m), 3.34 (dd, 1H).
13C NMR (D2O): 184.2, 177.6, 173.7, 141.5, 136.1, 131.9, 131.4, 105.6, 105.5, 105.4, 103.6, 93.2, 84.7, 81.5, 81.0, 80.8, 78.0, 77.6, 77.4, 77.1, 75.5, 75.2, 74.8, 74.0, 73.6, 72.9, 63.7, 62.8, 58.9, 56.4, 25.9, 22.9.
1-O-β-(4-클로로벤질)-LNnT(1-O-β-(4-chlorobenzyl)-LNnT)
1H NMR (D2O): 7.4 (s, 4H), 4.9 (d, 1H), 4.72 (m), 4.52 (d, 1H), 4.8 (d, 1H), 4.42 (d, 1H), 4.16 (d, 1H), 4.0-3.52 (m).
13C NMR (D2O): 138.9, 177.6, 138.3, 137.9, 136.2, 131.3, 105.6, 105.5, 105.4, 103.7, 93.2, 86.1, 84.7, 81.5, 81.0, 80.8, 78.0, 77.5, 77.4, 77.2, 77.1, 75.5, 75.2, 74.9, 63.7, 58.9, 57.8, 56.4, 24.8.
1-O-β-벤질-LNT(1-O-β-benzyl-LNT)
1H-NMR (D2O, 400 MHz) δ 2.03 (s, 3H, CH 3CONH), 3.35 (dd, 1H, J = 8.1 8.5 Hz, H-2), 3.49 (m, 1H, H-5``), 3.53 (m, H-2```), 3.65 (m, 1H, H-3```), 3.57 (dd, 1H, J = 8.1 9.0 Hz, H-4``), 3.58 (m, 1H, H-5), 3.59 (dd, 1H, J = 7.7 10.0 Hz, H-2`), 3.62 (m, 1H, H-3), 3.63 (m, 1H, H-4), 3.71 (m, 1H, H-5`), 3.71 (m, 1H, H-5```), 3.73 (dd, 1H, J = 3.3 10.0 Hz, H-3`), 3.76 (m, 2H, H-6ab```), 3.76(m, 2H, H-6ab`), 3.80 (m, 1H, H-6a``), 3.80 (dd, 1H, J = 5.0 12.2 Hz, H-6a), 3.82 (dd, 1H, J = 8.1 10.5 Hz, H-3``), 3.90 (m, 1H, H-6b``), 3.90 (dd, 1H, J = 8.4 10.5 Hz, H-2``), 3.92 (d, 1H, J = 3.3 Hz, H-4```), 3.98 (dd, 1H, J = 1.6 12.2 Hz, H-6b), 4.15 (d, 1H, J = 3.3 Hz, H-4`), 4.44 (d, 1H, J = 7.7 Hz, H-1`), 4.45 (d, 1H, J = 7.7 Hz, H-1```), 4.56 (d, 1H, J = 8.1 Hz, H-1), 4.73 (d, 1H, J = 8.4 Hz, H-1``), 4.76 (d, 1H, J = 11.7 Hz, CH 2Ph), 4.94 (d, 1H, J = 11.7 Hz, CH 2Ph), 7.40-7.50 (m, 5H, Ph).
13C-NMR (D2O, 100 MHz) δ 24.9 ( CH3CONH), 57.4 (C-2``), 62.8 (C-6), 63.2 (C-6``), 63.7 (C-6```), 63.7 (C-6`), 71.0 (C-4`), 71.2 (C-4```), 71.3 (C-4``), 72.7 (C-2`), 73.4 (C-2```), 74.2 (CH2Ph), 75.2 (C-3```), 75.5 (C-2), 77.1 (C-3), 77.5 (C-5`), 77.6 (C-5```), 77.9 (C-5), 78.0 (C-5``), 81.1 (C-4), 84.7 (C-3`), 84.8 (C-3``), 103.7 (C-1), 105.3 (C-1``), 105.6 (C-1`), 106.2 (C-1```), 131.1 (Ph), 131.4 (2C, Ph), 131.5 (2C, Ph), 139.2 (Ph), 177.7 (CH3 CONH).
M.p. 245 ℃(dec.). [α]D 22 = -10.3 (c = 1, H2O).
1-O-β-(4-메틸벤질)-LNT(1-O-β-(4-methylbenzyl)-LNT)
1H-NMR (D2O, 300 MHz) δ 1.97 (s, 3H), 2.29 (s, 3H), 3.27 (dd, 1H, J = 8.1 8.5 Hz), 3.39-3.87 (m, 21H), 3.92 (dd, 1H, J = 1.8 12.3 Hz), 4.09 (d, 1H, J = 3.3 Hz), 4.37 (d, 1H, J = 8.1Hz), 4.38 (d, 1H, J = 7.8 Hz), 4.47 (d, 1H, J = 8.1 Hz), 4.65 (d, 1H, J = 11.7 Hz), 4.67 (d, 1H, J = 8.1 Hz), 4.83 (d, 1H, J= 11.7 Hz), 7.22 (d, 2H, J= 8.1 Hz), 7.30 (d, 2H, J = 8.1 Hz).
3C-NMR (D2O, 75.4 MHz) δ 23.1, 25.0, 57.7, 62.8, 63.2, 63.7, 63.8, 71.0, 71.1, 71.3, 72.7, 73.4, 74.1, 75.2, 75.5, 77.1, 77.5, 77.6, 77.9, 78.0, 81.1, 84.7, 84.8, 103.6, 105.3, 105.7, 106.2, 131.7 (2C), 132.0 (2C), 136.2, 141.5, 177.7.
2. 트랜스-
시알릴화
반응들(
Trans
-
sialylation
reactions
)
일반 과정: 가스가 제거된 배양 완충용액(1.0 ml, 100 mM Tris/HCl, pH 7.5, 50 mg BSA, 0.02 % NaN3) 내의 2-O-(p-나이트로페닐)-α-D-시아로사이드(2-O-(p-nitrophenyl)-α-D-sialoside)(25 μmol)와 적절한 시알릴 수용체(35 μmol)가 23 ℃에서 T. 크루지(T. cruzi)로부터 유래된 재조합 트랜스시알리다아제((80 μl, 1.3 mg/ml)와 함께 24시간 동안 배양(incubatioin)되었다. 상기 반응은 TLC((뷰탄올(butanol)/아세트산(acetic acid)/물 5:2:2))에 의하여 모니터링되었다. 완료 후, 상기 효소들은 변성되었고, 원심분리된 후, 상층액을 동결건조하였다. 상기 건조 잔사는 물에 용해되었고, 물을 이용한 바이오겔 크로마토그래피(biogel chromatography)(P-2 Biogel, 16x900 mm) 또는 역상 크로마토그래피(reverse phase chromatography)로 정제되었다. 상기 수율은 45-85 % 사이에서 변한다.
4-클로로벤질 3'-O-(N-아세틸-뉴라미노실)-β-락토사이드(4-Chlorobenzyl 3'-O-(N-acetyl-neuraminosyl)-β-lactoside)
1H-NMR (500 MHz, D2O): δ [ppm] = 7.46-7.42 (m, 4H, H(a/b)arom); 4.91 (d, 1H, CH2a-Bn); 4.74 (d, 1H, CH2b-Bn); 4.55-4.52 (m, 2H, H-1/H-1'); 4.11 (dd, 1H, H-3'); 2.76 (dd, 1H, H-3''eq); 2.04 (s, 3H, COCH3); 1.81 (dd, 1H, H-3''ax).
J(a,b)- Bn = 11.8; J2' ,3' = 9.9; J3' ,4' = 2.9; J3''ax ,3'' eq = 12.4; J3''ax ,4'' = 12.1; J3''eq,4'' = 4.5 Hz.
13C-NMR (126 MHz, D2O): δ [ppm] = 135.2, 133.5 (quart. Carom); 130.2 (CHa-arom); 128.6 (CHb - arom); 102.6 (C-1'); 101.1 (C-1); 51.7 (C-5''); 39.6 (C-3''); 22.0 (COCH3).
4-메틸벤질 3'-O-(N-아세틸-뉴라미노실)-β-락토사이드(4-Methylbenzyl 3'-O-(N-acetyl-neuraminosyl)-β-lactoside)
1H-NMR (500 MHz, D2O): δ [ppm] = 7.36 (d, 2H, H-aarom); 7.28 (d, 2H, H-barom); 4.89 (d, 1H, CH2a-Bn); 4.72 (d, 1H, CH2b-Bn); 4.54-4.52 (m, 2H, H-1/H-1'); 4.12 (dd, 1H, H-3'); 2.76 (dd, 1H, H-3''eq); 2.35 (s, 3H, CH3-Tol); 2.04 (s, 3H, COCH3), 1.81 (dd, 1H, H-3''ax).
J(a,b)arom = 7.9; J(a,b)- Bn = 11.5; J2' ,3' = 9.9; J3' ,4' = 3.0; J3''ax ,3'' eq = 12.5; J3'',4'' = 12.2; J3''eq ,4'' = 4.6 Hz.
13C-NMR (126 MHz, D2O): δ [ppm] = 138.8, 133.4 (quart. Carom); 129.3 (CHa-arom); 129.0 (CHb - arom); 102.6 (C-1'); 100.9 (C-1); 99.8 (C-2''), 51.7 (C-5''); 39.6 (C-3''); 22.0 (COCH3); 20.2 (CH3-Tol).
2-나프틸메틸 3'-O-(N-아세틸-뉴라미노실)-β-락토사이드(2-Naphthylmethyl 3'-O-(N-acetyl-neuraminosyl)-β-lactoside)
H-NMR (500 MHz, D2O): δ [ppm] = 7.99-7.97 (m, 4H, H-arom); 7.62-7.59 (m, 3H, H-arom); 5.10 (d, 1H, CH2a-Bn); 4.95 (d, 1H, CH2b-Bn); 4.60 (d, 1H, H-1); 4.53 (d, 1H, H-1'); 4.12 (dd, 1H, H-3'); 2.77 (dd, 1H, H-3''eq); 2.04 (s, 3H, COCH3); 1.81 (dd, 1H, H-3''ax).
J(a,b)- Bn = 11.9; J1 ,2 = 8.0; J1' ,2' = 7.9; J2' ,3' = 9.9; J3' ,4' = 3.0; J3''ax ,3'' eq = 12.5; J3''ax , 4'' = 12.1; J3''eq , 4'' = 4.6 Hz.
13C-NMR (126 MHz, D2O): δ [ppm] = 128.3, 127.9, 127.7, 127.6, 126.6, 126.5 (CHarom); 102.6 (C-1'); 101.1 (C-1); 51.7 (C-5''); 22.0 (COCH3).
3-페닐벤질 3'-O-(N-아세틸-뉴라미노실)-β-락토사이드(3-Phenylbenzyl 3'-O-(N-acetyl-neuraminosyl)-β-lactoside)
1H-NMR (400 MHz, D2O): δ [ppm] = 7.75-7.44 (m, 9H, H-arom); 4.99 (d, 1H, CH2a-Bn); 4.82 (d, 1H, CH2b-Bn); 4.57 (d, 1H, H-1); 4.53 (d, 1H, H-1'); 4.13 (dd, 1H, H-3'); 2.78 (dd, 1H, H-3''eq); 2.05 (s, 3H, COCH3); 1.82 (dd, 1H, H-3''ax).
J(a,b)- Bn = 11.8; J1 ,2 = 8.0; J1' ,2' = 7.9; J2' ,3' = 9.9; J3' ,4' = 3.1; J3''ax ,3'' eq = 12.5; J3''ax ,4'' = 12.0; J3''eq ,4'' = 4.6 Hz.
13C-NMR (100 MHz, D2O): δ [ppm] = 140.9, 140.3, 137.5 (quart. Carom); 129.4, 129.2, 127.9, 127.8, 127.1, 127.0, 126.9, (CHarom); 102.7 (C-1'); 101.2 (C-1); 99.6 (C-2''); 51.8 (C-5''); 39.7 (C-3''); 22.1 (COCH3).
벤질 3'''-O-(N-아세틸-뉴라미노실)-β-LNnT(Benzyl 3'''-O-(N-acetyl-neuraminosyl)-β-LNnT)
1H-NMR (400 MHz, D2O): 도 1 참조.
<110> Glycom A/S
<120> Synthesis of New Sialooligosaccharide Derivatives
<130> 2013-FPA-5729
<150> GB1012036.8
<151> 2010-07-16
<150> EP11166036.1
<151> 2011-05-13
<160> 11
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Met Thr Glu Asn Gly Met Met Asn Thr Asn Asn Thr Val Cys Gly Ala
1 5 10 15
Asn His Asp Gly Ala Met Ser Leu Ala Ala Pro Gly Asp Tyr Gly Val
20 25 30
Ala Cys Tyr Arg Ile Pro Ala Leu Ala Glu Ala Pro Asn Gly Trp Ile
35 40 45
Leu Ala Ala Phe Asp Ala Arg Pro His Asn Cys Gln Asp Ala Pro Gln
50 55 60
Ala Asn Ser Ile Val Gln Arg Ile Ser Lys Asp Gly Gly Arg Ser Phe
65 70 75 80
Glu Pro Gln His Val Val Ala Ala Gly His Asp Gly Val Asp Lys Tyr
85 90 95
Gly Tyr Ser Asp Pro Ser Tyr Val Val Asp Arg Gln Thr Gly Glu Val
100 105 110
Phe Leu Phe Phe Val Lys Ser Tyr Asp Ala Gly Phe Gly Thr Ser Gln
115 120 125
Ala Gly Val Asp Pro Ser Ala Arg Glu Val Leu Gln Ala Ala Val Thr
130 135 140
Ser Ser Ile Asp Asn Gly Val Thr Trp Ser Glu Pro Arg Ile Ile Thr
145 150 155 160
Ala Asp Ile Thr Asn Ser Glu Ser Trp Ile Ser Arg Phe Ala Ser Ser
165 170 175
Gly Ala Gly Ile Gln Leu Thr Tyr Gly Glu His Ala Gly Arg Leu Ile
180 185 190
Gln Gln Tyr Thr Ile Lys Glu Leu Asp Gly Arg Tyr Arg Ala Val Ser
195 200 205
Val Phe Ser Asp Asp His Gly Ala Thr Trp His Ala Gly Thr Pro Val
210 215 220
Gly Asp His Met Asp Glu Asn Lys Val Val Glu Leu Ser Asp Gly Arg
225 230 235 240
Val Met Leu Asn Ser Arg Ser Ser Asp Gly Asn Gly Cys Arg Tyr Val
245 250 255
Ala Ile Ser Arg Asp Gly Gly Ala Thr Tyr Gly Pro Val Ile Arg Glu
260 265 270
Thr Gln Leu Pro Asp Pro Glu Asn Asn Ala Gln Ile Ala Arg Ala Phe
275 280 285
Pro Asp Ala Pro Glu Gly Ser Ala Gln Ala Lys Val Leu Leu Tyr Ser
290 295 300
Ser Ser Ser Pro Ser Asp Arg Ile Asp Gly Leu Val Arg Val Ser Ile
305 310 315 320
Asp Asp Gly Lys Thr Trp Ser Ala Gly Arg Arg Phe Thr Thr Gly Pro
325 330 335
Met Ala Tyr Ser Val Ile Ala Ala Leu Ser His Lys Ala Gly Gly Gly
340 345 350
Tyr Gly Leu Leu Tyr Glu Gly Asp Asn Asn Asn Ile Met Tyr Thr Arg
355 360 365
Ile Ser Leu Asp Trp Leu Asn Gly Gln Leu Asn Val Asp Gly Ile Gly
370 375 380
Gly Phe Pro Leu Ser Gly Glu Gly Gly
385 390
<210> 2
<211> 760
<212> PRT
<213> Bifidobacterium longum subsp. infantis ATCC 15697
<400> 2
Met Ala Ala Ser Asn Pro Ile Ser Trp Ser Gln Arg Thr Phe Pro Ser
1 5 10 15
Pro Glu Gly Thr Ile Ala Cys Arg Phe Arg Ala His Ala Asp Gly Arg
20 25 30
Ile Phe Asp Ala Val Asn Gly Ser Ala Asn Asp Ala Pro Leu Leu Ile
35 40 45
Cys Ala Ile Glu His Asp Ala Leu Arg Val Arg Ala Thr Thr Pro Arg
50 55 60
Gln His Val Asp Phe Asp Ile Glu Asp Thr Thr Gly Ile Ala Asp Gly
65 70 75 80
Ala Met His Thr Phe Ala Leu Thr Phe Gly Glu Phe Gly Thr Arg Val
85 90 95
Tyr Leu Asp Gly Ser Gln Cys Phe Ser Gly Thr Ala Asn Leu Cys Pro
100 105 110
Thr Thr Leu Thr Gly Thr Glu Gly Ser Gly Gln Gly Ala Ile Arg Leu
115 120 125
Ala Gly Pro Ser Ile Asp Val Thr Asp Met Arg Leu His Ala Ile Pro
130 135 140
Leu Thr Ser Glu Ser Ile Ala Ala Leu Thr Pro Arg Pro Ala Pro Asp
145 150 155 160
Ile Asp Phe Ala Ala Ala Gln Leu Ala Pro Arg Asp Val Arg Arg Val
165 170 175
Arg Thr Leu Arg Ser Gly Thr Ile Phe Met His Phe Arg Val Arg Gly
180 185 190
Pro Arg Gln Tyr Gly Thr Leu Leu Ala Ala Gly Glu Arg Gly Glu Glu
195 200 205
Arg Leu Ala Val Ser Ile Asp Asp Asn Gly Ile Thr Met Thr Ala Ala
210 215 220
Asp Gly Leu Tyr Glu Pro Ser Thr Tyr His Ala Arg Gly Ala Trp Asp
225 230 235 240
Asp Gly Arg Trp His Asp Leu Ser Ile Arg Ser Ala Arg Gly Ala Ile
245 250 255
Asp Met Tyr Val Asp Gly Trp His Glu Leu His Gln Ala Gly Gln Val
260 265 270
Phe Phe Gly Asp Trp Pro Gln Leu Asp Glu Val Ala Ile Gly Gln Asn
275 280 285
Thr Glu Gly Val Arg Leu Met Gly Glu Val Arg Asn Gly Gly Val Phe
290 295 300
Thr Thr Pro Leu Thr Asp Gly Ala Ile Arg Arg Leu Ser Asp Ala Pro
305 310 315 320
Ala Leu Thr Thr Thr Ala Leu Phe Asp Lys Gly Tyr His Gly Ser Val
325 330 335
Ser Tyr Arg Ile Pro Ser Ile Ile Arg Thr Pro His Gly Val Val Val
340 345 350
Ala Gly Ala Asp Gln Arg Thr Ala Ile Ala Asn Asp Ala Pro Asn His
355 360 365
Ile Asn Phe Val Met Arg Arg Ser Leu Asp Gly Gly Arg Thr Trp Leu
370 375 380
Asp Met Gln Thr Val Ile Ala Asn Pro Gly Glu Gly Val Asp Gly Ala
385 390 395 400
Cys Thr Ile Asp Ser Cys Leu Val Cys Asp Glu Arg Asn Gly Arg Leu
405 410 415
Thr Val Leu Ile Asp Arg Phe Ala Gly Gly Val Gly Leu Pro Asn Asn
420 425 430
Thr Pro Gly Thr Gly Val Asp Arg His Gly Arg Pro Cys Leu Tyr Asp
435 440 445
Arg Ala Gly Thr Arg Tyr Val Leu Ala Asp Asp Gly Thr Val Leu Asp
450 455 460
Gly Gly Gly Glu Arg Thr Gly Tyr Arg Val Asp Ala His Gly Asn Val
465 470 475 480
Thr His Glu Gly Arg Ala Ser Gly Asn Ile Tyr Leu Lys Glu Gly Ala
485 490 495
Asp Pro Asp Glu Ser Leu Leu Ile Glu Arg Thr Ser Phe Ile Ile Glu
500 505 510
Leu His Ser Asp Asp Asp Gly Glu Thr Trp Ser Thr Pro Arg Asn Ile
515 520 525
Asn His Met Ile Lys Glu Asp Trp Met His Phe Leu Gly Val Ser Pro
530 535 540
Gly Asn Gly Ile Gln Leu Gln Ala Ser Glu His Arg Gly Arg Leu Leu
545 550 555 560
Val Pro Phe Tyr Cys Thr Gly Ala Ser Leu Lys His Tyr Ser Gly Gly
565 570 575
Ala Leu Ile Ser Asp Asp Gly Gly Asp Thr Trp Arg Arg Gly Ser Met
580 585 590
Ile Asn Asp Gly Arg Ile Val Asn Gly Thr Ala Val Asp Pro Lys Asn
595 600 605
Ile Arg Asp Asp Asp Ala Thr Thr His Glu Ser Val Phe Val Glu Arg
610 615 620
Ala Asp Gly Thr Val Val Cys Phe Phe Arg Asn Gln Asn His Ala Gly
625 630 635 640
Arg Ile Gly Val Ala Leu Ser His Asp Gly Gly Glu Thr Trp Asp Asp
645 650 655
Leu Tyr Phe Asp Lys Asp Val Pro Asp Ile Phe Cys Gln Pro Asn Ala
660 665 670
Val Ala Cys Ala Pro Arg Ser Asp Thr Met Val Phe Ala Asn Ala Ser
675 680 685
Gln Met Leu Pro Tyr Arg Gly Asn Gly Val Leu Arg Leu Ser Leu Asp
690 695 700
Gly Ala Arg Thr Trp Ala Ala His Arg Cys Ile Asn Pro Tyr His Tyr
705 710 715 720
Gly Tyr Gln Cys Met Thr Met Leu Pro Asp Gly Glu Leu Gly Leu Leu
725 730 735
Trp Glu Arg Glu Thr Ala Gly Leu Tyr Phe Thr Thr Leu Pro Leu Ser
740 745 750
Val Phe Gly Ala Ala Glu Thr His
755 760
<210> 3
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<212> PRT
<213> Bifidobacterium bifidum
<400> 3
Met Val Arg Ser Thr Lys Pro Ser Leu Leu Arg Arg Leu Gly Ala Leu
1 5 10 15
Val Ala Ala Ala Ala Met Leu Val Val Leu Pro Ala Gly Val Ser Thr
20 25 30
Ala Ser Ala Ala Ser Asp Asp Ala Asp Met Leu Thr Val Thr Met Thr
35 40 45
Arg Thr Asp Thr Leu Gly Asp Glu Val Tyr Val Gly Asp Thr Leu Thr
50 55 60
Tyr Ser Phe Thr Asn Thr Asn Asn Thr Ser Ser Ala Phe Thr Ala Phe
65 70 75 80
Pro Ala Glu Ser Asn Leu Ser Gly Val Leu Thr Thr Gly Thr Pro Asn
85 90 95
Cys Arg Tyr Glu Asn Leu Ala Gly Gly Ala Ser Tyr Pro Cys Ser Thr
100 105 110
Ala Ser His Thr Ile Thr Ala Asp Asp Leu Thr Ala Gly Ser Phe Thr
115 120 125
Pro Arg Thr Val Trp Lys Ala Thr Ser Asp Arg Gly Gly Thr Gln Val
130 135 140
Leu Gln Asp Asn Ile Val Ser Thr Gly Asp Thr Val Thr Val Lys Glu
145 150 155 160
Gly Lys Arg Pro Asp Pro Ala Thr Ile Pro Thr Asp Arg Ala Asp Gly
165 170 175
Glu Ala Val Arg Leu Ala Thr Ala Arg Gln Asn Leu Gly Thr Glu Cys
180 185 190
Tyr Arg Ile Pro Ala Leu Ala Glu Ala Pro Asn Gly Trp Ile Leu Ala
195 200 205
Ala Phe Asp Gln Arg Pro Asn Thr Ala Met Ala Asn Gly Ser Gly Val
210 215 220
Lys Cys Trp Asp Ala Pro Gln Pro Asn Ser Ile Val Gln Arg Ile Ser
225 230 235 240
Lys Asp Gly Gly Lys Ser Trp Thr Pro Ile Gln Tyr Val Ala Gln Gly
245 250 255
Lys Asn Ala Pro Glu Arg Tyr Gly Tyr Ser Asp Pro Ser Tyr Val Val
260 265 270
Asp Glu Glu Thr Gly Glu Ile Phe Leu Phe Phe Val His Ser Tyr Asn
275 280 285
Lys Gly Phe Ala Asp Ser Gln Leu Gly Val Asp Glu Ser Asn Arg Asn
290 295 300
Val Leu His Ala Val Val Val Ser Ser Lys Asp Asn Gly Glu Thr Trp
305 310 315 320
Ser Lys Pro Arg Asp Ile Thr Ala Asp Ile Thr Lys Gly Tyr Glu Asn
325 330 335
Glu Trp Lys Ser Arg Phe Ala Thr Ser Gly Ala Gly Ile Gln Leu Lys
340 345 350
Tyr Gly Lys Tyr Lys Gly Arg Leu Ile Gln Gln Tyr Ala Val Gly Arg
355 360 365
Thr Thr Gly Ser Asn Ala Ala Val Ser Val Tyr Ser Asp Asp His Gly
370 375 380
Lys Thr Trp Gln Ala Gly Asn Pro Val Thr Gly Met Leu Met Asp Glu
385 390 395 400
Asn Lys Val Val Glu Leu Ser Asp Gly His Val Met Leu Asn Ser Arg
405 410 415
Pro Gly Asn Gly Ser Gly Tyr Arg Arg Val Ala Ile Ser Glu Asp Gly
420 425 430
Gly Val Asn Tyr Gly Thr Val Lys Asn Glu Thr Gln Leu Pro Asp Pro
435 440 445
Asn Asn Asn Ala His Ile Thr Arg Ala Phe Pro Asn Ala Pro Glu Gly
450 455 460
Ser Ala Lys Ala Lys Val Leu Leu Tyr Ser Ser Pro Arg Ala Asn Asn
465 470 475 480
Glu Gly Arg Ala Asn Gly Val Val Arg Ile Ser Leu Asp Asp Gly Thr
485 490 495
Thr Trp Ser Ser Gly Lys Leu Tyr Lys Ala Gly Ser Met Ala Tyr Ser
500 505 510
Val Ile Thr Ala Leu Ser Gly Ala Ala Gly Gly Gly Tyr Gly Leu Leu
515 520 525
Tyr Glu Gly Ala Trp Val Thr Gly Gly Gly Ile Asp Ser His Asp Ile
530 535 540
Met Tyr Thr His Ile Ser Met Asp Trp Leu Gly Tyr Leu Ser Ala Thr
545 550 555 560
Ala Asp Asp Val Thr Ala Ser Val Glu Glu Gly Ala Ser Thr Val Asp
565 570 575
Val Thr Val Pro Val Ser Asn Val Gly Ser Val Asp Tyr Thr Gly Val
580 585 590
Thr Val Thr Pro Ala Asp Leu Pro Thr Gly Trp Ser Ala Ser Pro Val
595 600 605
Asn Val Gly Ala Leu Ala Ser Gly Ala Ser Lys Asp Val Thr Val Thr
610 615 620
Val Asn Val Pro Ala Thr Ala Lys Lys Asp Asp Val Ala Lys Ile Val
625 630 635 640
Leu Arg Val Thr Gly Thr Ser Ala Ala Asn Ala Asp Ala Thr Thr Gly
645 650 655
Phe Asp Gly Ser Ile Thr Val Asn Val Thr Glu Lys Ser Glu Pro Asp
660 665 670
Pro Glu Pro Glu Pro Thr Ile Thr Gly Val Ser Ala Val Thr Ser Gln
675 680 685
Ala Gly Val Lys Val Gly Asp Val Phe Asp Ala Ser Lys Val Ser Val
690 695 700
Thr Ala Ala Met Ser Asp Gly Ser Ser Lys Ala Leu Ala Ala Gly Glu
705 710 715 720
Tyr Ser Leu Ser Ala Val Asp Ala Asp Gly Lys Ala Val Asp Leu Ala
725 730 735
Glu Pro Phe Ala Ala Ala Gly Val Val Thr Val Thr Val Ser Val Pro
740 745 750
Val Glu Gly Ala Asp Pro Leu Thr Ala Ser Phe Thr Ile Asp Val Ala
755 760 765
Glu Lys Ser Ala Asp Pro Glu Pro Lys Pro Glu Pro Glu Pro Lys Pro
770 775 780
Glu Pro Glu Lys Pro Ala Gly Pro Lys Val Asp Val Pro Thr Glu Lys
785 790 795 800
Pro Gly Leu Ser Lys Thr Gly Ala Ser Thr Ala Gly Met Ser Ile Val
805 810 815
Phe Val Leu Leu Ala Leu Ser Gly Val Ala Ala Leu Ser Leu Arg Arg
820 825 830
Arg Ser Val His
835
<210> 4
<211> 1795
<212> PRT
<213> Bifidobacterium bifidum
<400> 4
Met Thr Thr Ile Phe Arg Arg Ala Thr Ala Lys Thr Leu Met Arg Lys
1 5 10 15
Leu Ser Gly Leu Leu Val Ala Ile Ala Met Leu Ala Val Leu Pro Ala
20 25 30
Gly Thr Ile Ser Ala Asn Ala Ala Asp Glu Pro Pro Gln Glu Tyr Leu
35 40 45
Gln Leu Thr Leu Thr Arg Thr Asp Ser Asn Gly Thr Pro Ala Glu Val
50 55 60
Gly Asp Lys Leu Thr Tyr Ser Leu Gly Tyr Lys Asn Val Ser Asp Thr
65 70 75 80
Gly Phe Ile Val His Pro Thr Ala Ser Asn Leu Asn Asn Val Ala Thr
85 90 95
Pro Gln Ser Ala Ser Asn Pro Asn Pro Met Cys Arg Trp Gly Asn Leu
100 105 110
Ala Ala Gly Ala Ser Ala Ala Cys Thr Trp Ser Ala Ser Lys Glu Phe
115 120 125
Ala Tyr His Val Val Thr Glu Asp Asp Val Ala Asn Gly Phe Thr Pro
130 135 140
Thr Ala Thr Val Ser Ala Thr Thr Gln Asp Gly Thr Asn Gly Val Leu
145 150 155 160
Gln Ser Val Asp Ile Thr Gly Glu Thr Val Pro Ala Val Pro Ala Thr
165 170 175
Ser Thr Leu Arg Val Ala Met Gln Arg Thr Asp Thr Leu Gly Asp Asn
180 185 190
Val Lys Ile Gly Asp Arg Leu Thr Phe Asn Phe Thr Tyr Thr Asn Lys
195 200 205
Thr Ala Gln Lys Ile Tyr Ala Tyr Pro Ser Glu Ser Asn Ile Glu Arg
210 215 220
Val Asp Val Val Ser Phe Pro Arg Asn Ser Cys Arg Ser Gly Val Glu
225 230 235 240
Ala Asn Gln Thr Ala Ser Cys Gly Phe Ala Tyr His Val Ile Thr Ala
245 250 255
Glu Asp Val Val Ala Arg Arg Tyr Thr Pro Thr Ala Thr Phe Arg Ala
260 265 270
Thr Ser Asp Arg Asp Gly Thr Gln Val Leu Gln Asp Asp Met Thr Phe
275 280 285
Thr Thr Gly Thr Val Thr Val Ala Gly Pro Ala Asp Asp Ala Ala Ser
290 295 300
Thr Pro Thr Glu Arg Lys Asp Gly Glu Pro Leu Leu Leu Ala Thr Asn
305 310 315 320
Lys Gln Ile Gly Asn Thr Asp Tyr Tyr Arg Ile Pro Ala Ile Ala Gln
325 330 335
Ala Pro Asn Gly Trp Ile Leu Ala Ala Trp Asp Leu Arg Pro Lys Leu
340 345 350
Ala Ala Asp Ala Pro Asn Pro Asn Ser Ile Val Gln Arg Ile Ser Lys
355 360 365
Asp Gly Gly Lys Ser Trp Glu Thr Leu Ala Tyr Val Ala Gln Gly Arg
370 375 380
Ser Ala Thr Asn Lys Tyr Gly Tyr Ser Asp Pro Ser Tyr Val Val Asp
385 390 395 400
Glu Glu Ala Gly Lys Ile Phe Leu Phe Cys Val Lys Ser Tyr Asp Gln
405 410 415
Gly Tyr Phe Gly Ser Val Leu Gly Val Glu Asp Ala Arg Asn Val Leu
420 425 430
Gln Ala Val Val Met Glu Ser Asp Asp Asn Gly Ala Thr Trp Ser Glu
435 440 445
Pro Arg Asn Ile Thr Lys Asp Ile Thr Lys Gly His Glu Asp Glu Trp
450 455 460
Lys Ser Arg Phe Ala Ser Ser Gly His Gly Ile Gln Leu Lys Tyr Gly
465 470 475 480
Gln Tyr Lys Gly Arg Leu Ile Gln Gln Tyr Ala Val Arg Thr Thr Ser
485 490 495
Asn Thr Asn Ile Ala Val Ser Val Tyr Ser Asp Asp His Gly Lys Thr
500 505 510
Trp Lys Ala Gly Asn Pro Val Thr Glu Val Asn Met Asp Glu Asn Lys
515 520 525
Val Val Glu Leu Ser Asp Gly Arg Val Met Leu Asn Ser Arg Pro Gly
530 535 540
Ala Ala Gly Tyr Arg Arg Val Ala Ile Ser Glu Asp Gly Gly Val Asn
545 550 555 560
Tyr Gly Pro Ile Lys Ser Glu Thr Gln Leu Pro Asp Pro Asn Asn Asn
565 570 575
Ala Gln Ile Thr Arg Ala Phe Pro Asn Ala Pro Glu Gly Ser Ala Lys
580 585 590
Ala Lys Val Leu Leu Tyr Ser Ala Pro Arg Ala Ser Asn Glu Gly Arg
595 600 605
Ala Asn Gly Val Val Arg Val Ser Phe Asp Asp Gly Thr Thr Trp Ser
610 615 620
Ala Gly Lys Leu Phe Lys Ala Gly Ser Met Ala Tyr Ser Val Ile Thr
625 630 635 640
Ala Leu Asn Asp Ala Ala Gly Gly Gly Tyr Gly Leu Leu Tyr Glu Gly
645 650 655
Glu Ser Ile Thr Tyr Thr Arg Ala Ser Met Glu Trp Leu Gly Tyr Leu
660 665 670
Thr Ala Thr Ala Ser Gly Thr Ala Ala Val Lys Glu Gly Glu Gly Thr
675 680 685
Leu Thr Ala Pro Val Thr Val Thr Asn Asp Gly Leu Thr Asp Tyr Thr
690 695 700
Asn Val Thr Val Thr Pro Thr Gly Leu Pro Ser Gly Trp Ser Ala Glu
705 710 715 720
Ala Val Asn Val Gly Asn Leu Ala Ala Gly Gln Ser Ala Thr Val Asn
725 730 735
Val Pro Val Thr Val Pro Ala Ala Ala Val Ser Gly Thr Val Ala Lys
740 745 750
Ala Thr Met Lys Ile Thr Gly Lys Tyr Ala Gln Ser Glu Asp Thr Leu
755 760 765
His Ser Phe Ala Glu Gly Glu Leu Ala Val Thr Val Thr Asp Pro Asp
770 775 780
Pro Ala Ala Lys Arg Leu Lys Leu Thr Ile Glu Arg Thr Asp Asp Asn
785 790 795 800
Gly Asp Pro Val Lys Val Gly Asp Thr Leu Thr Tyr Arg Ile Thr Tyr
805 810 815
Glu Asn Val Gly Thr Gln Ser Phe Ala Val Tyr Pro Arg Glu Ser Asn
820 825 830
Leu Asp Gly Val Thr Thr Pro Gln Ser Ala Ser Asn Pro Ala Pro Val
835 840 845
Cys Arg Trp Ser Arg Leu Ala Pro Gly Ala Thr Gly Ala Cys Val Ser
850 855 860
Gly Asn Gly Lys Gln Leu Ala Tyr His Thr Val Thr Glu Ala Asp Ala
865 870 875 880
Thr Ala Gly Ser Phe Thr Pro Ser Ala Thr Ile Asp Ala Thr Ala Asp
885 890 895
Ala Ser Gly Glu Thr Val Leu Glu Ser Val Ser Ile Thr Gly Asp Pro
900 905 910
Val Thr Val Ser Gln Pro Val Glu Leu Pro Ala Asp Ile Ala Ala Trp
915 920 925
Lys Thr Arg Asn Glu Ala Leu Ala Asp Trp Gln Thr Leu Ser Glu Lys
930 935 940
Leu Ala Lys Thr Asp Arg Ile Asn Trp Leu Phe Thr Gly Asp Ser Ile
945 950 955 960
Thr His Gly Val Gln Phe Thr Arg Gly Tyr Arg Thr Tyr Ser Glu Leu
965 970 975
Phe Ala Asn His Leu Asp Thr Ala Ser Val Arg Gly Val Ser Arg Ala
980 985 990
Asn Asp Val Val Met Asn Thr Gly Ile Ser Ser Ala Asp Ala Ser Trp
995 1000 1005
Pro Leu Lys Asp Gly Ala Phe Glu Lys Trp Val Ser Asp Lys His Pro
1010 1015 1020
Asp Val Val Phe Leu Thr Phe Gly Met Asn Asp Gly Arg Thr Gly Gln
1025 1030 1035 1040
Ala Phe Thr Val Asp Gln Tyr Thr Ala Asn Leu Ser Thr Leu Ile Asp
1045 1050 1055
Lys Ile Arg Asp Leu Gly Ala Ile Pro Val Leu Gln Thr Gln Asn Tyr
1060 1065 1070
Thr Thr Asn Thr Thr Phe Asn Ala Asn Leu Asp Thr Tyr Phe Asp Ala
1075 1080 1085
Glu Arg Arg Leu Ala Leu Asp Lys Asn Val Leu Leu Val Asp Phe Asn
1090 1095 1100
Lys Gln Trp Leu Glu Leu Gly Gly Gly Asn Arg Glu Ser Gly Thr Tyr
1105 1110 1115 1120
Met Gly Ala Gly Asn Asp Ile His Pro Gly Glu Asn Gly His Ile Glu
1125 1130 1135
Trp Ala Lys Phe Thr Leu Gly Ala Leu Asn Met Ile Ala Asn Asp Asp
1140 1145 1150
Pro Leu Ala Arg Trp Ser Ser Ser Asp Thr Thr Leu Asp Lys Pro Thr
1155 1160 1165
Val Thr Val Asp Ala Asp Gly Asn Gly Leu Lys Gly Ser Asp Gly Leu
1170 1175 1180
Glu Pro Ala Pro Ala Ala Ala Lys Ser Val Gly Lys Phe Leu Ser Gly
1185 1190 1195 1200
Ala Gln Tyr Val Asp Leu Gly Gly Asp Val Val Ser Ala Val Ala Gly
1205 1210 1215
Lys Arg Glu Ser Asn Val Thr Ile Arg Phe Arg Ala Ser Ala Thr Gly
1220 1225 1230
Gln Pro Gln Thr Leu Phe Ser Leu Gly Asp Ser Asp Ser Ala Thr Arg
1235 1240 1245
Ala Thr Val Arg Leu Ser Ala Thr Gly Leu Val Gln Phe Leu Asn Ser
1250 1255 1260
Gly Asn Thr Gly Asp Phe Tyr Thr Val Gly Thr Asn Asp Leu Ala Asp
1265 1270 1275 1280
Gly Ala Trp His Thr Val Ser Val Asn Phe Val Ala Asn Gly Phe Thr
1285 1290 1295
Ile Tyr Val Asp Gly Ala Ala Met Arg Ala Ile Ser Gly Gly Ala Gly
1300 1305 1310
Thr Gln Leu Asn Val Pro Gly Ala Ile Thr Val Asn Thr Ala Thr Ala
1315 1320 1325
Gly Ala Ile Arg Gly Ala Asp Ser Ala Gly Gly Ala Gln Gln Leu Thr
1330 1335 1340
Gly Ile Val Asp Tyr Val Ala Ala Trp Ser Arg Thr Leu Thr Asp Ala
1345 1350 1355 1360
Glu Ala Lys Arg Ile Ser Ala Glu Thr Ser Ala Val Ala Val Thr Lys
1365 1370 1375
Val Asp Ala Ala Val Asn Ala Leu Gln Pro Ile Ile Ser Asp Thr Gly
1380 1385 1390
Ala Arg Lys Asn Ile Val Phe Val Gly Gly Glu Thr Ile Glu Gly Gly
1395 1400 1405
Tyr Thr Asp His Leu Ile Ala Lys Asn Ile Val Gln Leu Leu Asp Glu
1410 1415 1420
Arg Val Arg Trp Glu Tyr Val Thr Gly Leu Ser Ala Thr Asp Arg Glu
1425 1430 1435 1440
Arg Gln Arg Ala Lys Phe Phe Val Ala Ala Gly Gln Gly Gly Leu Thr
1445 1450 1455
Ala Lys Gln Met Asp Glu Asp Tyr Ala Ala Met Val Gly Glu Tyr Ser
1460 1465 1470
Pro Asp Ile Leu Phe Leu Ala Pro Asp Leu Tyr Asp Ala Asp Gly Asn
1475 1480 1485
Leu Ala Glu Ser Ala Ala Ala Ala Phe Ala Gly His Ile Arg Ser Val
1490 1495 1500
Ala Ala Lys Ala Lys Glu Ala Gly Ala Lys Val Val Leu Val Thr Pro
1505 1510 1515 1520
Val Thr Val Arg Gly Gly Glu Asp Glu Tyr Ala Gly Ala Met Arg Thr
1525 1530 1535
Val Ala Lys Glu Asp Asp Leu Pro Leu Ile Asp Ala Gln Ala Trp Ile
1540 1545 1550
Gly Lys Val Val Ala Ala Asp Ala Ser Val Lys Thr Ala Trp Phe Asn
1555 1560 1565
Lys Ala Gly Gln Leu Asn Tyr Ala Gly His Leu Gly Tyr Ala Arg Phe
1570 1575 1580
Met Met Arg Ser Leu Asp Leu Tyr Pro Ser Asn Val Ser Gly Ser Arg
1585 1590 1595 1600
Ile Ala Ser Leu Pro Tyr Asp Thr Ala Asn Val Thr Leu Val Gly Ala
1605 1610 1615
Ser Glu Asn Gly Gly Glu Leu Pro Val Gly Arg Val Glu Gly Thr Asp
1620 1625 1630
Arg Ala His Ile Asp Thr Met Gln Ile Gly Ala Ala Ala Ser Leu Val
1635 1640 1645
Val Val Asp Ser Tyr Ala Val Tyr Glu Ile Gly Glu Asp Gly Gly Arg
1650 1655 1660
Thr Leu Val Ala Asp Gly Leu Lys Pro Ala Asp Val Leu Ala Asp Gly
1665 1670 1675 1680
Ile Asp Val Thr Val Asn Asp Thr Ala Ala His Arg Tyr Glu Val Val
1685 1690 1695
Gly Ser Ala Asn Val Pro Glu Gly Ala Asp Ala Val Thr Val Thr Tyr
1700 1705 1710
Thr Ala Thr Leu Ala Ala Val Glu Glu Pro Glu Pro Gly Pro Asp Pro
1715 1720 1725
Asp Pro Thr Pro Asp Pro Ser Glu Lys Pro Asp Gly Asp Gly Thr Gly
1730 1735 1740
Asp Gly Thr Gly Ala Gly Thr Gly Asp Val Gln Lys Pro Thr Pro Asp
1745 1750 1755 1760
Ala Val Ala Lys Thr Gly Ala Asp Val Phe Gly Leu Leu Thr Ala Val
1765 1770 1775
Ala Ala Leu Leu Ala Ala Gly Gly Val Thr Leu Ser Leu Arg Arg Arg
1780 1785 1790
Ala Asn Arg
1795
<210> 5
<211> 1795
<212> PRT
<213> Bifidobacterium bifidum
<400> 5
Met Thr Thr Ile Phe Arg Arg Ala Thr Ala Lys Thr Leu Met Arg Lys
1 5 10 15
Leu Ser Gly Leu Leu Val Ala Ile Ala Met Leu Ala Val Leu Pro Ala
20 25 30
Gly Thr Ile Ser Ala Asn Ala Ala Asp Glu Pro Pro Gln Glu Tyr Leu
35 40 45
Gln Leu Thr Leu Thr Arg Thr Asp Ser Asn Gly Thr Pro Ala Glu Val
50 55 60
Gly Asp Lys Leu Thr Tyr Ser Leu Gly Tyr Lys Asn Val Ser Asp Thr
65 70 75 80
Gly Phe Ile Val His Pro Thr Ala Ser Asn Leu Asn Asn Val Ala Thr
85 90 95
Pro Gln Ser Ala Ser Asn Pro Asn Pro Met Cys Arg Trp Gly Asn Leu
100 105 110
Ala Ala Gly Ala Ser Ala Ala Cys Thr Trp Ser Ala Ser Lys Glu Phe
115 120 125
Ala Tyr His Val Val Thr Glu Asp Asp Val Ala Asn Gly Phe Thr Pro
130 135 140
Thr Ala Thr Val Ser Ala Thr Thr Gln Asp Gly Thr Asn Gly Val Leu
145 150 155 160
Gln Ser Val Asp Ile Thr Gly Glu Thr Val Pro Ala Val Pro Ala Thr
165 170 175
Ser Thr Leu Arg Val Ala Met Gln Arg Thr Asp Thr Leu Gly Asp Asn
180 185 190
Val Lys Ile Gly Asp Arg Leu Thr Phe Asn Phe Thr Tyr Thr Asn Lys
195 200 205
Thr Ala Gln Lys Ile Tyr Ala Tyr Pro Ser Glu Ser Asn Ile Glu Arg
210 215 220
Val Asp Val Val Ser Phe Pro Arg Asn Ser Cys Arg Ser Gly Val Glu
225 230 235 240
Ala Asn Gln Thr Ala Ser Cys Gly Phe Ala Tyr His Val Ile Thr Ala
245 250 255
Glu Asp Val Val Ala Arg Arg Tyr Thr Pro Thr Ala Thr Phe Arg Ala
260 265 270
Thr Ser Asp Arg Asp Gly Thr Gln Val Leu Gln Asp Asp Met Thr Phe
275 280 285
Thr Thr Gly Thr Val Thr Val Ala Gly Pro Ala Asp Asp Ala Ala Ser
290 295 300
Thr Pro Thr Glu Arg Lys Asp Gly Glu Pro Leu Leu Leu Ala Thr Asn
305 310 315 320
Lys Gln Ile Gly Asn Thr Asp Tyr Tyr Arg Ile Pro Ala Ile Ala Gln
325 330 335
Ala Pro Asn Gly Trp Ile Leu Ala Ala Trp Asp Leu Arg Pro Lys Leu
340 345 350
Ala Ala Asp Ala Pro Asn Pro Asn Ser Ile Val Gln Arg Ile Ser Lys
355 360 365
Asp Gly Gly Lys Ser Trp Glu Thr Leu Ala Tyr Val Ala Gln Gly Arg
370 375 380
Ser Ala Thr Asn Lys Tyr Gly Tyr Ser Asp Pro Ser Tyr Val Val Asp
385 390 395 400
Glu Glu Ala Gly Lys Ile Phe Leu Phe Cys Val Lys Ser Tyr Asp Gln
405 410 415
Gly Tyr Phe Gly Ser Val Leu Gly Val Glu Asp Ala Arg Asn Val Leu
420 425 430
Gln Ala Val Val Met Glu Ser Asp Asp Asn Gly Ala Thr Trp Ser Glu
435 440 445
Pro Arg Asn Ile Thr Lys Asp Ile Thr Lys Gly His Glu Asp Glu Trp
450 455 460
Lys Ser Arg Phe Ala Ser Ser Gly His Gly Ile Gln Leu Lys Tyr Gly
465 470 475 480
Gln Tyr Lys Gly Arg Leu Ile Gln Gln Tyr Ala Val Arg Thr Thr Ser
485 490 495
Asn Thr Asn Ile Ala Val Ser Val Tyr Ser Asp Asp His Gly Lys Thr
500 505 510
Trp Lys Ala Gly Asn Pro Val Thr Glu Ala Asn Met Asp Glu Asn Lys
515 520 525
Val Val Glu Leu Ser Asp Gly Arg Val Met Leu Asn Ser Arg Pro Gly
530 535 540
Ala Ala Gly Tyr Arg Arg Val Ala Ile Ser Glu Asp Gly Gly Val Asn
545 550 555 560
Tyr Gly Pro Ile Lys Ser Glu Thr Gln Leu Pro Asp Pro Asn Asn Asn
565 570 575
Ala Gln Ile Thr Arg Ala Phe Pro Asn Ala Pro Glu Gly Ser Ala Lys
580 585 590
Ala Lys Val Leu Leu Tyr Ser Ala Pro Arg Ala Ser Asn Glu Gly Arg
595 600 605
Ala Asn Gly Val Val Arg Val Ser Phe Asp Asp Gly Thr Thr Trp Ser
610 615 620
Ala Gly Lys Leu Phe Lys Glu Gly Ser Met Ala Tyr Ser Val Ile Thr
625 630 635 640
Ala Leu Asn Asp Ala Ala Gly Gly Gly Tyr Gly Leu Leu Tyr Glu Gly
645 650 655
Glu Ser Ile Thr Tyr Thr Arg Val Ser Met Glu Trp Leu Gly Tyr Leu
660 665 670
Thr Ala Thr Ala Ser Gly Thr Ala Thr Val Lys Glu Gly Glu Gly Thr
675 680 685
Leu Thr Ala Pro Val Thr Val Thr Asn Asp Gly Leu Thr Asp Tyr Thr
690 695 700
Asn Val Thr Val Thr Pro Thr Gly Leu Pro Ser Gly Trp Ser Ala Glu
705 710 715 720
Ala Val Asn Val Gly Asn Leu Ala Ala Gly Gln Ser Ala Thr Val Asn
725 730 735
Val Pro Val Thr Val Pro Ala Ala Ala Val Ser Gly Thr Val Ala Lys
740 745 750
Ala Thr Met Lys Ile Thr Gly Lys Tyr Ala Gln Ser Glu Asp Thr Leu
755 760 765
His Ser Phe Ala Glu Gly Glu Leu Ala Val Thr Val Thr Glu Pro Asp
770 775 780
Pro Ala Ala Lys Arg Leu Lys Leu Thr Ile Glu Arg Thr Asp Asp Asn
785 790 795 800
Gly Ala Pro Val Lys Val Gly Asp Thr Leu Thr Tyr Arg Ile Thr Tyr
805 810 815
Glu Asn Val Gly Thr Gln Ser Phe Ala Val Tyr Pro Arg Lys Ser Asn
820 825 830
Leu Asp Gly Val Thr Thr Pro Gln Ser Ala Ser Asn Pro Ala Pro Val
835 840 845
Cys Arg Trp Ser Arg Leu Asp Pro Gly Thr Thr Gly Ala Cys Val Ser
850 855 860
Gly Asn Gly Lys Arg Leu Ala Tyr His Thr Val Thr Glu Ala Asp Ala
865 870 875 880
Thr Ala Gly Ser Phe Thr Pro Ser Ala Thr Ile Asp Ala Thr Ala Asp
885 890 895
Thr Ser Gly Glu Thr Val Leu Glu Ser Val Ser Ile Thr Gly Asp Pro
900 905 910
Val Thr Val Ser Gln Pro Val Glu Leu Pro Ala Asp Ile Ala Ala Trp
915 920 925
Lys Thr Arg Asn Glu Ala Leu Asp Asp Trp Gln Thr Leu Ser Glu Lys
930 935 940
Leu Ala Lys Thr Asp Arg Ile Asn Trp Leu Phe Thr Gly Asp Ser Ile
945 950 955 960
Thr His Gly Val Gln Leu Thr Arg Gly Tyr Arg Thr Tyr Ser Glu Leu
965 970 975
Phe Ala Asn His Leu Asp Thr Ala Ser Val Arg Gly Val Ser Arg Ala
980 985 990
Asn Asp Val Val Met Asn Thr Gly Ile Ser Ser Ala Asp Ala Ser Trp
995 1000 1005
Pro Leu Lys Asp Gly Ala Phe Glu Lys Trp Val Ser Asp Lys His Pro
1010 1015 1020
Asp Val Val Phe Leu Thr Phe Gly Met Asn Asp Gly Arg Thr Gly Gln
1025 1030 1035 1040
Ala Phe Thr Val Asp Gln Tyr Thr Ala Asn Leu Ser Thr Leu Ile Asp
1045 1050 1055
Lys Ile Arg Asp Leu Gly Ala Ile Pro Val Leu Gln Thr Gln Asn Tyr
1060 1065 1070
Thr Thr Asn Thr Thr Phe Asn Ala Asn Leu Asp Thr Tyr Phe Asp Ala
1075 1080 1085
Glu Arg Arg Leu Ala Leu Asp Lys Asn Val Leu Leu Val Asp Phe Asn
1090 1095 1100
Lys Gln Trp Leu Glu Leu Gly Gly Gly Asn Arg Glu Ser Gly Thr Tyr
1105 1110 1115 1120
Met Gly Ala Gly Asn Asp Ile His Pro Gly Glu Asn Gly His Ile Glu
1125 1130 1135
Trp Ala Lys Phe Thr Leu Gly Ala Leu Asn Met Ile Ala Asn Asp Asp
1140 1145 1150
Pro Leu Ala Arg Trp Ser Ser Ser Asp Thr Thr Leu Asp Lys Pro Thr
1155 1160 1165
Val Thr Val Asp Ala Asp Gly Asn Gly Leu Lys Gly Ser Asp Gly Leu
1170 1175 1180
Glu Pro Ala Pro Ala Ala Ala Lys Ser Val Gly Lys Phe Leu Ser Gly
1185 1190 1195 1200
Ala Gln Tyr Val Asp Leu Gly Gly Asp Val Val Ser Ala Val Ala Gly
1205 1210 1215
Lys Arg Glu Ser Asn Val Thr Ile Arg Phe Arg Ala Ser Ala Thr Gly
1220 1225 1230
Gln Pro Gln Thr Leu Phe Ser Leu Gly Asp Ser Asp Ser Ala Thr Arg
1235 1240 1245
Ala Thr Val Arg Leu Ser Ala Thr Gly Leu Val Gln Phe Leu Asn Ser
1250 1255 1260
Gly Asn Thr Gly Asp Phe Tyr Thr Val Gly Thr Asn Asp Leu Ala Asp
1265 1270 1275 1280
Gly Ala Trp His Thr Val Ser Val Asn Phe Val Ala Asn Gly Phe Thr
1285 1290 1295
Ile Tyr Val Asp Gly Ala Ala Met Arg Ala Ile Ser Gly Gly Ala Gly
1300 1305 1310
Thr Gln Leu Asn Val Pro Gly Ala Ile Thr Val Asn Thr Ala Thr Ala
1315 1320 1325
Gly Ala Ile Arg Gly Ala Asp Ser Ala Gly Gly Ala Gln Gln Leu Thr
1330 1335 1340
Gly Ile Val Asp Tyr Val Ala Ala Trp Ser Arg Thr Leu Thr Asp Ala
1345 1350 1355 1360
Glu Ala Lys Arg Ile Ser Ala Glu Thr Ser Ala Val Ala Val Thr Lys
1365 1370 1375
Val Asp Ala Ala Val Asn Ala Leu Gln Pro Ile Ile Ser Asp Thr Gly
1380 1385 1390
Ala Arg Lys Asn Ile Val Phe Val Gly Gly Glu Thr Ile Glu Gly Gly
1395 1400 1405
Tyr Thr Asp His Leu Ile Ala Lys Asn Ile Val Gln Leu Leu Asp Glu
1410 1415 1420
Arg Val Arg Trp Glu Tyr Val Thr Gly Leu Ser Ala Thr Asp Arg Glu
1425 1430 1435 1440
Leu Gln Arg Ala Lys Phe Phe Val Ala Ala Gly Gln Gly Gly Leu Thr
1445 1450 1455
Ala Lys Gln Met Asp Glu Asp Tyr Ala Ala Met Val Gly Glu Tyr Ser
1460 1465 1470
Pro Asp Ile Leu Phe Leu Ala Pro Asp Leu Tyr Asp Ala Asp Gly Ile
1475 1480 1485
Leu Ala Glu Ser Asp Ala Ala Ala Phe Ala Gly His Ile Arg Ser Val
1490 1495 1500
Ala Ala Lys Ala Lys Glu Ala Gly Ala Lys Val Val Leu Val Thr Pro
1505 1510 1515 1520
Val Thr Val Arg Gly Gly Glu Asp Glu Tyr Ala Gly Ala Met Arg Thr
1525 1530 1535
Val Ala Lys Glu Asp Asp Leu Pro Leu Ile Asp Ala Gln Ala Trp Ile
1540 1545 1550
Gly Lys Val Val Ala Ala Asp Ala Ser Val Lys Thr Ala Trp Phe Asn
1555 1560 1565
Lys Ala Gly Gln Leu Asn Tyr Ala Gly His Leu Gly Tyr Ala Arg Phe
1570 1575 1580
Met Met Arg Ser Leu Asp Leu Tyr Pro Ser Asn Val Ser Gly Ser Arg
1585 1590 1595 1600
Ile Ala Ser Leu Pro Tyr Asp Thr Ala Asn Val Thr Leu Val Gly Ala
1605 1610 1615
Ser Glu Asn Gly Gly Glu Leu Pro Val Gly Arg Val Glu Gly Thr Asp
1620 1625 1630
Arg Ala His Ile Asp Thr Met Gln Ile Gly Ala Ala Ala Ser Leu Val
1635 1640 1645
Val Thr Asp Ser Tyr Ala Val Tyr Glu Ile Gly Glu Asp Gly Gly Arg
1650 1655 1660
Thr Leu Val Ala Asp Gly Leu Lys Pro Ala Asp Val Leu Ala Asp Gly
1665 1670 1675 1680
Ile Asp Val Thr Val Asn Asp Thr Ala Ala His Arg Tyr Glu Val Val
1685 1690 1695
Gly Ser Ala Asn Val Pro Glu Gly Ala Asp Ala Val Thr Val Thr Tyr
1700 1705 1710
Thr Ala Thr Leu Ala Ala Val Glu Glu Pro Glu Pro Gly Pro Asp Pro
1715 1720 1725
Asp Pro Thr Pro Asp Pro Ser Glu Lys Pro Asp Gly Asp Gly Thr Gly
1730 1735 1740
Asp Gly Thr Gly Ala Gly Ala Gly Asp Val Gln Lys Pro Thr Pro Asp
1745 1750 1755 1760
Ala Val Ala Lys Thr Gly Ala Asp Val Phe Gly Leu Leu Ala Ala Val
1765 1770 1775
Ala Val Leu Leu Ala Ala Gly Gly Val Thr Leu Ser Leu Arg Arg Arg
1780 1785 1790
Ala Asn Arg
1795
<210> 6
<211> 770
<212> PRT
<213> Bifidobacterium bifidum
<400> 6
Met Val Arg Ser Thr Lys Pro Ser Leu Leu Arg Arg Phe Gly Ala Leu
1 5 10 15
Val Ala Ala Ala Ala Met Leu Val Val Leu Pro Ala Gly Val Ser Thr
20 25 30
Ala Ser Ala Ala Ser Asp Asp Ala Asp Met Leu Thr Val Thr Met Thr
35 40 45
Arg Thr Asp Ala Leu Gly Asp Glu Val Tyr Val Gly Asp Thr Leu Thr
50 55 60
Tyr Ser Phe Thr Asn Thr Asn Asn Thr Ser Ser Ala Phe Thr Ala Phe
65 70 75 80
Pro Ala Glu Ser Asn Leu Ser Gly Val Leu Thr Thr Gly Thr Pro Asn
85 90 95
Cys Arg Tyr Glu Asn Leu Ala Gly Gly Ala Ser Tyr Pro Cys Ser Thr
100 105 110
Ala Ser His Thr Ile Thr Ala Asp Asp Leu Thr Ala Gly Ser Phe Thr
115 120 125
Pro Arg Thr Val Trp Lys Ala Thr Ser Asp Arg Gly Gly Thr Gln Val
130 135 140
Leu Gln Asp Asn Ile Val Ser Thr Gly Asp Thr Val Thr Val Lys Glu
145 150 155 160
Gly Lys Arg Pro Asp Pro Ala Thr Ile Pro Thr Asp Arg Ala Asp Gly
165 170 175
Glu Ala Val Arg Leu Ala Thr Ala Arg Gln Asn Leu Gly Thr Glu Cys
180 185 190
Tyr Arg Ile Pro Ala Leu Ala Glu Ala Pro Asn Gly Trp Ile Leu Ala
195 200 205
Ala Phe Asp Gln Arg Pro Asn Thr Ala Met Ala Asn Gly Ser Gly Val
210 215 220
Lys Cys Trp Asp Ala Pro Gln Pro Asn Ser Ile Val Gln Arg Ile Ser
225 230 235 240
Lys Asp Gly Gly Lys Ser Trp Thr Pro Ile Gln Tyr Val Ala Gln Gly
245 250 255
Lys Asn Ala Pro Glu Arg Tyr Gly Tyr Ser Asp Pro Ser Tyr Val Val
260 265 270
Asp Lys Glu Thr Gly Glu Ile Phe Leu Phe Phe Val His Ser Tyr Asn
275 280 285
Lys Gly Phe Ala Asp Ser Gln Leu Gly Val Asp Glu Ser Asn Arg Asn
290 295 300
Val Leu His Ala Val Val Val Ser Ser Lys Asp Asn Gly Glu Thr Trp
305 310 315 320
Ser Lys Pro Arg Asp Ile Thr Ala Asp Ile Thr Lys Gly Tyr Glu Asn
325 330 335
Glu Trp Lys Ser Arg Phe Ala Thr Ser Gly Ala Gly Ile Gln Leu Lys
340 345 350
Tyr Gly Lys Tyr Lys Gly Arg Leu Ile Gln Gln Tyr Ala Val Gly Arg
355 360 365
Thr Thr Gly Ser Asn Ala Ala Val Ser Val Tyr Ser Asp Asp His Gly
370 375 380
Lys Thr Trp Gln Ala Gly Asn Pro Val Thr Gly Met Leu Met Asp Glu
385 390 395 400
Asn Lys Val Val Glu Leu Ser Asp Gly Arg Val Met Leu Asn Ser Arg
405 410 415
Pro Gly Asn Gly Ser Gly Tyr Arg Arg Val Ala Ile Ser Glu Asp Gly
420 425 430
Gly Val Asn Tyr Gly Thr Val Lys Asn Glu Thr Gln Leu Pro Asp Pro
435 440 445
Asn Asn Asn Ala His Ile Thr Arg Ala Phe Pro Asn Ala Pro Glu Gly
450 455 460
Ser Ala Lys Ala Lys Val Leu Leu Tyr Ser Ser Pro Arg Ala Asn Asn
465 470 475 480
Glu Gly Arg Ala Asn Gly Val Val Arg Ile Ser Leu Asp Asp Gly Thr
485 490 495
Thr Trp Ser Ser Gly Lys Leu Tyr Lys Glu Gly Ser Met Ala Tyr Ser
500 505 510
Val Ile Thr Ala Leu Ser Gly Ala Ala Gly Gly Gly Tyr Gly Leu Leu
515 520 525
Tyr Glu Gly Ala Trp Val Thr Gly Gly Gly Ile Asp Ser His Asp Ile
530 535 540
Met Tyr Thr His Ile Ser Met Asp Trp Leu Gly Tyr Leu Ser Ala Thr
545 550 555 560
Ala Asp Asp Val Thr Ala Ser Val Glu Glu Gly Ala Ser Thr Val Asp
565 570 575
Val Thr Val Pro Val Ser Asn Val Gly Ser Val Asp Tyr Thr Gly Val
580 585 590
Thr Val Thr Pro Ala Asp Leu Pro Thr Gly Trp Ser Ala Ser Pro Val
595 600 605
Asn Val Gly Ala Leu Ala Ser Gly Ala Ser Lys Asp Val Thr Val Thr
610 615 620
Val Asn Val Pro Ala Thr Ala Lys Lys Asp Asp Val Ala Lys Ile Val
625 630 635 640
Leu Arg Val Thr Gly Thr Ser Ala Ala Asn Ala Asn Ala Thr Thr Gly
645 650 655
Phe Asp Gly Ser Ile Thr Val Asn Val Thr Glu Lys Ser Glu Pro Asp
660 665 670
Pro Glu Pro Glu Pro Thr Ile Thr Gly Val Ser Ala Val Thr Ser Gln
675 680 685
Ala Gly Val Lys Val Gly Asp Val Phe Asp Ala Ser Lys Val Ser Val
690 695 700
Thr Ala Ala Met Ser Asp Gly Ser Ser Lys Ala Leu Ala Ala Gly Glu
705 710 715 720
Tyr Ser Leu Ser Ala Val Asp Ala Asp Gly Lys Ala Val Asp Leu Ala
725 730 735
Glu Pro Phe Ala Ala Ala Gly Val Val Thr Val Thr Val Ser Val Pro
740 745 750
Val Glu Gly Ala Asp Pro Leu Thr Ala Ser Phe Thr Ile Asp Val Ala
755 760 765
Glu Lys
770
<210> 7
<211> 834
<212> PRT
<213> Bifidobacterium bifidum
<400> 7
Met Val Arg Ser Thr Lys Pro Ser Leu Leu Arg Arg Leu Gly Ala Leu
1 5 10 15
Val Ala Ala Ala Ala Met Leu Val Val Leu Pro Ala Gly Val Ser Thr
20 25 30
Ala Ser Ala Ala Ser Asp Asp Ala Asp Met Leu Thr Val Thr Met Thr
35 40 45
Arg Thr Asp Ala Leu Gly Asp Glu Val Tyr Val Gly Asp Thr Leu Thr
50 55 60
Tyr Ser Phe Thr Asn Thr Asn Asn Thr Ser Ser Ala Phe Thr Ala Phe
65 70 75 80
Pro Ala Glu Ser Asn Leu Ser Gly Val Leu Thr Thr Gly Thr Pro Asn
85 90 95
Cys Arg Tyr Glu Asn Leu Ala Gly Gly Ala Ser Tyr Pro Cys Ser Thr
100 105 110
Ala Ser His Thr Ile Thr Ala Asp Asp Leu Thr Ala Gly Ser Phe Thr
115 120 125
Pro Arg Thr Val Trp Lys Ala Thr Ser Asp Arg Gly Gly Thr Gln Val
130 135 140
Leu Gln Asp Asn Ile Val Ser Thr Gly Asp Thr Val Thr Val Lys Glu
145 150 155 160
Gly Lys Arg Pro Asp Pro Ala Thr Ile Pro Thr Asp Arg Ala Asp Gly
165 170 175
Glu Ala Val Arg Leu Ala Thr Ala Arg Gln Asn Leu Gly Thr Glu Cys
180 185 190
Tyr Arg Ile Pro Ala Leu Ala Glu Ala Pro Asn Gly Trp Ile Leu Ala
195 200 205
Ala Phe Asp Gln Arg Pro Asn Thr Ala Met Ala Asn Gly Ser Gly Val
210 215 220
Lys Cys Trp Asp Ala Pro Gln Pro Asn Ser Ile Val Gln Arg Ile Ser
225 230 235 240
Lys Asp Gly Gly Lys Ser Trp Thr Pro Ile Gln Tyr Val Ala Gln Gly
245 250 255
Lys Asn Ala Pro Glu Arg Tyr Gly Tyr Ser Asp Pro Ser Tyr Val Val
260 265 270
Asp Glu Glu Thr Gly Glu Ile Phe Leu Phe Phe Val His Ser Tyr Asn
275 280 285
Lys Gly Phe Ala Asp Ser Gln Leu Gly Val Asp Glu Ser Asn Arg Asn
290 295 300
Val Leu His Ala Val Val Val Ser Ser Lys Asp Asn Gly Glu Thr Trp
305 310 315 320
Ser Lys Pro Arg Asp Ile Thr Ala Asp Ile Thr Lys Gly Tyr Glu Asn
325 330 335
Glu Trp Lys Ser Arg Phe Ala Thr Ser Gly Ala Gly Ile Gln Leu Lys
340 345 350
Tyr Gly Lys Tyr Lys Gly Arg Leu Ile Gln Gln Tyr Ala Val Gly Arg
355 360 365
Thr Thr Gly Ser Asn Ala Ala Val Ser Val Tyr Ser Asp Asp His Gly
370 375 380
Lys Thr Trp Gln Ala Gly Asn Pro Val Thr Gly Met Leu Met Asp Glu
385 390 395 400
Asn Lys Val Val Glu Leu Ser Asp Gly Arg Val Met Leu Asn Ser Arg
405 410 415
Pro Gly Asn Gly Ser Gly Tyr Arg Arg Val Ala Ile Ser Lys Asp Gly
420 425 430
Gly Val Asn Tyr Gly Thr Val Lys Asn Glu Thr Gln Leu Pro Asp Pro
435 440 445
Asn Asn Asn Ala His Ile Thr Arg Ala Phe Pro Asn Ala Pro Glu Gly
450 455 460
Ser Ala Lys Ala Lys Val Leu Leu Tyr Ser Ser Pro Arg Ala Asn Asn
465 470 475 480
Glu Gly Arg Ala Asn Gly Val Val Arg Ile Ser Leu Asp Asp Gly Thr
485 490 495
Thr Trp Ser Ser Gly Lys Leu Tyr Lys Ala Gly Ser Met Ala Tyr Ser
500 505 510
Val Ile Thr Ala Leu Ser Gly Ala Ala Gly Gly Gly Tyr Gly Leu Leu
515 520 525
Tyr Glu Gly Ala Trp Val Thr Gly Gly Gly Ile Asp Ser His Asp Ile
530 535 540
Met Tyr Thr His Ile Ser Met Asp Trp Leu Gly Tyr Leu Ser Ala Thr
545 550 555 560
Ala Asp Asp Val Thr Ala Ser Val Glu Glu Gly Ala Ser Thr Val Asp
565 570 575
Val Thr Val Pro Val Ser Asn Ile Gly Ser Val Asp Tyr Thr Gly Val
580 585 590
Thr Val Thr Pro Ala Asp Leu Pro Thr Gly Trp Ser Ala Ser Pro Val
595 600 605
Asn Val Gly Ala Leu Ala Ser Gly Ala Ser Lys Asp Val Thr Val Thr
610 615 620
Val Asn Val Pro Ala Thr Ala Lys Lys Asp Asp Val Ala Lys Ile Val
625 630 635 640
Leu Arg Val Thr Gly Thr Ser Ala Ala Asn Ala Asp Ala Thr Thr Gly
645 650 655
Phe Asp Gly Ser Ile Thr Val Asn Val Thr Glu Lys Ser Glu Pro Asp
660 665 670
Pro Glu Pro Glu Pro Thr Ile Thr Gly Val Ser Ala Val Thr Ser Gln
675 680 685
Ala Gly Val Lys Val Gly Asp Val Phe Asp Ala Ser Lys Val Ser Val
690 695 700
Thr Ala Ala Met Ser Asp Gly Ser Ser Lys Ala Leu Ala Ala Gly Glu
705 710 715 720
Tyr Ser Leu Ser Ala Val Asp Ala Asp Gly Lys Ala Val Asp Leu Ala
725 730 735
Glu Pro Phe Ala Ala Ala Gly Val Val Thr Val Thr Val Ser Val Pro
740 745 750
Val Glu Gly Ala Asn Pro Leu Thr Ala Ser Phe Thr Ile Asp Val Ala
755 760 765
Glu Lys Ser Val Asp Pro Glu Pro Lys Pro Glu Pro Lys Pro Glu Pro
770 775 780
Glu Lys Pro Ala Gly Pro Lys Val Asp Val Pro Thr Glu Gln Pro Gly
785 790 795 800
Leu Ser Lys Thr Gly Ala Ser Thr Ala Gly Met Ser Ile Val Phe Val
805 810 815
Leu Leu Ala Leu Ser Gly Val Ala Ala Leu Ser Leu Arg Arg Arg Ser
820 825 830
Ala His
<210> 8
<211> 1782
<212> PRT
<213> Bifidobacterium bifidum
<400> 8
Met Arg Lys Leu Ser Gly Leu Leu Val Ala Ile Ala Met Leu Ala Val
1 5 10 15
Leu Pro Ala Gly Thr Ile Ser Ala Asn Ala Ala Asp Glu Pro Pro Gln
20 25 30
Glu Tyr Leu Gln Leu Thr Leu Thr Arg Thr Asp Ser Asn Gly Thr Pro
35 40 45
Ala Glu Val Gly Asp Lys Leu Thr Tyr Ser Leu Gly Tyr Lys Asn Val
50 55 60
Ser Asp Thr Gly Phe Ile Val His Pro Thr Ala Ser Asn Leu Asn Asn
65 70 75 80
Val Ala Thr Pro Gln Ser Ala Ser Asn Pro Asn Pro Met Cys Arg Trp
85 90 95
Gly Asn Leu Ala Ala Gly Ala Ser Ala Ala Cys Thr Trp Ser Ala Ser
100 105 110
Lys Glu Phe Ala Tyr His Val Val Thr Glu Asp Asp Val Ala Asn Gly
115 120 125
Phe Thr Pro Thr Ala Thr Val Ser Ala Thr Thr Gln Asp Gly Thr Asn
130 135 140
Gly Val Leu Gln Ser Val Asp Ile Thr Gly Glu Thr Val Pro Ala Val
145 150 155 160
Pro Ala Thr Ser Thr Leu Arg Val Ala Met Gln Arg Thr Asp Thr Leu
165 170 175
Gly Asp Asn Val Lys Ile Gly Asp Arg Leu Thr Phe Asn Phe Thr Tyr
180 185 190
Thr Asn Lys Thr Ala Gln Lys Ile Tyr Ala Tyr Pro Ser Glu Ser Asn
195 200 205
Ile Glu Arg Val Asp Val Val Ser Tyr Pro Arg Asn Ser Cys Arg Ser
210 215 220
Gly Val Glu Ala Asn Gln Thr Ala Ser Cys Gly Phe Ala Tyr His Val
225 230 235 240
Ile Thr Ala Glu Asp Val Val Ala Arg Arg Tyr Thr Pro Thr Ala Thr
245 250 255
Phe Arg Ala Thr Ser Asp Arg Asp Gly Thr Gln Val Leu Gln Asp Asp
260 265 270
Met Thr Phe Thr Thr Gly Thr Val Thr Val Ala Gly Pro Ala Asp Asp
275 280 285
Ala Ala Ser Thr Pro Thr Glu Arg Lys Asp Gly Glu Pro Leu Leu Leu
290 295 300
Ala Thr Asn Lys Gln Ile Gly Asn Thr Asp Tyr Tyr Arg Ile Pro Ala
305 310 315 320
Ile Ala Gln Ala Pro Asn Gly Trp Ile Leu Ala Ala Trp Asp Leu Arg
325 330 335
Pro Ser Ser Ala Ala Asp Ala Pro Asn Pro Asn Ser Ile Val Gln Arg
340 345 350
Ile Ser Lys Asp Gly Gly Lys Ser Trp Glu Thr Leu Ala Tyr Val Ala
355 360 365
Gln Gly Arg Ser Ala Thr Asn Lys Tyr Gly Tyr Ser Asp Pro Ser Tyr
370 375 380
Val Val Asp Glu Glu Ala Gly Lys Ile Phe Leu Phe Cys Val Lys Ser
385 390 395 400
Tyr Asp Gln Gly Tyr Phe Gly Ser Val Leu Gly Val Glu Asp Ala Arg
405 410 415
Asn Val Leu Gln Ala Val Val Met Glu Ser Asp Asp Asn Gly Ala Thr
420 425 430
Trp Ser Glu Pro Arg Asn Ile Thr Lys Asp Ile Thr Lys Gly His Glu
435 440 445
Asp Glu Trp Lys Ser Arg Phe Ala Ser Ser Gly His Gly Ile Gln Leu
450 455 460
Lys Tyr Gly Gln Tyr Lys Gly Arg Leu Ile Gln Gln Tyr Ala Val Arg
465 470 475 480
Thr Thr Ser Asn Thr Asn Ile Ala Val Ser Val Tyr Ser Asp Asp His
485 490 495
Gly Lys Thr Trp Lys Ala Gly Asn Pro Val Thr Glu Val Asn Met Asp
500 505 510
Glu Asn Lys Val Val Glu Leu Ser Asp Gly Arg Val Met Leu Asn Ser
515 520 525
Arg Pro Gly Ala Ala Gly Tyr Arg Arg Val Ala Ile Ser Glu Asp Gly
530 535 540
Gly Val Asn Tyr Gly Pro Ile Lys Ser Glu Thr Gln Leu Pro Asp Pro
545 550 555 560
Asn Asn Asn Ala Gln Ile Thr Arg Ala Phe Pro Asn Ala Pro Glu Gly
565 570 575
Ser Ala Lys Ala Lys Val Leu Leu Tyr Ser Ala Pro Arg Ala Ser Asn
580 585 590
Glu Gly Arg Ala Asn Gly Val Val Arg Val Ser Phe Asp Asp Gly Thr
595 600 605
Thr Trp Ser Ala Gly Lys Leu Phe Lys Glu Gly Ser Met Ala Tyr Ser
610 615 620
Val Ile Thr Ala Leu Asn Asp Ala Ala Gly Gly Gly Tyr Gly Leu Leu
625 630 635 640
Tyr Glu Gly Glu Ser Ile Thr Tyr Thr Arg Ala Ser Met Glu Trp Leu
645 650 655
Gly Tyr Leu Thr Ala Thr Ala Ser Gly Thr Ala Thr Val Lys Glu Gly
660 665 670
Glu Gly Thr Leu Thr Ala Pro Val Thr Val Thr Asn Asp Gly Leu Thr
675 680 685
Asp Tyr Thr Asn Val Asn Val Thr Pro Thr Gly Leu Pro Ser Gly Trp
690 695 700
Ser Ala Glu Ala Val Asn Val Gly Asn Leu Ala Ala Gly Gln Ser Ala
705 710 715 720
Thr Val Asn Val Pro Val Thr Val Pro Ala Ala Ala Val Ser Gly Thr
725 730 735
Val Ala Lys Ala Thr Met Lys Ile Thr Gly Lys Tyr Ala Gln Ser Glu
740 745 750
Asp Thr Leu His Ser Phe Ala Glu Gly Glu Leu Ala Val Thr Val Thr
755 760 765
Asp Pro Asp Pro Ala Ala Lys Arg Leu Lys Leu Thr Ile Glu Arg Thr
770 775 780
Asp Asp Asn Gly Asp Pro Val Lys Val Gly Asp Thr Leu Thr Tyr Arg
785 790 795 800
Ile Thr Tyr Glu Asn Val Gly Thr Gln Ser Phe Ala Val Tyr Pro Arg
805 810 815
Glu Ser Asn Leu Asp Gly Val Thr Thr Pro Gln Ser Ala Ser Asn Pro
820 825 830
Ala Pro Val Cys Arg Trp Ser Arg Leu Ala Pro Gly Thr Thr Gly Ala
835 840 845
Cys Val Ser Gly Asn Gly Lys Gln Leu Ala Tyr His Thr Val Thr Glu
850 855 860
Ala Asp Ala Thr Ala Gly Ser Phe Thr Pro Ser Ala Thr Ile Asp Ala
865 870 875 880
Thr Ala Asp Ala Ser Gly Glu Met Val Leu Glu Ser Val Ser Ile Thr
885 890 895
Gly Asp Pro Val Thr Val Ser Gln Pro Val Glu Leu Pro Ala Asp Ile
900 905 910
Ala Ala Trp Lys Thr Arg Asn Glu Ala Leu Asp Asp Trp Gln Ala Leu
915 920 925
Ser Glu Lys Leu Ala Lys Thr Asp Arg Ile Asn Trp Leu Phe Thr Gly
930 935 940
Asp Ser Ile Thr His Gly Val Gln Phe Thr Arg Gly Tyr Arg Thr Tyr
945 950 955 960
Ser Glu Leu Phe Ala Asn His Leu Asp Thr Ala Ser Val Arg Gly Val
965 970 975
Ser Arg Ala Asn Asp Val Val Met Asn Thr Gly Ile Ser Ser Ala Asp
980 985 990
Ala Ser Trp Pro Leu Lys Asp Gly Ala Phe Glu Lys Trp Val Ser Asp
995 1000 1005
Lys His Pro Asp Val Val Phe Leu Thr Phe Gly Met Asn Asp Gly Arg
1010 1015 1020
Thr Gly Gln Ala Phe Thr Val Asp Gln Tyr Thr Ala Asn Leu Ser Thr
1025 1030 1035 1040
Leu Ile Asp Lys Ile Arg Asp Ile Gly Ala Ile Pro Val Leu Gln Thr
1045 1050 1055
Gln Asn Tyr Thr Thr Asn Thr Thr Phe Asn Ala Asn Leu Asp Thr Tyr
1060 1065 1070
Phe Asp Ala Glu Arg Arg Leu Ala Leu Asp Lys Asn Val Leu Leu Val
1075 1080 1085
Asp Phe Asn Lys Gln Trp Leu Ala Leu Gly Gly Gly Asn Arg Glu Ser
1090 1095 1100
Gly Thr Tyr Met Gly Ala Gly Asn Asp Ile His Pro Gly Glu Asn Gly
1105 1110 1115 1120
His Ile Glu Trp Ala Lys Phe Thr Leu Gly Ala Leu Asn Met Ile Ala
1125 1130 1135
Asn Asp Asp Pro Leu Ala Arg Trp Ser Ser Ser Asp Thr Thr Leu Asp
1140 1145 1150
Lys Pro Thr Val Thr Val Asp Ala Asp Gly Asn Gly Leu Lys Gly Ser
1155 1160 1165
Asp Gly Leu Glu Pro Ala Pro Ala Ala Ala Lys Ser Val Gly Lys Phe
1170 1175 1180
Leu Ser Gly Ala Gln Tyr Val Asp Leu Gly Gly Asp Val Val Ser Ala
1185 1190 1195 1200
Val Ala Gly Lys Arg Glu Ser Asn Val Thr Ile Arg Phe Arg Ala Ser
1205 1210 1215
Ala Thr Gly Gln Pro Gln Thr Leu Phe Ser Leu Gly Asp Ser Asp Ser
1220 1225 1230
Ala Thr Arg Ala Thr Val Arg Leu Ser Ala Thr Gly Leu Val Gln Phe
1235 1240 1245
Leu Asn Ser Gly Asn Thr Gly Asp Phe Tyr Thr Val Gly Thr Asn Asp
1250 1255 1260
Leu Ala Asp Gly Ala Trp His Thr Val Ser Val Asn Phe Val Ala Asn
1265 1270 1275 1280
Gly Phe Thr Ile Tyr Val Asp Gly Ala Ala Met Arg Ala Ile Ser Gly
1285 1290 1295
Gly Thr Gly Thr Gln Leu Asn Val Pro Gly Ala Ile Thr Val Asn Thr
1300 1305 1310
Ala Thr Ala Gly Ala Ile Arg Gly Ala Asp Ser Ala Gly Gly Ala Gln
1315 1320 1325
Gln Leu Thr Gly Ile Val Asp Tyr Val Ala Ala Trp Ser Arg Thr Leu
1330 1335 1340
Thr Gly Ala Glu Ala Lys Arg Ile Ser Ala Glu Thr Ser Ala Val Ala
1345 1350 1355 1360
Val Thr Lys Val Asp Ala Ala Val Asn Ala Leu Gln Pro Ile Ile Ser
1365 1370 1375
Asp Thr Gly Ala Arg Lys Asn Ile Val Phe Val Gly Gly Glu Thr Ile
1380 1385 1390
Glu Gly Gly Tyr Thr Asp His Leu Ile Ala Lys Asn Ile Val Gln Leu
1395 1400 1405
Leu Asp Glu Arg Val Arg Trp Glu Tyr Val Thr Gly Leu Ser Ala Thr
1410 1415 1420
Asp Arg Glu Arg Gln Arg Ala Lys Phe Phe Val Ala Ala Gly Gln Gly
1425 1430 1435 1440
Gly Leu Thr Ala Lys Gln Met Asp Glu Asp Tyr Ala Ala Met Val Gly
1445 1450 1455
Glu Tyr Ser Pro Asp Ile Leu Phe Leu Ala Pro Asp Leu Tyr Asp Ala
1460 1465 1470
Asp Gly Asn Leu Ala Glu Ser Asp Ala Ala Ala Phe Ala Gly His Ile
1475 1480 1485
Arg Ser Val Ala Ala Lys Ala Lys Glu Ala Gly Ala Lys Val Val Leu
1490 1495 1500
Val Thr Pro Val Thr Val Arg Gly Gly Glu Asp Glu Tyr Ala Gly Ala
1505 1510 1515 1520
Met Arg Thr Val Ala Lys Glu Asp Asp Leu Pro Leu Ile Asp Ala Gln
1525 1530 1535
Ala Trp Ile Gly Lys Val Val Ala Ala Asp Ala Ser Val Lys Thr Ala
1540 1545 1550
Trp Phe Asn Lys Ala Gly Gln Leu Asn Tyr Ala Gly His Leu Gly Tyr
1555 1560 1565
Ala Arg Phe Met Met Arg Ser Leu Asp Leu Tyr Pro Ser Asn Val Ser
1570 1575 1580
Gly Ser Arg Ile Ala Ser Leu Pro Tyr Asp Thr Ala Asn Val Thr Leu
1585 1590 1595 1600
Val Gly Ala Ser Glu Asn Gly Gly Glu Leu Pro Val Gly Arg Val Glu
1605 1610 1615
Gly Thr Asp Arg Ala His Ile Asp Thr Met Gln Ile Gly Ala Ala Ala
1620 1625 1630
Ser Leu Val Val Ala Asp Ser Tyr Ala Val Tyr Glu Ile Gly Glu Asp
1635 1640 1645
Gly Gly Arg Thr Leu Val Ala Asp Gly Leu Lys Pro Ala Asp Val Leu
1650 1655 1660
Ala Asp Gly Ile Asp Val Thr Val Asn Asp Thr Ala Ala His Arg Tyr
1665 1670 1675 1680
Glu Val Val Gly Ser Ala Asn Val Pro Glu Gly Ala Asp Ala Val Thr
1685 1690 1695
Val Thr Tyr Thr Ala Thr Leu Ala Ala Val Glu Glu Pro Glu Pro Gly
1700 1705 1710
Pro Asp Pro Asp Pro Thr Pro Asp Pro Ser Glu Lys Pro Asp Gly Asp
1715 1720 1725
Gly Thr Gly Asp Gly Thr Gly Ala Gly Thr Gly Asp Val Gln Lys Pro
1730 1735 1740
Thr Pro Asp Ala Val Ala Lys Thr Gly Ala Asp Val Phe Gly Leu Leu
1745 1750 1755 1760
Ala Ala Val Ala Val Leu Leu Ala Ala Gly Ser Val Thr Leu Ser Leu
1765 1770 1775
Arg Arg Arg Ala Asn Arg
1780
<210> 9
<211> 835
<212> PRT
<213> Bifidobacterium bifidum
<400> 9
Met Val Arg Ser Thr Lys Pro Ser Leu Leu Arg Arg Phe Gly Ala Leu
1 5 10 15
Val Ala Ala Ala Ala Met Leu Val Val Leu Pro Ala Gly Val Ser Thr
20 25 30
Ala Ser Ala Ala Ser Asp Asp Ala Asp Met Leu Thr Val Thr Met Thr
35 40 45
Arg Thr Asp Ala Leu Gly Asp Glu Val Tyr Val Gly Asp Thr Leu Thr
50 55 60
Tyr Ser Phe Thr Asn Thr Asn Asn Thr Ser Ser Ala Phe Thr Ala Phe
65 70 75 80
Pro Ala Glu Ser Asn Leu Ser Gly Val Leu Thr Thr Gly Thr Pro Asn
85 90 95
Cys Arg Tyr Glu Asn Leu Ala Gly Gly Ala Ser Tyr Pro Cys Ser Thr
100 105 110
Ala Ser His Thr Ile Thr Ala Asp Asp Leu Thr Ala Gly Ser Phe Thr
115 120 125
Pro Arg Thr Val Trp Lys Ala Thr Ser Asp Arg Gly Gly Thr Gln Val
130 135 140
Leu Gln Asp Asn Ile Val Ser Thr Gly Asp Thr Val Thr Val Lys Glu
145 150 155 160
Gly Lys Arg Pro Asp Pro Ala Thr Ile Pro Thr Asp Arg Ala Asp Gly
165 170 175
Glu Ala Val Arg Leu Ala Thr Ala Arg Gln Asn Leu Gly Thr Glu Cys
180 185 190
Tyr Arg Ile Pro Ala Leu Ala Glu Ala Pro Asn Gly Trp Ile Leu Ala
195 200 205
Ala Phe Asp Gln Arg Pro Asn Thr Ala Met Ala Asn Gly Ser Gly Val
210 215 220
Lys Cys Trp Asp Ala Pro Gln Pro Asn Ser Ile Val Gln Arg Ile Ser
225 230 235 240
Lys Asp Gly Gly Lys Ser Trp Thr Pro Ile Gln Tyr Val Ala Gln Gly
245 250 255
Lys Asn Ala Pro Glu Arg Tyr Gly Tyr Ser Asp Pro Ser Tyr Val Val
260 265 270
Asp Lys Glu Thr Gly Glu Ile Phe Leu Phe Phe Val His Ser Tyr Asn
275 280 285
Lys Gly Phe Ala Asp Ser Gln Leu Gly Val Asp Glu Ser Asn Arg Asn
290 295 300
Val Leu His Ala Val Val Val Ser Ser Lys Asp Asn Gly Glu Thr Trp
305 310 315 320
Ser Lys Pro Arg Asp Ile Thr Ala Asp Ile Thr Lys Gly Tyr Glu Asn
325 330 335
Glu Trp Lys Ser Arg Phe Ala Thr Ser Gly Ala Gly Ile Gln Leu Lys
340 345 350
Tyr Gly Lys Tyr Lys Gly Arg Leu Ile Gln Gln Tyr Ala Val Gly Arg
355 360 365
Thr Thr Gly Ser Asn Ala Ala Val Ser Val Tyr Ser Asp Asp His Gly
370 375 380
Lys Thr Trp Gln Ala Gly Asn Pro Val Thr Gly Met Leu Met Asp Glu
385 390 395 400
Asn Lys Val Val Glu Leu Ser Asp Gly Arg Val Met Leu Asn Ser Arg
405 410 415
Pro Gly Ala Ala Gly Tyr Arg Arg Val Ala Ile Ser Glu Asp Gly Gly
420 425 430
Val Asn Tyr Gly Thr Val Lys Asn Glu Thr Gln Leu Pro Asp Pro Asn
435 440 445
Asn Asn Ala His Ile Thr Arg Ala Phe Pro Asn Ala Pro Glu Gly Ser
450 455 460
Ala Lys Ala Lys Val Leu Leu Tyr Ser Ser Pro Arg Ala Asn Asn Glu
465 470 475 480
Gly Arg Ala Asn Gly Val Val Arg Ile Ser Leu Asp Asp Gly Thr Thr
485 490 495
Trp Ser Ser Gly Lys Leu Tyr Lys Glu Gly Ser Met Ala Tyr Ser Val
500 505 510
Ile Thr Ala Leu Ser Asp Ala Ala Gly Gly Gly Tyr Gly Leu Leu Tyr
515 520 525
Glu Gly Ala Trp Val Thr Gly Gly Gly Ile Asp Ser His Asp Ile Met
530 535 540
Tyr Thr His Ile Ser Met Asp Trp Leu Gly Tyr Leu Ser Ala Thr Ala
545 550 555 560
Asp Asp Val Thr Ala Ser Val Glu Glu Gly Ala Ser Thr Val Asp Val
565 570 575
Thr Val Pro Val Ser Asn Val Gly Ser Val Asp Tyr Thr Gly Val Thr
580 585 590
Val Thr Pro Ala Asp Leu Pro Thr Gly Trp Ser Ala Ser Pro Val Asn
595 600 605
Val Gly Ala Leu Ala Ser Gly Thr Ser Lys Asp Val Thr Val Thr Val
610 615 620
Asn Val Pro Ala Thr Ala Lys Lys Asp Asp Val Ala Lys Ile Val Leu
625 630 635 640
Arg Val Thr Gly Thr Ser Ala Ala Asn Ala Asn Ala Thr Thr Gly Phe
645 650 655
Asp Gly Ser Ile Thr Val Asn Val Thr Glu Lys Ser Glu Pro Asp Pro
660 665 670
Glu Pro Glu Pro Thr Ile Thr Gly Val Ser Ala Val Thr Ser Gln Ala
675 680 685
Gly Val Lys Val Gly Asp Val Phe Asp Ala Ser Lys Val Ser Val Thr
690 695 700
Ala Ala Met Ser Asp Gly Ser Ser Lys Ala Leu Ala Ala Gly Glu Tyr
705 710 715 720
Ser Leu Ser Ala Val Asp Ala Asp Gly Lys Ala Val Asp Leu Ala Glu
725 730 735
Pro Phe Ala Ala Ala Gly Val Val Thr Val Thr Val Ser Val Pro Val
740 745 750
Glu Gly Ala Gly Pro Leu Thr Ala Ser Phe Thr Ile Asp Val Ala Glu
755 760 765
Lys Ser Val Asp Pro Glu Pro Lys Pro Glu Pro Glu Pro Lys Pro Glu
770 775 780
Pro Glu Lys Pro Ala Gly Pro Lys Val Asp Val Pro Thr Glu Gln Pro
785 790 795 800
Gly Leu Ser Lys Thr Gly Ala Ser Thr Ala Gly Met Ser Ile Val Phe
805 810 815
Val Leu Leu Ala Leu Ser Gly Ile Ala Ala Leu Ser Leu Arg Arg Arg
820 825 830
Ser Val His
835
<210> 10
<211> 1060
<212> PRT
<213> Trypanosoma cruzi
<400> 10
Met Gly Lys Thr Val Val Gly Ala Ser Arg Met Phe Trp Leu Met Phe
1 5 10 15
Phe Val Pro Leu Leu Leu Ala Leu Cys Pro Ser Glu Pro Ala His Ala
20 25 30
Leu Ala Pro Gly Ser Ser Arg Val Glu Leu Phe Lys Arg Gln Ser Ser
35 40 45
Lys Val Pro Phe Glu Lys Gly Gly Lys Val Thr Glu Arg Val Val His
50 55 60
Ser Phe Arg Leu Pro Ala Leu Val Asn Val Asp Gly Val Met Val Ala
65 70 75 80
Ile Ala Asp Ala Arg Tyr Glu Thr Ser Asn Asp Asn Ser Leu Ile Asp
85 90 95
Thr Val Ala Lys Tyr Ser Val Asp Asp Gly Glu Thr Trp Glu Thr Gln
100 105 110
Ile Ala Ile Lys Asn Ser Arg Ala Ser Ser Val Ser Arg Val Val Asp
115 120 125
Pro Thr Val Ile Val Lys Gly Asn Lys Leu Tyr Val Leu Val Gly Ser
130 135 140
Tyr Asn Ser Ser Arg Ser Tyr Trp Thr Ser His Gly Asp Ala Arg Asp
145 150 155 160
Trp Asp Ile Leu Leu Ala Val Gly Glu Val Thr Lys Ser Thr Ala Gly
165 170 175
Gly Lys Ile Thr Ala Ser Ile Lys Trp Gly Ser Pro Val Ser Leu Lys
180 185 190
Glu Phe Phe Pro Ala Glu Met Glu Gly Met His Thr Asn Gln Phe Leu
195 200 205
Gly Gly Ala Gly Val Ala Ile Val Ala Ser Asn Gly Asn Leu Val Tyr
210 215 220
Pro Val Gln Val Thr Asn Lys Lys Lys Gln Val Phe Ser Lys Ile Phe
225 230 235 240
Tyr Ser Glu Asp Glu Gly Lys Thr Trp Lys Phe Gly Glu Gly Arg Ser
245 250 255
Asp Phe Gly Cys Ser Glu Pro Val Ala Leu Glu Trp Glu Gly Lys Leu
260 265 270
Ile Ile Asn Thr Arg Val Asp Tyr Arg Arg Arg Leu Val Tyr Glu Ser
275 280 285
Ser Asp Met Gly Asn Ser Trp Val Glu Ala Val Gly Thr Leu Ser Arg
290 295 300
Val Trp Gly Pro Ser Pro Lys Ser Asn Gln Pro Gly Ser Gln Ser Ser
305 310 315 320
Phe Thr Ala Val Thr Ile Glu Gly Met Arg Val Met Leu Phe Thr His
325 330 335
Pro Leu Asn Phe Lys Gly Arg Trp Leu Arg Asp Arg Leu Asn Leu Trp
340 345 350
Leu Thr Asp Asn Gln Arg Ile Tyr Asn Val Gly Gln Val Ser Ile Gly
355 360 365
Asp Glu Asn Ser Ala Tyr Ser Ser Val Leu Tyr Lys Asp Asp Lys Leu
370 375 380
Tyr Cys Leu His Glu Ile Asn Ser Asn Glu Val Tyr Ser Leu Val Phe
385 390 395 400
Ala Arg Leu Val Gly Glu Leu Arg Ile Ile Lys Ser Val Leu Gln Ser
405 410 415
Trp Lys Asn Trp Asp Ser His Leu Ser Ser Ile Cys Thr Pro Ala Asp
420 425 430
Pro Ala Ala Ser Ser Ser Glu Arg Gly Cys Gly Pro Ala Val Thr Thr
435 440 445
Val Gly Leu Val Gly Phe Leu Ser His Ser Ala Thr Lys Thr Glu Trp
450 455 460
Glu Asp Ala Tyr Arg Cys Val Asn Ala Ser Thr Ala Asn Ala Glu Arg
465 470 475 480
Val Pro Asn Gly Leu Lys Phe Ala Gly Val Gly Gly Gly Ala Leu Trp
485 490 495
Pro Val Ser Gln Gln Gly Gln Asn Gln Arg Tyr His Phe Ala Asn His
500 505 510
Ala Phe Thr Leu Val Ala Ser Val Thr Ile His Glu Val Pro Ser Val
515 520 525
Ala Ser Pro Leu Leu Gly Ala Ser Leu Asp Ser Ser Gly Gly Lys Lys
530 535 540
Leu Leu Gly Leu Ser Tyr Asp Glu Lys His Gln Trp Gln Pro Ile Tyr
545 550 555 560
Gly Ser Thr Pro Val Thr Pro Thr Gly Ser Trp Glu Met Gly Lys Arg
565 570 575
Tyr His Val Val Leu Thr Met Ala Asn Lys Ile Gly Ser Val Tyr Ile
580 585 590
Asp Gly Glu Pro Leu Glu Gly Ser Gly Gln Thr Val Val Pro Asp Gly
595 600 605
Arg Thr Pro Asp Ile Ser His Phe Tyr Val Gly Gly Tyr Gly Arg Ser
610 615 620
Asp Met Pro Thr Ile Ser His Val Thr Val Asn Asn Val Leu Leu Tyr
625 630 635 640
Asn Arg Gln Leu Asn Ala Glu Glu Ile Arg Thr Leu Phe Leu Ser Gln
645 650 655
Asp Leu Ile Gly Thr Glu Ala His Met Gly Ser Ser Ser Gly Ser Ser
660 665 670
Ala His Ser Thr Pro Ser Thr Pro Ala Asp Asn Gly Ala His Ser Thr
675 680 685
Pro Ser Thr Pro Ala Asp Ser Ser Ala His Ser Thr Pro Ser Thr Pro
690 695 700
Ala Asp Ser Ser Ala His Ser Thr Pro Ser Ala Pro Gly Asp Asn Gly
705 710 715 720
Ala His Ser Thr Pro Ser Thr Pro Gly Asp Ser Ser Ala His Ser Thr
725 730 735
Pro Ser Thr Pro Ala Asp Asn Gly Ala His Ser Thr Pro Ser Ala Pro
740 745 750
Ala Asp Ser Asn Ala His Ser Thr Pro Ser Thr Pro Ala Asp Asn Gly
755 760 765
Ala His Ser Thr Pro Ser Thr Pro Ala Asp Asn Gly Ala His Ser Thr
770 775 780
Pro Ser Thr Pro Gly Asp Asn Gly Ala His Ser Thr Pro Ser Thr Pro
785 790 795 800
Gly Asp Ser Ser Ala His Ser Thr Pro Ser Thr Pro Ala Asp Asn Gly
805 810 815
Ala His Ser Thr Pro Ser Ala Pro Ala Asp Ser Asn Ala His Ser Thr
820 825 830
Pro Ser Thr Pro Gly Asp Asn Gly Ala His Ser Thr Pro Ser Ala Pro
835 840 845
Ala Asp Ser Asn Ala His Ser Thr Pro Ser Thr Pro Ala Asp Ser Ser
850 855 860
Ala His Ser Thr Pro Ser Ala Pro Gly Asp Asn Gly Ala His Ser Thr
865 870 875 880
Pro Ser Ala Pro Ala Asp Ser Ser Ala His Ser Thr Pro Ser Ala Pro
885 890 895
Gly Asp Asn Gly Ala His Ser Thr Pro Ser Ala Pro Ala Asp Asn Gly
900 905 910
Ala His Ser Thr Pro Ser Ala Pro Gly Asp Ser Asn Ala His Ser Thr
915 920 925
Pro Ser Thr Pro Ala Asp Ser Ser Ala His Ser Thr Pro Ser Thr Pro
930 935 940
Ala Asp Ser Ser Ala His Ser Thr Pro Ser Ala Pro Gly Asp Asn Gly
945 950 955 960
Ala His Ser Thr Pro Ser Ala Pro Ala Asp Ser Ser Ala His Ser Thr
965 970 975
Pro Ser Ile Pro Gly Asp Ser Ser Ala His Ser Thr Pro Ser Ala Pro
980 985 990
Ala Asp Ser Ser Ala His Ser Thr Pro Ser Ala Pro Gly Asp Asn Gly
995 1000 1005
Ala His Ser Thr Pro Ser Thr Pro Ala Asp Asn Gly Ala Asn Gly Thr
1010 1015 1020
Val Leu Ile Leu His Asp Gly Ala Ala Phe Ser Ala Phe Ser Gly Gly
1025 1030 1035 1040
Gly Leu Leu Leu Cys Ala Gly Ala Leu Leu Leu His Val Phe Val Met
1045 1050 1055
Ala Val Phe Phe
1060
<210> 11
<211> 642
<212> PRT
<213> Trypanosoma cruzi
<400> 11
Met Leu Ala Pro Gly Ser Ser Arg Val Glu Leu Phe Lys Arg Gln Ser
1 5 10 15
Ser Lys Val Pro Phe Glu Lys Asp Gly Lys Val Thr Glu Arg Val Val
20 25 30
His Ser Phe Arg Leu Pro Ala Leu Val Asn Val Asp Gly Val Met Val
35 40 45
Ala Ile Ala Asp Ala Arg Tyr Glu Thr Ser Asn Asp Asn Ser Leu Ile
50 55 60
Asp Thr Val Ala Lys Tyr Ser Val Asp Asp Gly Glu Thr Trp Glu Thr
65 70 75 80
Gln Ile Ala Ile Lys Asn Ser Arg Ala Ser Ser Val Ser Arg Val Val
85 90 95
Asp Pro Thr Val Ile Val Lys Gly Asn Lys Leu Tyr Val Leu Val Gly
100 105 110
Ser Tyr Asn Ser Ser Arg Ser Tyr Trp Thr Ser His Gly Asp Ala Arg
115 120 125
Asp Trp Asp Ile Leu Leu Ala Val Gly Glu Val Thr Lys Ser Thr Ala
130 135 140
Gly Gly Lys Ile Thr Ala Ser Ile Lys Trp Gly Ser Pro Val Ser Leu
145 150 155 160
Lys Glu Phe Phe Pro Ala Glu Met Glu Gly Met His Thr Asn Gln Phe
165 170 175
Leu Gly Gly Ala Gly Val Ala Ile Val Ala Ser Asn Gly Asn Leu Val
180 185 190
Tyr Pro Val Gln Val Thr Asn Lys Lys Lys Gln Val Phe Ser Lys Ile
195 200 205
Phe Tyr Ser Glu Asp Glu Gly Lys Thr Trp Lys Phe Gly Lys Gly Arg
210 215 220
Ser Ala Phe Gly Cys Ser Glu Pro Val Ala Leu Glu Trp Glu Gly Lys
225 230 235 240
Leu Ile Ile Asn Thr Arg Val Asp Tyr Arg Arg Arg Leu Val Tyr Glu
245 250 255
Ser Ser Asp Met Gly Asn Ser Trp Leu Glu Ala Val Gly Thr Leu Ser
260 265 270
Arg Val Trp Gly Pro Ser Pro Lys Ser Asn Gln Pro Gly Ser Gln Ser
275 280 285
Ser Phe Thr Ala Val Thr Ile Glu Gly Met Arg Val Met Leu Phe Thr
290 295 300
His Pro Leu Asn Phe Lys Gly Arg Trp Leu Arg Asp Arg Leu Asn Leu
305 310 315 320
Trp Leu Thr Asp Asn Gln Arg Ile Tyr Asn Val Gly Gln Val Ser Ile
325 330 335
Gly Asp Glu Asn Ser Ala Tyr Ser Ser Val Leu Tyr Lys Asp Asp Lys
340 345 350
Leu Tyr Cys Leu His Glu Ile Asn Ser Asn Glu Val Tyr Ser Leu Val
355 360 365
Phe Ala Arg Leu Val Gly Glu Leu Arg Ile Ile Lys Ser Val Leu Gln
370 375 380
Ser Trp Lys Asn Trp Asp Ser His Leu Ser Ser Ile Cys Thr Pro Ala
385 390 395 400
Asp Pro Ala Ala Ser Ser Ser Glu Arg Gly Cys Gly Pro Ala Val Thr
405 410 415
Thr Val Gly Leu Val Gly Phe Leu Ser His Ser Ala Thr Lys Thr Glu
420 425 430
Trp Glu Asp Ala Tyr Arg Cys Val Asn Ala Ser Thr Ala Asn Ala Glu
435 440 445
Arg Val Pro Asn Gly Leu Lys Phe Ala Gly Val Gly Gly Gly Ala Leu
450 455 460
Trp Pro Val Ser Gln Gln Gly Gln Asn Gln Arg Tyr Arg Phe Ala Asn
465 470 475 480
His Ala Phe Thr Val Val Ala Ser Val Thr Ile His Glu Val Pro Ser
485 490 495
Val Ala Ser Pro Leu Leu Gly Ala Ser Leu Asp Ser Ser Gly Gly Lys
500 505 510
Lys Leu Leu Gly Leu Ser Tyr Asp Glu Arg His Gln Trp Gln Pro Ile
515 520 525
Tyr Gly Ser Thr Pro Val Thr Pro Thr Gly Ser Trp Glu Met Gly Lys
530 535 540
Arg Tyr His Val Val Leu Thr Met Ala Asn Lys Ile Gly Ser Glu Tyr
545 550 555 560
Ile Asp Gly Glu Pro Leu Glu Gly Ser Gly Gln Thr Val Val Pro Asp
565 570 575
Glu Arg Thr Pro Asp Ile Ser His Phe Tyr Val Gly Gly Tyr Lys Arg
580 585 590
Ser Asp Met Pro Thr Ile Ser His Val Thr Val Asn Asn Val Leu Leu
595 600 605
Tyr Asn Arg Gln Leu Asn Ala Glu Glu Ile Arg Thr Leu Phe Leu Ser
610 615 620
Gln Asp Leu Ile Gly Thr Glu Ala His Met Asp Ser Ser Ser Asp Thr
625 630 635 640
Ser Ala
Claims (23)
- 트랜스시알리다아제 활성을 가지는 효소의 촉매 작용 하에서, 화학식 SA-OR2 및 그의 염들의 시알릴 공여체가 일반 화학식 2A 및 그의 염들의 시알릴 수용체와 반응되는 것을 특징으로 하는 일반 화학식 1A의 화합물 및 그의 염들의 합성 방법:
화학식 SA-OR2에서, R2는 단-, 이- 또는 올리고당, 당지질(glycolipid), 당단백질 또는 당펩티드, 고리형 또는 비고리형 지방족 기, 또는 아릴 잔기이고, SA는 α-시알릴 모이어티이고,
일반 화학식 1A에서, R 기들 중의 하나는 α-시알릴 모이어티, 다른 하나는 H이고, X1은 탄수화물 링커를 나타내고, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, R1은 가수소분해에 의해 제거될 수 있는 보호기이고, m은 0 또는 1의 정수이며,
일반 화학식 2A에서, X1, A, m 및 R1은 상기에서 정의한 바와 같다.
- 청구항 1에 있어서, 상기 트랜스-시알리다아제 활성을 가지는 효소는 비피도박테리움속(Bifidobacterium) 종들로부터 유래된 시알리다아제 및 트리파노소마 크루지(Trypanosoma cruzi)로부터 유래된 트랜스-시알리다아제로부터 선택되는 방법.
- 청구항 1 또는 청구항 2에 있어서, 상기 트랜스-시알리다아제 활성을 가지는 효소는 조작된 효소인 방법.
- 청구항 1 내지 청구항 3 중 어느 한 항에 있어서, 상기 시알릴 공여체는 2-O-(p-나이트로페닐)-α-D-시알로사이드(2-O-(p-nitrophenyl)-α-D-sialoside), 2-O-(4-메틸움벨리페릴)-α-D-시알로사이드(2-O-(4-methylumbelliferyl)-α-D-sialoside), 페투인(fetuin) 및 3'-O-시알릴-락토스(3'-O-sialyl-lactose)로 구성되는 군에서 선택되는 방법.
- 청구항 1 내지 청구항 4 중 어느 한 항에 있어서, 상기 일반 화학식 1A의 화합물 및 그의 염들은 일반 화학식 1-3A의 화합물 및 그의 염들인 것을 특징으로 하는 방법:
일반 화학식 1-3A에서, SA는 α-시알릴 모이어티이고, R1, A, X1 및 m은 청구항 1에서 정의한 바와 같다.
- 청구항 5에 있어서, 상기 일반 화학식 1-3A의 화합물 및 그의 염들은 일반 화학식 1-3B 또는 1-3C의 화합물 및 그의 염들인 것을 특징으로 하는 방법:
일반 화학식 1-3B 또는 1-3C에서, R3는 푸코실 또는 H이고, B는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미하고, R1 및 A는 청구항 1에서 정의한 바와 같다.
- 청구항 6에 있어서, 상기 일반 화학식 1-3B 또는 1-3C의 화합물 및 그의 염들은 일반 화학식 1-3D의 인유 올리고당 및 그의 염인 방법:
일반 화학식 1-3D에서, Y는 독립적으로, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 독립적으로 0, 1 또는 2의 정수이고, R4'는 일반 화학식 3-3 및 4-3로 특징화되는 기들에서 선택되고, R5'는 H, α-시알릴 모이어티, 일반 화학식 3-3의 기 및 일반 화학식 4-3의 기에서 선택되고,
일반 화학식 3-3 또는 4-3에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이고, SA는 α-시알릴 모이어티이다.
- 청구항 6 또는 청구항 7에 있어서, 일반 화학식 1-3B, 1-3C 또는 1-3D의 화합물들 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/ 또는 푸코실 잔기로 치환되고, 말단 갈락토실(galactosyl) 잔기의 3-OH에 시알릴 치환기를 갖는 락토스(lactose), 락토-N-네오테트라오스(lacto-N-neotetraose), 파라-락토-N-헥사오스(para-lacto-N-hexaose), 파라-락토-N-네오헥사오스(para-lacto-N-neohexaose), 락토-N-네오헥사오스(lacto-N-neohexaose), 파라-락토-N-옥타오스(para-lacto-N-octaose), 락토-N-네오옥타오스(lacto-N-neooctaose), 락토-N-테트라오스(lacto-N-tetraose), 락토-N-헥사오스(lacto-N-hexaose), 락토-N-옥타오스(lacto-N-octaose), 아이소-락토-N-옥타오스(iso-lacto-N-octaose), 락토-N-데카오스(lacto-N-decaose) 및 락토-N-네오데카오스(lacto-N-neodecaose)의 R1-배당체(glycoside)들, 및 그의 염들로 구성된 군으로부터 선택되는 방법.
- 청구항 8에 있어서, 상기 화합물들은 Neu5Acα2-3Galβ1-4Glc (3'-O-(N-아세틸-뉴라미노실)-락토스), Neu5Acα2-3Galβ1-4(Fucα1-3)Glc (3-O-푸코실-3'-O-(N-아세틸-뉴라미노실)-락토스), Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LST a), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FLST a), Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (DSLNT), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FDSLNT I), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FDSLNT II), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc의 R1-배당체(glycoside)들, 및 그의 염들로 구성된 군으로부터 선택되는 방법.
- 청구항 1 내지 청구항 9 중 어느 한 항에 있어서, 상기 R1은 페닐, 알킬 또는 할로젠으로 구성되는 군에서 선택되는 적어도 하나의 기로 선택적으로 치환된 벤질 또는 2-나프틸메틸 기들인 방법.
- 일반 화학식 1A'의 화합물 및 그의 염들:
일반 화학식 1A'에서, R 기들 중의 하나는 α-시알릴 모이어티, 다른 하나는 H이고, R1은 가수소분해에 의해 제거될 수 있는 보호기이고, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, m은 0 또는 1의 정수이고, X1은 탄수화물 링커를 나타내며,
단, 3'-O-(N-아세틸-뉴라미노실)-락토스((3'-O-(N-acetyl-neuraminosyl)-lactose)) 나트륨 염의 1-O-β-벤질(1-O-β-benzyl) 및 1-O-β-(4,5-다이메톡시-2-나이트로)-벤질(1-O-β-(4,5-dimethoxy-2-nitro)-benzyl) 배당체들, 및 6'-O-(N-아세틸-뉴라미노실)-락토스(6'-O-(N-acetyl-neuraminosyl)-lactose) 나트륨 염의 1-O-β-벤질(1-O-β-benzyl) 배당체는 제외된다.
- 청구항 11에 있어서, 일반 화학식 1A'의 화합물 및 그의 염들은 일반 화학식 1'-3A의 화합물 및 그의 염들인 것을 특징으로 하는 화합물:
일반 화학식 1A'에서, SA는 α-시알릴 모이어티이고, R1, A, X1 및 m은 청구항 11에서 정의한 바와 같다.
- 청구항 12에 있어서, 상기 일반 화학식 1'-3A의 화합물 및 그의 염들은 일반 화학식 1'-3B 또는 1'-3C의 화합물 및 그의 염들인 것을 특징으로 하는 화합물:
일반 화학식 1'-3B 또는 1'-3C에서, R3는 푸코실 또는 H이고, B는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미하고, R1 및 A는 청구항 11에서 정의한 바와 같다.
- 청구항 13에 있어서, 상기 일반 화학식 1'-3B 또는 1'-3C의 화합물들 및 그의 염들은 일반 화학식 1'-3D의 인유 올리고당 및 그의 염인 화합물:
일반 화학식 1'-3D에서, Y는 독립적으로, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 독립적으로 0, 1 또는 2의 정수이고, R4'는 일반 화학식 3-3 및 4-3에 의하여 특징화되는 기들로부터 선택되고, R5'는 H, α-시알릴 모이어티, 일반 화학식 3-3의 기 및 일반 화학식 4-3의 기로부터 선택되고,
일반 화학식 3-3 또는 4-3에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이고, SA는 α-시알릴 모이어티이다.
- 청구항 13 또는 청구항 14에 있어서, 상기 일반 화학식 1'-3B, 1'-3C 또는 1'-3D의 화합물들 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/ 또는 푸코실 잔기로 치환되고, 말단 갈락토실 잔기의 3-OH에 시알릴 치환기를 갖는 락토스(lactose), 락토-N-네오테트라오스(lacto-N-neotetraose), 파라-락토-N-헥사오스(para-lacto-N-hexaose), 파라-락토-N-네오헥사오스(para-lacto-N-neohexaose), 락토-N-네오헥사오스(lacto-N-neohexaose), 파라-락토-N-옥타오스(para-lacto-N-octaose), 락토-N-네오옥타오스(lacto-N-neooctaose), 락토-N-테트라오스(lacto-N-tetraose), 락토-N-헥사오스(lacto-N-hexaose), 락토-N-옥타오스(lacto-N-octaose), 아이소-락토-N-옥타오스(iso-lacto-N-octaose), 락토-N-데카오스(lacto-N-decaose) 및 락토-N-네오데카오스(lacto-N-neodecaose)의 R1-배당체(glycoside)들, 및 그의 염들로 구성된 군으로부터 선택되는 화합물.
- 청구항 15에 있어서, 상기 화합물들은 Neu5Acα2-3Galβ1-4Glc (3'-O-(N-아세틸-뉴라미노실)-락토스), Neu5Acα2-3Galβ1-4(Fucα1-3)Glc (3-O-푸코실-3'-O-(N-아세틸-뉴라미노실)-락토스), Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LST a), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FLST a), Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc, Neu5Acα2-3Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (DSLNT), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (FDSLNT I), Neu5Acα2-3Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (FDSLNT II), Neu5Acα2-3Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Neu5Acα2-3Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc의 R1-배당체(glycoside)들, 및 그의 염들로 구성된 군으로부터 선택되는 화합물.
- 청구항 11 내지 청구항 16 중 어느 한 항에 있어서, 상기 R1은 페닐, 알킬 또는 할로젠으로 구성되는 군으로부터 선택되는 적어도 하나의 기로 선택적으로 치환된 벤질 또는 2-나프틸메틸 기들인 화합물.
- 일반 화학식 2A'의 화합물 및 그의 염들:
일반 화학식 2A'에서, A는 선택적으로 푸코실로 치환된 D-글루코피라노실 단위이고, X1은 탄수화물 링커를 나타내고, m은 0 또는 1의 정수이고,
단, a) m이 0일 때, 상기 A는 푸코실로 치환되고, b) 1-O-β-벤질-LNT(1-O-β-benzyl-LNT), 1-O-β-(4-하이드록시메틸벤질)-LNnT(1-O-β-(4-hydroxymethylbenzyl)-LNnT) 및 1-O-β-벤질-LNnT(1-O-β-benzyl-LNnT)는 제외된다.
- 청구항 18에 있어서, 상기 일반 화학식 2A'의 화합물 및 그의 염들은 일반 화학식 2B' 또는 2C'의 화합물 및 그의 염들인 것을 특징으로 하는 화합물:
일반 화학식 2B' 또는 2C'에서, R3는 푸코실이고, B는 선택적으로 푸코실 및/또는 시알릴로 치환된 N-아세틸-글루코사미노피라노실 단위이며, 링커 X2는 글루코스, N-아세틸-글루코사민, 갈락토스, 푸코스 및 시알산으로부터 선택되는 단당류 구성 단위들을 갖는 선형 또는 분지형 구조를 나타내는 단-, 이-, 삼-, 사-, 오- 또는 올리고당을 의미하고, R1 및 A는 청구항 18에서 정의한 바와 같다.
- 청구항 19에 있어서, 상기 일반 화학식 2B' 또는 2C'의 화합물들 및 그의 염들은 일반 화학식 2D'의 인유 올리고당 유도체들 및 그의 염인 화합물:
일반 화학식 2D'에서, R1은 가수소분해에 의해 제거될 수 있는 기이고, R3는 H 또는 푸코실이고, Y는 독립적으로, 선택적으로 시알릴 및/또는 푸코실 잔기로 치환된 N-아세틸-락토사미닐 기이고, p는 독립적으로 0, 1 또는 2의 정수이고, R8은 일반 화학식 5 및 6에 의하여 특징화되는 기들로부터 선택되고, R9는 H, α-시알릴 모이어티, 일반 화학식 5의 기 및 일반 화학식 6의 기로부터 선택되고,
일반 화학식 5 또는 6에서, R6은 H 또는 푸코실 잔기이고, R7은 H 또는 α-시알릴 모이어티이다.
- 청구항 19 또는 청구항 20에 있어서, 상기 일반 화학식 2B', 2C' 또는 2D'의 화합물들 및 그의 염들은 선택적으로 하나 이상의 시알릴 및/ 또는 푸코실 잔기로 치환되고, 비치환된 말단 갈락토실(galactosyl) 잔기를 갖는 락토-N-네오테트라오스(lacto-N-neotetraose), 파라-락토-N-헥사오스(para-lacto-N-hexaose), 파라-락토-N-네오헥사오스(para-lacto-N-neohexaose), 락토-N-네오헥사오스(lacto-N-neohexaose), 파라-락토-N-옥타오스(para-lacto-N-octaose), 락토-N-네오옥타오스(lacto-N-neooctaose), 락토-N-테트라오스(lacto-N-tetraose), 락토-N-헥사오스(lacto-N-hexaose), 락토-N-옥타오스(lacto-N-octaose), 아이소-락토-N-옥타오스(iso-lacto-N-octaose), 락토-N-데카오스(lacto-N-decaose) 및 락토-N-네오데카오스(lacto-N-neodecaose)의 R1-배당체(glycoside)들, 및 그의 염들로 구성된 군으로부터 선택되는 화합물.
- 청구항 18 내지 청구항 21 중 어느 한 항에 있어서, 상기 화합물들은 Galβ1-4(Fucα1-3)Glc (3-O-푸코실락토스(3-O-fucosyllactose)), Galβ1-3GlcNAcβ1-3Galβ1-4Glc (LNT), Galβ1-4GlcNAcβ1-3Galβ1-4Glc (LNnT), Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc (LNFP II), Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4Glc (LNFP III), Galβ1-3GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNFP V), Galβ1-3(Fucα1-4)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNDFH II), Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4Glc (LSTb), Galβ1-3(Neu5Acα2-6)(Fucα1-4)GlcNAcβ1-3Galβ1-4Glc, Galβ1-3(Neu5Acα2-6)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Galβ1-4GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc, Galβ1-4(Fucα1-3)GlcNAcβ1-3Galβ1-4(Fucα1-3)Glc (LNDFH III)의 R1-배당체(glycoside)들, 및 그의 염들로 구성된 군으로부터 선택되는 화합물.
- 청구항 18 내지 청구항 22 중 어느 한 항에 있어서, 상기 R1은 페닐, 알킬 또는 할로젠으로 구성되는 군으로부터 선택되는 적어도 하나의 기로 선택적으로 치환된 벤질 또는 2-나프틸메틸 기들인 화합물.
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| PCT/EP2011/062184 WO2012007588A1 (en) | 2010-07-16 | 2011-07-15 | Synthesis of new sialooligosaccharide derivatives |
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| Publication number | Publication date |
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| KR20140011296A (ko) | 2014-01-28 |
| US9102966B2 (en) | 2015-08-11 |
| CA2805499A1 (en) | 2012-01-19 |
| JP2013531049A (ja) | 2013-08-01 |
| WO2012007585A1 (en) | 2012-01-19 |
| WO2012007585A9 (en) | 2012-07-26 |
| EP2593465A1 (en) | 2013-05-22 |
| RU2013106897A (ru) | 2014-08-27 |
| JP2013532470A (ja) | 2013-08-19 |
| CN103108881A (zh) | 2013-05-15 |
| AU2011278239B2 (en) | 2014-03-27 |
| US20130171696A1 (en) | 2013-07-04 |
| CN103108956A (zh) | 2013-05-15 |
| CA2805501A1 (en) | 2012-01-19 |
| AU2011278239A1 (en) | 2013-02-07 |
| RU2013106896A (ru) | 2014-08-27 |
| AU2011278236A1 (en) | 2013-02-07 |
| US20160024129A1 (en) | 2016-01-28 |
| US20130172548A1 (en) | 2013-07-04 |
| WO2012007588A9 (en) | 2012-07-05 |
| WO2012007588A1 (en) | 2012-01-19 |
| EP2593559A1 (en) | 2013-05-22 |
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