CN1293096C - 合成甲状旁腺素类似物和甲状旁腺素相关肽的方法 - Google Patents
合成甲状旁腺素类似物和甲状旁腺素相关肽的方法 Download PDFInfo
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Abstract
本发明提供了合成甲状旁腺素(PTH)类似物和甲状旁腺素相关肽(PTHrP)的片段缩合方法,在所述的类似物和相关肽中,氨基酸残基22-31形成一个合成的两亲性α-螺旋。
Description
本发明涉及用于合成在治疗骨质疏松上有用的某些新的甲状旁腺素类似物和甲状旁腺素相关肽的方法。
骨质疏松是最普通的代谢性骨疾病形式,可被认为是骨丧失(骨质减少)的有症状的骨折阶段。虽然骨质疏松可以继发于许多以下所述的疾病,但总共90%的病例显得是自发性的。经绝后的妇女特别具有患自发性骨质疏松(经绝后骨质疏松或I型骨质疏松)的危险性。另一个自发性骨质疏松高风险人群是男女性年老者(老年性骨质疏松或II型骨质疏松)。骨质疏松也与皮质甾类使用、固定或长期卧床休息、酒精中毒、糖尿病、性腺毒性化疗、血促性腺激素过多、神经性食欲不振、原发性和继发性经闭以及卵巢切除有关。
在骨质疏松的各种形式中,骨折经常发生,其是达到机械性丧失点的骨丧失的结果。经绝后的骨质疏松以手腕和脊柱骨折为特征,而股颈项骨折似乎是老年性骨质疏松的明显特征。
骨质疏松骨丧失的机制被认为牵涉到骨骼自我更新过程的不平衡。这一过程被称为骨改造(remodeling)。其发生于一系列分散的活性容器(pockets)中。这些容器作为骨吸收点自发地出现在给定的骨表面上的骨基质内。破骨细胞(骨溶解或吸收细胞)在一般恒定大小的骨部分的吸收中起作用。这一吸收过程之后出现成骨细胞(骨形成细胞),然后其用新的骨再充填由破骨细胞留下的空穴。
在健康成年受试者中,破骨细胞和成骨细胞所形成的速率是使骨形成和骨吸收平衡的速率。然而,在骨质疏松中,在骨改造过程中产生的不平衡导致骨丧失,其速率快于骨形成的速率。尽管这种不平衡以某种程度出现在大多数年老的个体中,但在经绝后的骨质疏松中或卵巢切除术后其更严重并出现在年轻个体中。
Adachi等在关节炎和风湿症研讨(22:6,375-84(1993年6月))中报道,尽管有关皮质甾类诱导的骨质疏松的病理生理学有很多冲突的数据,人们通常认为存在骨形成的相对降低和骨吸收的相对增加。骨丧失以及所形成的骨折和骨质疏松常常是皮质甾类治疗的结果。有证据显示在皮质甾类治疗的头6至12个月之内迅速发生骨丧失;骨丧失速率和皮质甾类剂量之间也显示出一种密切关系。人类对皮质甾类的作用同样地敏感。估计骨折和骨质疏松的发生率在30%到50%之间。
已有治疗骨质疏松的许多尝试,这些尝试的目的是减慢进一步的骨丧失或者更好地是产生骨质(bone mass)的净增加。某些药剂(如雌激素和二膦酸酯(bisphosphonates))在骨质疏松中表现出减慢进一步的丧失。由于骨吸收和形成的不同的时期,减慢骨丧失的药剂显示出增加骨质(以3至7%数量级)。然而,这个明显的增加在时间上是有限的,不是进行性的,并且是因为″改造空间″的减少。此外,由于吸收和形成之间的密切联系,阻止骨吸收的治疗也最终阻止骨形成。
已有人提出,以甲状旁腺素(PTH)治疗将导致增加的骨更新和阳性钙平衡。然而,人类临床试验曾显示任何柱骨上的增加由皮骨上的减少补偿,这样在总骨上没有净增加。
Hefti等在临床科学(1982)62,389-396中,曾报道在正常的和骨质疏松成年雌性大鼠中,bPTH(1-84)或hPTH(1-34)的每日皮下用药增加整体钙和个体骨的灰分重量。
Liu等在骨矿化研究杂志(J.Bone Miner.Res.)6,10,1071-1080(1991)已注意到,成年雌性大鼠的卵巢切除术诱导最接近的胫骨干骺端的柱骨的百分比中的47%丧失,伴随着成骨细胞和柱破骨细胞数量的明显增加。每日的皮下注射hPTH(1-34)完全逆转柱骨丧失,并导致柱骨的量超过假操作对照的量。成骨细胞的数量增加,且破骨细胞的数量降低。
Hock等在骨矿化研究杂志7,1,65-71(1992)中已报道,在健康成年雄性大鼠中,12天内每日皮下注射hPTH(1-34)增加柱骨和皮骨钙和干重。总骨质,柱骨体积,柱厚度和数量以及成骨细胞表面增加。
哺乳动物的甲状旁腺激素(例如人(hPTH),牛(bPTH),和猪(pPTH))是具有84个氨基酸残基的单一多肽链,具有大约9500的分子量。其生物学活性与N-末端部分(具有明显最低需要的残基1-34)相关。
人PTH的N-末端片段与牛和猪激素的N-末端片段的不同仅仅分别为三个和两个氨基酸残基:
hPTH(1-34):
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu
1 5 10 15
Asn Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp
20 25 30
Val His Asn Phe(SEQ ID NO:1);
bPTH(1-34):
Ala Val Ser Glu Ile Gln Phe Met His Asn Leu Gly Lys His Leu
1 5 10 15
Ser Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp
20 25 30
Val His Asn Phe(SEQ ID NO:2);
pPTH(1-34):
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu
1 5 10 15
Ser Ser Leu Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp
20 25 30
Val His Asn Phe(SEQ ID NO:3)
PTH的主要功能在于引发适应性变化,这些变化用以保持胞外液中Ca2+的恒定浓度。PTH在肾中发生作用,增加Ca2+从尿中的小管再吸收,并刺激骨化二醇转化成为骨化三醇,后者对Ca2+从肠的吸收起作用。一种显著的作用是促进Ca2+从骨中的活动化。PTH作用在骨上增加Ca2+和磷酸盐的吸收速率。PTH经破骨细胞刺激骨吸收速率,增加间质细胞分化成破骨细胞的速率,并延长这些后来的细胞的半衰期。由于PTH延长的作用,骨形成成骨细胞的数量增加;这样,骨更新和改造的速率得到提高。然而,单独的成骨细胞显示出比正常活性低的活性。
Rosenblatt等在US 4,423,037,4,968,669和5,001,223中公开了PTH拮抗剂,其是经缺失N-末端(1-6)氨基酸和选择性取代Phe7、Met8,18和Gly12获得的。据报道Tyr34-NH2增加了这些化合物的活性与稳定性。
甲状旁腺素-相关肽(PTHrp)(一种140个氨基酸的蛋白质)和其片段产生PTH的主要生物学活性。PTHrp被用一些人类和动物肿瘤与其它组织详细地说明,并且可以在恶性血钙过多中起作用。hPTHrp(1-34)的序列如下:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile
1 5 10 15
Gln Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile Ala Glu
20 25 30
Ile His Thr Ala(SEQ ID NO:4)
hPTH和hPTHrp之间的序列同源性极大地受制于13个N-末端残基,其中的8个是相同的;在hPTHrp中仅hPTH(25-34)受体结合区的10个氨基酸中的1个是保守的。构象类似性可以是构成共同活性的基础。Cohen等在生物化学杂志266,3,1997-2004(1991)中已提出,在特定的区域(5-18)和(21-34)中,PTH(1-34)和PTHrp(1-34)的许多序列采取a-螺旋构型,但注意到这些构型在生理条件下对羧基末端而言是否盛行存在某些问题。这种二级结构对类脂相互作用、受体相互作用和/或结构稳定性来说可能是重要的。
PTH类似物和PTHrp类似物的改进的治疗性质(有关包括患有骨质疏松的那些在内的哺乳动物受试者中的骨质恢复)已在国际专利申请出版物WO94/01460中公开。
本发明的一个目的是提供一种合成甲状旁腺素(PTH)合成多肽类似物或甲状旁腺素相关肽(PTHrP)或其盐的方法,在所述类似物、相关肽和其盐中,选自SEQ ID NOS:85、86、26、27、28、29和30的氨基酸残基22-31形成一个两亲性α-螺旋,该方法包括:a)经溶液或固相技术分别合成所述多肽的前体肽片段;b)使所述片段相互缩合,形成所需的多肽产物;和c)除去氨基酸保护基。
在一个实施方案中,本发明提供了这样一种改进的方法,该方法包括a)在树脂支持物上分别合成所述多肽的前体肽片段;b)从它们各自的树脂支持物上切下所述多肽的片段;c)依次使所说的片段缩合,形成所需的多肽产物;和d)除去氨基酸保护基。
在一个优选的实施方案中,从它们各自的树脂支持物上切下除所述多肽的C-末端片段外的所有部分;c)使所说的片段依次与树脂结合的C-末端片段缩合,形成所需的多肽产物;d)除去氨基酸保护基,并从树脂支持物上切下所述的多肽产物。
在一个优选的实施方案中,所述的方法用三个前体肽片段实施:所述片段是N-末端片段、中部片段和C-末端片段。在一个更优选的实施方案中,所说的多肽产物是从三个前体肽片段制备的,所述片段是N-末端片段、中部片段和C-末端片段,其中所说的N-末端片段具有作为其C-末端的Gly,中部片段具有作为其C-末端的Leu,并且C-末端片段具有作为其N-末端的Leu。在另一个实施方案,所说的中部肽片段具有C-末端Glu,所说的C-末端片段具有N-末端Leu。
此外,本发明的另一个目的是提供一种制备药物组合物的方法,特别是提供一种制备用于治疗骨质疏松(尤其是骨折愈合)的药物组合物的方法,该方法的特征在于,实施如上所述的制备PTH或PTHrP类似物的方法,并且将所获得的PTHrP类似物与一种或多种药学上可接受的添加剂混合。
各种普通核苷酸碱基和氨基酸的单字母和三字母缩写是纯粹应用化学31,639-645(1972)和40,277-290(1974)中和IUPAC-IUB生物化学命名委员会所推荐的,并且符合37CFRξ1.822(55FR18245,1990年5月1日)。所说的单字母和三字母缩写如下:
氨基酸 三字母代码 单字母代码
丙氨酸 Ala A
精氨酸 Arg R
天冬酰胺 Asn N
天冬氨酸 Asp D
Asn+Asp Asx B
半胱氨酸 Cys C
谷氨酰胺 Gln Q
谷氨酸 Glu E
Gln+Glu Glx Z
甘氨酸 Gly G
组氨酸 His H
异亮氨酸 Ile I
亮氨酸 Leu L
赖氨酸 Lys K
甲硫氨酸 Met M
苯丙氨酸 Phe F
脯氨酸 Pro P
丝氨酸 Ser S
苏氨酸 Thr T
色氨酸 Trp W
酪氨酸 Tyr Y
缬氨酸 Val V
其它氨基酸 Xaa X
除非另外指定为D-或D,L-,以上缩写代表L-氨基酸。某些氨基酸(天然的和非天然的)是非手性的,例如甘氨酸。所有肽序列以N-末端氨基酸在左边,C-末端氨基酸在右边表示。
本文使用的代表其它氨基酸和化合物的缩写是:
hSer 高丝氨酸
hSerlac 高丝氨酸内酯
Nle 正亮氨酸
″PTH或PTHrp的生理活性截短的类似物″指具有包含比在PTH或PTHrp中发现的氨基酸的全长补体(full complement)更少的序列,但引发类似的生理反应的多肽。截短的PTH或PTHrp不必与引发类似生理反应的PTH或PTHrp完全同源。PTH(1-34)和PTHrp(1-34)是这一组优选的例子,但不是仅有的例子。
″两亲性α-螺旋″指由某些多肽显示的二级结构,在所述肽中氨基酸采取α-螺旋构型,其具有沿螺旋长轴取向的相对的极性和非极性端面(faces)。在兴趣多肽中的α-螺旋结构的可能性在某种程度上可由合适节距(pitch)的“Schiffer-Edmundson wheel”构建[M.Schiffer和A.B.Edmundson,生物物理杂志1,121(1967)]并注意到在限制螺旋的圆筒的相反端面上亲水和亲油残基的分离探索。另外,经验性的证据(如圆二色性或X光衍射数据)可以用来指示在给定多肽中α-螺旋区的存在。一个理想的α-螺旋每圈具有3.6个氨基酸残基,具有由100°弧分隔的邻近侧链。Eisenberg等在自然299,371-374(1982)和美国科学院学报81,140-144(1984)中已组合了疏水性尺度与螺旋圈以量化两亲性环(helices)的概念。平均疏水因素(moment)被定义为构成螺旋的组分氨基酸的疏水性的载体总数。下列氨基酸的疏水性是由Eisenberg(1984)报道的作为″共有尺度″的那些:
Ile 0.73;Phe 0.61;Val 0.54;Leu 0.53;Trp 0.37;
Met 0.26;Ala 0.25;Gly 0.16;Cys 0.04;Tyr 0.02;
Pro-0.07;Thr-0.18;Ser-0.26;His-0.40;Glu-0.62;
Asn-0.64;Gln-0.69;Asp-0.72;Lys-1.10;Arg-1.76。
每圈具有3.6个残基(或者侧链间100°弧(=360°/3.6))的理想α-螺旋的疏水因素μH可由下式计算:
μH=[(∑HNSin(N-1))2+(∑HNcos(N-1))2]_,
其中HN是Nth氨基酸的疏水性值,总数用周期性=100°从序列中的N氨基酸取得。疏水因素可以经μH除以N得<μH>用每个残基的平均疏水因素表示。在100°±20°时约0.2或更大的<μH>值提示两亲性螺旋的形成。hPTHrp(22-31)和hPTH(22-31)在100°的值分别为0.19和0.37。
Cornett等在分子生物学杂志195,659-685(1987)中曾进一步通过引入″两亲性指数″作为两亲性指标广泛研究了两亲性α-环。他们得出结论:大约一半所有已知的是两亲性α-环,占优势的频率是97.5°,而非100°,每圈残基的数量更接近3.7而不是3.6。这样的修正在科学上是有意义的,Eisenberg等的基本方法足以把一种给定的序列分类为两亲性,特别是当人们从头开始设计序列形成两亲性α-螺旋时。
替换性α-螺旋氨基酸序列可以缺乏与天然产生的多肽的给定的片段之序列的同源性,但产生一个类似的二级结构,例如,在生理环境中具有相反极性和非极性端面的α-螺旋。用其它氨基酸序列取代天然产生的氨基酸序列可以有利地影响生理活性、稳定性或改变的亲本多肽的其它性质。J.L.Krstenansky等,FEBS Letters 242,2,409-413(1989)和J.P.Segrest等,蛋白质:构造,功能,和遗传学8,103-117(1990)中提供了指导这样的设计和序列选择的方法。
用于确定一种序列是否是足够两亲性的本发明的序列的一种方便的方法是如上所述计算平均疏水因素。如果在100°±20°时每个残基的峰值平均因素超过约0.20,则该序列将形成两亲性螺旋,并且是本发明的序列。
例如,SEQ ID NO:26(Xaa=Glu)在100°时每个残基的平均疏水因素计算如下:
A.A. HN (N-1) H sin(N-1) H cos(N-1)
E -.62 0 0 -.62
L .53 100 .52 -.17
L .53 200 -.18 -.50
E -.62 300 .34 -.31
K -1.1 400 -.70 -.85
L .53 500 .34 -.41
L .53 600 -.46 -.27
E -.62 700 .21 -.58
K -1.1 800 -1.08 -.19
L .53 900 0 -.53
∑=0.81 ∑=-4.43
μH=[(0.81)2+(-4.43)2]_=4.50
<μH>=4.50/10=0.45
对这一序列,平均峰值疏水因素出现在92°,具有0.48的值。
一方面,本发明提供了一种合成PTH,PTHrP,以及PTH和PTHrp生理活性类似物或其盐(在所述物质中,氨基酸残基22-31形成两亲性α-螺旋)的方法,所说残基(22-31)的序列选自:
a)Xaa1 Xaa2 Leu Xaa4 Xaa5 Leu Xaa7 Xaa8 Xaa9 Xaa10,其中
Xaa1和Xaa4分别是Glu、Glu(OCH3)、His或Phe;
Xaa2是Leu或Phe;
Xaa5是Lys或His;
Xaa7和Xaa10分别是Leu或Ile;
Xaa8是Ala,Arg或Glu;和
Xaa9是Lys或Glu(SEQ ID NO:85);
优选地是Glu Leu Leu Glu Lys Leu Leu Xaa Lys Leu,其中
Xaa是Glu或Arg(SEQ ID NO:26);
b)Xaa1 Xaa2 Leu Xaa4 Arg Leu Leu Xaa8 Arg Leu,其中
Xaa1和Xaa4分别是Glu、Glu(OCH3)、His或Phe;
Xaa2是Leu或Phe;
Xaa8是Glu或Lys(SEQ ID NO:86);
优选地是Glu Leu Leu Glu Arg Leu Leu Xaa Arg Leu,其中
Xaa是Glu或Lys(SEQ ID NO:27);
c)Ala Leu Ala Glu Ala Leu Ala Glu Ala Leu(SEQ ID NO:28);
d)Ser Leu Leu Ser Ser Leu Leu Ser Ser Leu(SEQ ID NO:29);
e)Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu(SEQ ID NO:30)。
另一方面,本发明提供了一种具有下式的PTH,PTHrP以及PTH和PTHrP生理活性类似物或其盐和其药学上可接受的盐的方法:
Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Leu His Asp Xaa11 Gly Xaa13 Ser Ile GlnAsp Leu Xaa19 Xaa20 Xaa21 Xaa22-31Xaa32 Xaa33 Xaa34 Xaa35 Xaa36 Xaa37 Xaa38 Term,其中:
Xaa1不存在或者是Ala;
Xaa2不存在或者是Val;
Xaa3不存在或者是Ser;
Xaa4不存在或者是Glu或Glu(OCH3);
Xaa5不存在或者是His或Ala;
Xaa6不存在或者是Gln;
Xaa7不存在或者是Leu;
Xaa11是Lys、Arg、或Leu;
Xaa13是Lys、Arg、Tyr、Cys、Leu、Cys(CH2CONH(CH2)2NH(生物素基))、Lys(7-二甲氨基-2-氧代-2H-1-苯并吡喃-4-乙酰基)、或Lys(二氢肉桂酰基);
Xaa20是Arg或Leu;
Xaa19和Xaa21分别是Lys、Ala、或Arg;
Xaa22-31选自SEQ ID NOS:85、86、26、27、28、29或30;
Xaa32是His、Pro、或Lys;
Xaa33不存在或者是Pro、Thr、Glu或Ala;
Xaa34不存在或者是Pro、Arg、Met、Ala、hSer、hSer内酯、Tyr或Leu;
Xaa35不存在或者是Pro、Glu、Ser、Ala或Gly;
Xaa36不存在或者是Ala、Arg或Ile;
Xaa37不存在或者是Arg、Trp或3-(-2-萘基)-L-丙氨酸;
Xaa38不存在或者是Ala或hSer或者Xaa38-42是Thr Arg Ser Ala Trp;
并且Term是OR或NR2,这里各R分别是H、(C1-C4)烷基或苯基(C1-C4)烷基。
另一方面,本发明包括合成如下式(I)所示的生理活性截短的同系物hPTHrp(1-34)之多肽类似物和它们的药学上可接受的盐的方法:
Ala Val Ser Glu Xaa5 Gln Leu Leu His Asp Xaa11 Gly Xaa13 Ser Ile GlnAsp Leu Xaa19 Arg Xaa21 Xaa22-31Xaa32 Xaa33 Xaa34Term,其中:
Xaa5是His或Ala;
Xaa11和Xaa13分别是Lys、Arg或Leu;
Xaa19和Xaa21分别是Ala或Arg;
Xaa22-31选自:
a)Glu Leu Leu Glu Lys Leu Leu Xaa Lys Leu,其中
Xaa是Glu或Arg(SEQ ID NO:26);
b)Glu Leu Leu Glu Arg Leu Leu Xaa Arg Leu,其中
Xaa是Glu或Lys(SEQ ID NO:27);
c)Ala Leu Ala Glu Ala Leu Ala Glu Ala Leu(SEQ ID NO:28);
d)Ser Leu Leu Ser Ser Leu Leu Ser Ser Leu(SEQ ID NO:29);
e)Ala Phe Tyr Asp LysVal Ala Glu Lys Leu(SEQ ID NO:30);
Xaa32是His或Lys;
Xaa33是Thr、Glu或Ala;
Xaa34是Ala、hSer、Tyr或Leu;
并且Term是Gly Arg Arg、内酯、OH或NR2,这里R是H或(C1-C4)烷基。
本发明的一个更特定的方面包括合成其中Xaa22-31是SEQ ID NO:26的式(I)的那些多肽,其<μH>在100°时超过0.45。本发明的另一个更特定的方面包括其中Xaa22-31是SEQ ID NO:26的那些式(I)的多肽;Xaa11和Xaa13两者是Lys;并且Xaa19和Xaa21两者都是Arg。可以用本文所公开的方法制备的代表性多肽包括但不限于:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Arg LysLeu His Thr Ala OH(SEQ ID NO:5);
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu LysLeu His Thr Ala OH(SEQ ID NO:6);
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu LysLeu His Thr Ala NH2(SEQ ID NO:7);
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGin Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu LysLeu His Thr hSer NH2(SEQ ID NO:8);
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu LysLeu His Thr hSerlac(SEQ ID NO:9);
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu LysLeu His Thr Ala Gly Arg Arg OH(SEQ ID NO:10);和
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu LysLeu Lys Glu Leu NH2(SEQ ID NO:11)。
本发明的另一方面包括其中Xaa22-31是SEQ ID NO:26的式(I)的那些多肽;Xaa11和Xaa13两者都是Lys;并且Xaa19和Xaa21两者之一是Arg,另一个是Ala。可以用本文所公开的方法制备的这一亚类的代表性多肽包括但不限于:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Ala Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu LysLeu His Thr Ala NH2(SEQ ID NO:12)和
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Ala Glu Leu Leu Glu Lys Leu Leu Glu LysLeu His Thr Ala NH2(SEQ ID NO:13)。
本发明的另一方面包括其中Xaa22-31是SEQ ID NO:26的式(I)的那些多肽;Xaa11和Xaa13两者之一是Leu,另一个是Lys;并且Xaa19和Xaa21两者都是Arg。可以用本文所公开的方法制备的这一亚类的代表性多肽包括但不限于:
Ala Val Ser Glu Ala Gln Leu Leu His Asp Leu Gly Lys Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu LysLeu His Ala Leu OH(SEQ ID NO:14)。
另一方面,本发明包括合成其中Xaa22-31是SEQ ID NO:27的式(I)的那些多肽,其<μH>在100°时超过0.50。本发明的另一方面包括合成其中Xaa22-31是SEQ ID NO:27的那些式(I)的多肽;Xaa11和Xaa13两者是Lys或者两者是Arg;并且Xaa19和Xaa21两者都是Arg。可以用本发明的方法制备的这一亚类的代表性多肽包括但不限于:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu ArgLeu His Thr Ala OH(SEQ ID NO:15);
Ala Val Ser Glu His Gln Leu Leu His Asp Arg Gly Arg Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu ArgLeu His Thr Ala OH(SEQ ID NO:16);
Ala Val Ser Glu His Gln Leu Leu His Asp Arg Gly Arg Ser IleGln Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Lys ArgLeu His Thr Ala OH(SEQ ID NO:17);
另一方面,本发明包括合成其中Xaa22-31是SEQ ID NO:28的式(I)的那些多肽,其<μH>在100°时约0.25。可以用本发明的方法制备的这一亚类的代表性多肽包括但不限于:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Ala Leu Ala Glu Ala Leu Ala Glu AlaLeu His Thr Ala NH2(SEQ ID NO:20)。
另一方面,本发明包括合成其中Xaa22-31是SEQ ID NO:29的式(I)的那些多肽,其<μH>在100°时约0.28。可以用本发明的方法制备的这一亚类的代表性多肽包括但不限于:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Ser Leu Leu Ser Ser Leu Leu Ser SerLeu His Thr Ala NH2(SEQ ID NO:21)。
另一方面,本发明包括合成其中Xaa22-31是SEQ ID NO:30的式(I)的那些多肽,其<μH>在100°时约0.29。可以用本发明的方法制备的这一亚类的代表性多肽包括但不限于:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser IleGln Asp Leu Arg Arg Arg Ala Phe Tyr Asp Lys Val Ala Glu LysLeu His ThrAla NH2(SEQ ID NO:22)
另一方面,本发明包括合成如式(II)所示的bPTH(1-34)的生理活性同系物的多肽类似物和其药学上可接受的盐:
Xaa1 Val Ser Glu Ile Gln Xaa7 Xaa8 His Asn Leu Gly Lys HisLeu Xaa16 Ser Xaa18 Xaa19 Arg Xaa21 Xaa22-31His Asn Xaa34Term,其中:
Xaa1是Ser或Ala;
Xaa7是Leu或Phe;
Xaa8是Met或Nle;
Xaa16是Asn或Ser;
Xaa18是Leu、Met或Nle;
Xaa19是Glu或Arg;
Xaa21是Val或Arg;
Xaa22-31选自SEQ ID NO:26、27、28、29和30;
Xaa34是Phe或Tyr;
Term是OH或NR2,这里各R是H或(C1-C4)烷基。
可以用本发明的方法合成的代表性多肽包括但不限于:
Ala Val Ser Glu Ile Gln Phe Nle His Asn Leu Gly Lys His LeuSer Ser Nle Glu Arg Val Glu Leu Leu Glu Lys Leu Leu Glu LysLeu His Asn Tyr NH2(SEQ ID NO:23)和
Ala Val Ser Glu Ile Gln Phe Nle His Asn Leu Gly Lys His LeuSer Ser Nle Arg Arg Arg Glu Leu Leu Glu LysL eu Leu Glu LysLeu His Asn Tyr NH2(SEQ ID NO:24)。
另一方面,本发明提供了合成具有少于34个氨基酸的PTH和PTHrP类似物的方法。这些化合物具有以下通式:
Ala Val Ser Glu Xaa5 Gln Leu Leu His Asp Xaa11 Gly Xaa13 SerIle Gln Asp Leu Xaa19 Arg Xaa21 Xaa22-31 Xaa32 Xaa33 Xaa34 Term,
可以用本发明的方法制备的代表性多肽包括但不限于:
化合物41:AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHP-NH2
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile
1 5 10 15
Gln Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys
20 25 30
Leu His Pro NH2(SEQ ID NO:55)
化合物42:AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LP-NH2
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile
1 5 10 15
Gln Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys
20 25 30
Leu Pro NH2(SEQ ID NO:56)
技术人员清楚,所述多肽类似物的许多取代体可被合成,倘若具有在100°±20°时的大于0.20的平均疏水因素(每个残基)的氨基酸序列在位置22-31插入,则所述取代体将具有本文所描述的那些的理想的属性。
本发明的多肽片段可以由以下文献中提出的那些方法合成:G.Barany,R.B.肽中的修饰,E.Gross和J.Meienhofer编者,学术出版社,纽约(1979),Vol.2,pp.1-284;J.M.Stewart和J.D.Young,固相肽的合成,第二板,Pierce化学公司,Rockford,Illinois(1984),和J.Meienhofer,激素蛋白质和肽,Vol.2,学术出版社,纽约(1973)(有关固相合成),以及E.Schroder和K.Lubke,肽,Vol.1,学术出版社,纽约(1965)(有关溶液合成)。一般来说,这些方法包括依次添加保护的氨基酸来增长肽链。通常第一氨基酸的氨基或羧基基团和任何反应性侧链基团被保护。然后将这种保护的氨基酸连接到固体支持物上或者使用在溶液中,也被适当保护的下一个氨基酸依次在能够形成酰胺键的条件下添加。最后,所需氨基酸被以合适的顺序连接,除去保护基和任何固体支持物,产生粗的多肽。将这种多肽脱盐和纯化,优选地是用色谱纯化,获得最终产物。
在本发明的实践中,前体肽片段可以用溶液或固相技术或者其任何组合制备。例如,可以在溶液中制备一些片段,然后缩合成树脂结合的C-末端片段,或者可以经固相方法制备各片段,从树脂上切下,并在溶液中缩合,或者可以采用溶液和固相合成的混合方案。
制备本发明的具有少于约40个氨基酸的PTH和PTHrP类似物的一种优选的方法涉及固相片段缩合肽合成。按这种方法,最终产物由若干肽前体片段的缩合产生。依技术人员的爱好,可以使用任何片段的组合。例如34个氨基酸的产物可以从两个17个氨基酸的肽前体片段,三个不同长度的前体片段,四个前体片段等制备。说明性的讨论参见P.LLoyd-Williams等,″集合性固相肽合成″,Tetrahedron,49,11065-11133,(1993)。
一般地,α-氨基(Nα)功能基和任何反应性侧链用酸-或碱-敏感基团保护。所述保护基应该对肽键形成条件稳定,而且易于除去并不影响延长的多肽链。合适的氨基保护基包括但不限于:叔丁氧羰基(Boc)、苯氧羰基(Cbz)、O-氯苄氧羰基、二苯基异丙氧羰基、叔戊氧羰基(Amoc)、异冰片氧羰基、α,α-二甲基-3,5-二甲氧苄氧羰基、对硝基苯基亚氧硫基、2-氰基-叔丁氧羰基,优选的是9-芴基(fluorenyl)甲氧羰基(Fmoc)。合适的侧链保护基包括但不限于:乙酰基、苄基(Bzl)、苄氧甲基(Bom)、叔丁基、环己基、邻溴苄氧羰基、叔丁基二甲基甲硅烷基、2-氯苄基(C1-z)、2,6-二氯苄基、2,4-二硝基苯基、环戊基、异丙基、新戊酰、四氢吡喃-2-基、甲苯磺酰基(Tos)、三甲基甲硅烷基、甲基三苯甲基、果磺酰(Mts)、4-甲氧-2,3,6-三甲基苯磺酰基(Mtr)、2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基(Pbf)、2,2,5,7,8-五甲基苯并二氢吡喃-6-磺酰(Pmc)和三苯甲基(Trt)。
在固相合成中,C-末端氨基酸是首先连接到合适的树脂支持物上的。合适的树脂支持物是对试剂和逐步缩合和去保护反应的反应条件呈惰性并且在所使用的介质中不溶性的那些材料。市售的树脂的例子包括用反应性基团改性的苯乙烯/二乙烯基苯树脂,例如,氯甲基化的共-聚(苯乙烯-二乙烯基苯)、羟甲化物的共-聚(苯乙烯-二乙烯基苯)和苄化的,羟甲基化的苯基乙酰氨基甲基(PAM)树脂。为制备酸末端肽,可以使用Wang树脂。一种优选的树脂是对甲基二苯甲氨基-共-聚(苯乙烯-二乙烯基苯)树脂(MBHA)。
在优选的实施方案中,除C-末端片段之外,所有片段都在一种酸敏感的树脂上制备,所述树脂例如Sasrin(2-甲氧基4-烷氧基苄醇)或4-羟甲基-3-甲氧苯氧丁酸4-甲基二苯甲胺(HMPB-MBHA)。HMPA-MBHA、HMPB-BHA和HMPA-BHA树脂也适用于羧基终止(terminated)肽。利用Knorr处理-MBHA树脂制备C-末端片段。Sieber酰胺树脂、Rink接头-MBHA或BHA树脂、和Ramage接头-MBHA或BHA树脂都适用于酰胺终止肽。这些树脂是市售的,其第一氨基酸已被结合或者第一氨基酸可以连接到接头上。HMPB-MBHA和Knorr处理树脂可以按以下实施例1,2和3中的描述从MBHA树脂制备。可以用本领域熟知的方法进行剩下的保护的氨基酸的后续连接。最好将各保护的氨基酸以约1.5到2.5倍摩尔过量引入,连接在惰性、非水、极性溶剂中进行,所述溶剂例如N-甲基吡咯烷酮(NMP)、二氯甲烷、N,N-二甲基甲酰胺(DMF)、二甲亚砜(DMSO)或它们的混合物,优选的是在室温下进行。代表性的连接剂是N,N-二环己基-碳化二亚胺(DCC)、N,N-二异丙基碳化二亚胺(DIC)或其它碳化二亚胺,它们单独使用或者在下列物质存在下使用:1-羟基苯并三唑(HOBt)、O-酰基尿素、苯并三唑-1-基-氧三(oxytris)(吡咯烷)磷六氟磷酸盐(PyBop)、N-羟基琥珀酰亚胺、其它N-羟基酰亚胺或肟。另外,也可以使用保护的氨基酸活性酯(例如,硝基苯基、五氟苯基等)或对称的酸酐。后续Fmoc-保护的氨基酸的连接用仲胺(例如吡啶)溶液进行,以除去Fmoc基。在各连接步骤后经Kaiser试验检查肽树脂的完全连接。
在固相合成的最后,采用不导致侧链保护基过早去保护的条件从树脂上除去完全保护的肽。可以经皂化或酯交换或温和的酸性去保护法(采用例如1%三氟乙酸(TFA))切下所述的肽。可以用硅胶色谱纯化保护的肽。
可以使溶液脱盐(例如,用BioRad AG-3阴离子交换树脂),并用任何或所有下列类型的系列色谱步骤纯化所说的肽:在未衍生化的(underivatized)共-聚(苯乙烯-二乙烯基苯)(例如AmberliteXAD)上的疏水吸附色谱;硅胶吸附色谱;在羧甲基纤维素上的阳离子交换色谱;分配色谱(例如在SephadexG-25上);逆流分配;反相高效液相色谱(HPLC),尤其是阳离子交换和在辛基-或十八基甲硅烷基二氧化硅(ODS)键合相填充柱上的反相HPLC。
在一个多片段合成的实施方案中,分离中部和N-末端片段并连续缩合到C-末端片段上。使所述多肽去保护,并从树脂上切下,进一步纯化。纯化步骤一般是一系列色谱分离。HPLC分析决定纯化方法的顺序和选择。一种典型的顺序包括阳离子交换、反相HPLC和反相浓缩柱。对最终的溶液进行冷冻干燥,将药物产物保存在琥珀色瓶子中。保护的氨基酸是从Genzyme(剑桥,MA,美国)、Propeptide(普林斯顿,NJ,美国)或Synthetec(Albany,OR,美国)获得的。
实施例
采用三-片段缩合法制备SEQ ID NO:7的多肽,一个34个氨基酸的肽,AVSEHQLLHDKGKSIQDLRR RELLEKLLEKLHTA-NH2。N-末端片段是由氨基酸1至12组成的,中部片段是由氨基酸13至23组成的,C-末端片段是由氨基酸24至34组成的。在Vega 296自动肽合成仪上经固相法制备各片段。自动模式用于切下Nα-保护基和连接后的洗涤。在连接步骤中手工将连接试剂和溶剂添加到反应器中。经HPLC纯化中部和N-末端片段,并连续缩合到C-末端片段上。使最终的肽去保护,从树脂上切下,并纯化。
实施例1 制备N-末端片段
以250毫摩尔规模在酸敏感树脂(4-羟甲基-3-甲氧苯氧丁酸4-甲基二苯甲胺(HMPB-MBHA))上制备由氨基酸1至12组成的N-末端片段(AVSEHQLLHDKG)。这一树脂是按如下方法从MBHA树脂(Novabiochem)制备的:
步骤 | 内容 | 时间(分钟) | 重复 |
1.2.3.4.5.26.27.18.29.3 | CH2Cl2/DMF(1/1)洗涤在CH2Cl2中的10%Et3NCH2Cl2/DMF(1/1)5HMPB接头(1.15当量)/在CH2Cl2/DMF(1/1)中的PyBOP/DIPEACH2Cl2洗涤DMF洗涤CH2Cl2洗涤i-PrOH洗涤CH2Cl2洗涤 | 6053300@40C500@RT | 1211.51.51.51.51.5 |
在至少一次DMF CH2Cl2洗涤后,按以下方案用Fmoc-GlyOH(1.5-2.2当量)、DIC(1.5-2.2当量)和DMAP(0.05当量)在DMF/CH2Cl2(1/1)中于
室温下进行第一氨基酸(12Gly)的连接大约15小时:
步骤 | 内容 | 时间(分钟) | 重复 |
1.2.13.4.25.26.7.28. | DMF/CH2Cl2(1/1)Fmoc-X-OH(2当量)/在CH2Cl2/DMF(1/1)中的DIC-DMAP(0.05当量)CH2Cl2洗涤DMF洗涤i-PrOH洗涤DMF/CH2Cl2(1/1)i-PrOHCH2Cl2洗涤 | 601.51.51.5 | 190021.51.521.53 |
然后通过重复步骤3到8洗涤树脂,采用以下方案加帽:
步骤 | 内容 | 时间(分钟) | 重复 |
9.110.111.212.2 | DMF在DMF/CH2Cl2中的PhCOCl(0.18M)/吡啶(0.36M)CH2Cl2洗涤DMF洗涤 | 1530-1801.51.5 |
13.214.115.3 | i-PrOH洗涤DMF/CH2Cl2(1/1)洗涤CH2Cl2洗涤 | 1.51.51.5 |
在后续结合循环中以相反(reverse)顺序采用下列保护的氨基酸将剩下的氨基酸连接到树脂上:
aa11 Nα-Fmoc-Nε-叔丁氧羰基-L-赖氨酸
aa10 Nα-Fmoc-L-天冬氨-β-叔丁基酯
aa9 Nα-Fmoc-Nim-三苯甲基-L-组氨酸
aa8 Nα-Fmoc-L-亮氨酸
aa7 Nα-Fmoc-L-亮氨酸
aa6 Nα-Fmoc-Ng-三苯甲基-L-谷氨酰胺
aa5 Nα-Fmoc-Nim-三苯甲基-L-组氨酸
aa4 Nα-Fmoc-L-谷氨酸-_-叔丁基酯
aa3 Nα-Fmoc-O-叔丁基-L-丝氨酸
aa2 Nα-Fmoc-L-缬氨酸
aal Nα-叔丁氧羰基-L-丙氨酸
使用1.5至2.2当量氨基酸(0.1-0.25M)、HOBt和DIC于室温下在NMP中进行连接。在1.5-3小时后,添加DMSO,并且使连接反应继续1.5-3小时。各连接反应包括以下步骤:
步骤 | 内容 | 时间(分钟) | 重复 |
1.12.3.4.2 | DMF洗涤在NMP中的20%哌啶在NMP中的20%哌啶DMF洗涤 | 314 | 2.5-30111.5 |
5.26.2-57.2-38.19.210.211.212.213.114.3 | CH2Cl2洗涤i-PrOH洗涤DMF/CH2Cl2(1/1)洗涤连接CH2Cl2洗涤DMF洗涤i-PrOH洗涤DMF/CH2Cl2洗涤i-PrOHCH2Cl2洗涤 | 1.51.5-2.51.52401.51.51.51.51.51.5 |
用Kaiser试验证实连接反应的完成;如果试验是阳性,则重复步骤8至14,可以用也可以不用PyBOP作为偶合剂。
为了从树脂切下保护的肽,于0℃或室温下在1%TFA(CH2Cl2中)中搅拌树脂的悬液(4ml/gm树脂)至多15分钟。将溶液过滤,并以5%NaHCO3提取。重复树脂的TFA处理三次。合并有机相,并用水、5%NaHSO4和水(再次)洗涤。在硫酸钠上干燥并蒸发有机相。经如下HPLC纯化剩余物:
柱:Zorbax Pro-10/150 C8,6″×40cm
柱温:环境温度
流速:2.2-3.0ml/分钟·厘米2
检测波长:250nm
流动相:0.1%HOAc(pH6-6.2)和三乙胺、CH3CN
将保护的肽上柱(65-70%CH3CN)。增加CH3CN的比例至85%进行梯度洗脱。合并各组份,浓缩,经CH2Cl2抽取分离产物。用碳酸氢钠稀溶液和水洗涤有机相,用硫酸钠干燥,过滤并蒸发。
实施例2 制备中部片段
以230毫摩尔规模在酸敏感树脂(4-羟甲基-3-甲氧苯氧丁酸4-甲基二苯甲胺(HMPB-MBHA))上制备由氨基酸13至23组成的中部片段,KSIQDLRRREL。这一树脂是按以上实施例1描述的方法从MBHA树脂制备的。如所示用Fmoc-L-亮氨酸掺合进第一氨基酸(aa24)。用实施例1的方法在后续连接循环中将剩下的氨基酸连接到树脂上:
aa23 Nα-Fmoc-L-谷氨酸-_-叔丁基酯
aa22 Nα-Fmoc-Ng-4-甲氧基-2,3,6-三甲苄磺酰基-L-精氨酸
aa21 Nα-Fmoc-Ng-4-甲氧基-2,3,6-三甲苄磺酰基-L-精氨酸
aa20 Nα-Fmoc-Ng-4-甲氧基-2,3,6-三甲苄磺酰基-L-精氨酸
aa19 Nα-Fmoc-L-亮氨酸
aa18 Nα-Fmoc-L-天冬氨酸-β-叔丁基酯
aa17 Nα-Fmoc-Ng-三苯甲基-L-谷氨酰胺
aa16 Nα-Fmoc-L-异亮氨酸
aa15 Nα-Fmoc-O-叔丁基-L-丝氨酸
aa14 Nα-Fmoc-Nε-叔丁氧羰基-L-赖氨酸
按实施例1的教导从树脂上以游离酸切下肽,抽提有机物,干燥并蒸发。通过溶解到二氯甲烷中,并添加进叔丁基甲基醚(t-BuOMe)沉淀剩余物。过滤后,用t-BuOMe洗涤并真空干燥,产物在以上描述的Zorbax柱上经HPLC纯化,用75%CH3CN无梯度洗脱;检测波长为267nm。
实施例3 制备C-末端片段
按以下步骤使用Fmoc-2,4-二甲氧-4′-(羧甲氧)-二苯甲胺接头在MBHA树脂上以130mm规模制备由氨基酸24-34组成的C-末端片段,LEKLLEKLHTA:
步骤 | 内容 | 时间(分钟) | 重复 |
1.2.3.4.5.16.7.8.29.10.211.12.13.14.15.216.217.18.3 | CH2Cl2洗涤在CH2Cl2中的10%DIPEACH2Cl2DMF在CH2Cl2/DMF(1/1)中的接头/HOBt/DIC(1.5当量)CH2Cl2DMFiPrOHCH2Cl2/DMFiPrOHCH2Cl2在DMF/CH2Cl2中的DMF在DMF/CH2Cl2中的Ac2O,DIPEACH2Cl2洗涤DMF洗涤i-PrOH洗涤DMF/CH2Cl2洗涤CH2Cl2洗涤 | 605551.51.51.51.51030-351.51.5 | 1233300-420222.522.531121.51.511.5 |
在后续结合循环中以相反顺序采用下列保护的氨基酸将剩下的氨基酸连接到树脂上:
aa34 Nα-Fmoc-L-丙氨酸
aa33 Nα-Fmoc-O-叔丁基-L-苏氨酸
aa32 Nα-Fmoc-Nim-三苯甲基-L-组氨酸
aa31 Nα-Fmoc-L-亮氨酸
aa30 Nα-Fmoc-Nε-叔丁氧羰基-L-赖氨酸
aa29 Nα-Fmoc-L-谷氨酸-γ-叔丁基酯
aa28 Nα-Fmoc-L-亮氨酸
aa27 Nα-Fmoc-L-亮氨酸
aa26 Nα-Fmoc-Nε-叔丁氧羰基-L-赖氨酸
aa25 Nα-Fmoc-L-谷氨酸-γ-叔丁基酯
aa24 Nα-Fmoc-L-亮氨酸
使用1.5至2.2当量氨基酸、HOBt和DIC于室温下在NMP中进行连接1.5-3小时(对氨基酸34至36)。对氨基酸24和25,使用3当量的氨基酸、HOBt和DIC。1.5-3小时后,添加20%DMSO,并且使连接反应继续1.5-3小时,各连接反应涉及以下步骤,包括Fmoc断裂和连接后洗涤:
步骤 | 内容 | 时间(分钟) | 重复 |
1.2.3.4.5.6.7.8.9.10.11.12.13.14.Kaiser试验15.16. | DMF洗涤在NMP中的20%哌啶在NMP中的20%哌啶DMF洗涤CH2Cl2洗涤i-PrOH洗涤DMF/CH2Cl2洗涤连接CH2Cl2洗涤DMF洗涤i-PrOH洗涤DMF/CH2Cl2洗涤iPrOH洗涤CH2Cl2洗涤DMFAc2O/DIPEA/ | 2.5-303141.51.51.5-2.51.52401.51.51.5-2.51.52.51.52.5-1530-35 | 111322-63122222311 |
17.18.19.20.21. | CH2Cl2/DMFCH2Cl2洗涤DMF洗涤i-PrOH洗涤DMF/CH2Cl2洗涤CH2Cl2洗涤 | 1.51.51.51.51.5 | 22213 |
用Kaiser试验证实连接反应的完成;如果试验是阳性(_1.5%未偶合),则重复步骤8至14,如果试验是阴性,则树脂被乙酰化。
实施例4 缩合三种片段
如以上实施例1,2和3所述制备三种片段。用以上最后描述的实施例3的方案的步骤1-7除去C-末端片段的保留的Nα-Fmoc基团。
将中部片段B(172g,61.8毫摩尔)、HOBt(59.2毫摩尔)、HOAt(3.7毫摩尔)和DIC(61.9毫摩尔)添加到在NMP(900ml)和CH2Cl2中的C-末端片段树脂(190g,41毫摩尔)上。将混合物在室温搅拌22小时。添加DIPEA(7ml),并且继续搅拌另一天。如实施例1所述(步骤9至13)洗涤树脂。Kaiser试验显示出少于2%的未结合的剩余物。乙酰化树脂(实施例3,步骤14至20)并除去Fmoc基团(实施例3,步骤1至7)。
将钠盐形式的N-末端片段A(153g,62.4毫摩尔)、HOBt(59.2毫摩尔)、HOAt(3.7毫摩尔),PyBOP(62.5毫摩尔)和DIPEA(125.15毫摩尔)添加到在NMP(900ml)和CH2Cl2中的树脂上。将混合物在室温搅拌24小时。过滤并洗涤(实施例3,步骤9-13)。Kaiser试验显示出少于1%的未结合的剩余物。使树脂乙酰化(实施例3,步骤14至20),从反应器中除去,并在真空下干燥。
在N2下,将在苯硫基甲烷(152.6ml)和TFA(1L)中的苯酚(60.3g)溶液添加到肽-树脂(64g)上。将混合物冷却至-10℃,缓慢添加TMSBr。在一封闭系统中于-10℃下搅拌混合物0.5小时,于室温下搅拌1-2小时。于50℃在真空下将混合物浓缩至一半体积,过滤树脂,用TFA(250ml)和冰醋酸(250ml)洗涤两次。通过添加叔丁基甲基醚∶己烷的3∶1的混合物(6.5L)使滤液沉淀。过滤粗肽,用叔丁基甲基醚、甲苯和叔丁基甲基醚(各2×250ml)洗涤,通过在甲醇(500ml)中溶解并加入到叔丁基甲基醚(7L)中再沉淀。过滤粗产物,以叔丁基甲基醚洗涤,在真空下干燥,产生肽33g。
用合适的树脂来代替酸终止(terminated)肽,以同样的方式可以制备下列PTHrP类似物:
AVSEHQLLHDKGKSIQDLRRRELLEKLLEKLHTA-OH(SEQ ID NO:6)
AVSEHQLLHDKGKSIQDLRRRELLERLLERLHTA-OH(SEQ ID NO:15)
AVSEHQLLHDRGRSIQDLRRRELLERLLERLHTA-OH(SEQ ID NO:16)
AVSEHQLLHDRGRSIQDLRRRELLERLLKRLHTA-OH(SEQ ID NO:17)
AVSEHQLLHDKGKSIQDLRRRELLEKLLRKLHTA-OH(SEQ ID NO:5)
AVSEHQLLHDKGKSIQDLRRRE LLEKLLEKLHTAGRR-OH(SEQ ID NO:10)
AVSEAQLLHDLGKSIQDLRRRELLEKLLEKLHAL-OH(SEQ ID NO:14)
AVSEHQLLHDKGKSIQDLRRRELLEKLLELLKE L-NH2(SEQ ID NO:11)
AVSEIQFXHNLGKHLSSXERVELLEKLLEKLHNY-NH2(X=Nle,SEQ ID NO:23)
AVSE IQFXHNLGKHLSSXRRRELLEKLLEKLHNY-NH2(X=Nle,SEQ ID NO:24)
AVSEHQL LHD KGKSIQDLRRRALAEALAEALHTA-NH2(SEQ ID NO:20)
AVSE HQLLHDKGKSIQDLARRE LLEKLLEKLHTA-NH2(SEQ ID NO:12)
AVSEHQLLHDKGKSIQDLRRAELLEKLLEKLHTA-NH2(SEQ ID NO:13)
AVSEHQLLHDKGKSIQDLRRRSLLSSLLSSLHTA-NH2(SEQ ID NO:21)
AVSEHQLLHDKGKSIQDLRRRAFYDKVAEKLHTA-NH2(SEQ ID NO:22)
AVSEIQFLHN LGKHLSSLRR RELLEKLLEK LHNY-NH2(SEQ ID NO:35)
AVSEHQLLHD KGKSIQDLKL KELLEKLLEK LHTA-NH2(SEQ ID NO:38)
AVSEHQLLHD KGKSIQDLRR RELLERLLER LHTA-NH2(SEQ ID NO:39)
AVSEHQLLHD KGKSIQDLRR RELLERLLER LHTAP-OH(SEQ ID NO:40)
AVSEHQLLHD KGKSIQDLRR RELLERLLER LHTAGRR-OH(SEQ ID NO:41)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTY-NH2(SEQ ID NO:43)
AVSEHQLLHD KGYSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:44)
AVSEHQLLHD KGCSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:45)
AVSEHQLLHD KGXSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:46)(X=Cys(CH2CONH(CH2)2NH(生物素基)))
AVSEHQLLHD KGXSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:47)(X=Lys(7-二甲氨基-2-氧代-2H-1-苯并吡喃-4-乙酰基))
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAG-OH(SEQ ID NO:48)
AVSX1HQLLHX2 KGKSIQX2LRR RX1LLX1KLLX1K LHA-OH(SEQ ID NO:49)(X1=Glu(OCH3);X2=Asp(OCH3))
AVSX1HQLLHX2 KGKSIQX2 LRR RX1LLX1KLLX1K LHA-OCH3(SEQ ID NO:50)(X1=Glu(OCH3);X2=Asp(OCH3))
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAP-OH(SEQ ID NO:52)AVSEHQLLHDKGKSIQDLRR RELLEKLLEK LHTP-OH(SEQ ID NO:53)AVSEHQLLHD KGKSIQDLRRRELLEKLLEK LHTP-NH2(SEQ ID NO:54)AVSEHQLLHD KGKSIQDLRR RELLEKLLEKLHP-NH2(SEQ ID NO:55)AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LP-NH2(SEQID NO:56)AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTRSAW-OH(SEQ ID NO:57)AVSEHQLLHD RGRSIQDLRR RELLERLLER LHTAGRRTRSAW-OH(SEQ ID NO:58)AVSEHQLLHD RGRSIQDLRR RELLERLLER LHTAGRRTRSAW-NH2(SEQ ID NO:59)AVSEHQLLHD RGXSIQDLRR RELLERLLER LHTAGRRTRSAW-OH(SEQ ID NO:60)(X=Lys(二氢肉桂酰基))
AVSEIQFXHN LGKHLSSXTR SAWLRKKLQD VHNY-NH2(SEQ ID NO:61)(X=正亮氨酸)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTMA-NH2(SEQ ID NO:62)AVSEHQLLHDKGKSIQDLRR RFFLEKLLEK LHTA-NH2(SEQ ID NO:64)AVSEHQLLHD KGKSIQDLRRRELLHKLLEK LHTA-NH2(SEQ ID NO:65)AVSEHQLLHD KGKSIQDLRR RELLEHLLEKLHTA-NH2(SEQ ID NO:66)
AVSEHQLLHD KGKSIQDLRR RELLEKLIAK LHTA-NH2(SEQ ID NO:67)AVSEHQLLHDKGKSIQDLRR RELLEKLLEE IHTA-NH2(SEQ ID NO:68)AVSEHQLLHD KGKSIQDLRRRELLEKLLEK LHTRSAW-NH2(SEQ ID NO:72)AVSEHQLLHD KGKSIQDLRRRELLEKLLEK LHTRSAX-OH(SEQ ID NO:73)(X=Nal(2)=3-(2-萘基)-L-丙氨酸)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTASAW-OH(SEQ ID NO:74)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAEIRA-OH(SEQ ID NO:75)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAEIR-OH(SEQ ID NO:76)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAEI-OH(SEQ ID NO:77)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAE-OH(SEQ ID NO:78)
SEHQLLHD KGKSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:80)
LLHD KGKSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:81)
LHD KGKSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:82)
SEHQLLHD RGRSIQDLRR RELLERLLER LHAGRRTRSAW-OH(SEQ ID NO:83)
LLHD RGRSIQDLRR RELLERLLER LHAGRRTRSAW-OH(SEQ ID NO:84)
按照以上的方法可以制备和纯化[Met34,Ala35](SEQ ID NO:25),(AVSEHQLLHDKGKSIQDLRRRE LLEKLLEKLHTMA-NH2,SEQ ID NO:25)。按以下所述可以将这一多肽转化成高丝氨酸内酯。将纯化的肽溶解在44%甲酸中。在0℃将这一溶液与溴化氰(700mg)与苯酚(1.6mg)在44%甲酸中的预混合溶液混合。于0℃搅拌所述溶液2小时,于室温下搅拌2小时。可以用HPLC(VydacC-18,300A°,4.6×250mm,流速1.2ml/分钟,在0.1%TFA中的25-45%乙腈梯度洗脱10分钟)监测产物的形成。浓缩样品,并用制备型RP-HPLC(VydacC-18,在0.1%TFA中的25-45%乙腈梯度洗脱)纯化,产生SEQ ID NO:9。
AVSEHQLLHDKGKSIQDLRR RELLEKLLEKLHTX(X=hSerlac,SEQ ID NO:9)
同样地,可以按照这一方法制备SEQ ID NO:79。
AVSEIQFX1HN KGKHLSSX1ER VEWLRKKLQD VHNX2(SEQ ID NO:79)(X1=L-正亮氨酸;X2=高丝氨酸内酯)
为了制备高丝氨酸酰胺,将粗hSer内酯类似物(化合物4)浓缩,用25ml甲醇中饱和的NH3处理。于0℃搅拌所述溶液2小时,于室温下搅拌16小时。可以用HPLC(VydacC-18,300A°,4.6×250mm,流速1.2ml/分钟,在0.1%TFA中的20-45%乙腈梯度洗脱10分钟)监测反应。浓缩溶液,并用制备型RP-HPLC(VydacC-18,在0.1%TFA中的25-45%乙腈梯度洗脱)纯化,收集高丝氨酸酰胺肽部分并冻干,产生SEQ ID NO:8。AVSEHQLLHDKGKSIQDLRRRELLEKLLEKLHTX-NH2(X=hSer,SEQ ID NO:8)
同样地,用甲硫氨酸作为C-末端,可以用这一方法制备化合物22、23和28。
AVSEIQFLHN LGKHLSSLRR RELLEKLLEK LHNX-NH2(SEQ ID NO:36)(X=高丝氨酸)
AVSEIQFLHN KGKHLSSLRR RELLEKLLEK LHNX-NH2(SEQ ID NO:37)(X=高丝氨酸)
AVSEHQLLHD KGKSIQDLRR RELLERLLER LHTAGRRX-NH2(SEQ ID NO:42)(X=高丝氨酸)
通过在包含过量的相应烷基胺的DMF中溶解高丝氨酸内酯,类似地从高丝氨酸内酯制备高丝氨酸烷基酰胺。在室温下搅拌几天后(反应可以用分析型HPLC监测),将混合物蒸发至干,用制备型HPLC纯化肽。代表性的高丝氨酸烷基酰胺是化合物55和56。
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTX-NHCH2CH3(SEQ ID NO:69)(X=高丝氨酸)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTX-NHCH2CH2C6H5(SEQ ID NO:70)(X=高丝氨酸)
以上高丝氨酸内酯类似物含水溶液也可以用猪肝脏酯酶(西格马化学公司,圣路易斯,MO)处理。可以用分析型HPLC监测所述内酯向C-末端高丝氨酸的水解。当判断出水解完全时,可以按如上所述经制备型HPLC纯化所述的物质。
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTX-OH(SEQ ID NO:51)(X=高丝氨酸)
尽管本发明通过用公开从3个片段合成34个氨基酸多肽的方法例证性说明,但其同样适用于从不同片段合成不同长度的PTH和PTHrP类似物。一般地,谷氨酸、甘氨酸、亮氨酸和脯氨酸是理想的片段C-末端。在前面的实施例中,在片段2和3之间的亮氨酸-亮氨酸连接给出了意想不到的高产率。同样地,亮氨酸-亮氨酸连接可以被从片段1-7、8-23、24-27和28-34制备SEQ ID NO:7的多肽所采用。在另一个实施方案中,当氨基酸24-27(LEKL)与28-31相同时,通过溶液或固相技术可以制备4个氨基酸的片段,缩合其自身给出片段24-31。此外,可以制备4个氨基酸的片段23-26(LLEK)并使其自身缩合给出23-30片段。使用易于结晶的较小片段可以使纯化容易进行。然而,片段数量的增加需要更多的片段缩合步骤。
序列表(1)一般信息:
(i)申请人:F.HOFFMANN-LA ROCHE AG
(ii)发明名称:合成甲状旁腺素类似物和甲状旁腺素相关肽的方法
(iii)序列数:86
(iv)通讯地址:
(A)收信人:F.HOFFMANN-LA ROCHE AG
(B)街道:Grenzacherstrasse 124.
(C)城市:Basle
(D)州:BS
(E)国家:瑞士
(F)邮编:CH-4070
(v)计算机可读形式:
(A)介质类型:软盘
(B)计算机:IBM PC兼容机
(C)操作系统:PC-DOS/MS-DOS
(D)软件:PatentIn Release #1.0,版本# 1.25(2)SEQ ID NO:1的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:1:
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Asn
1 5 10 15
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30
Asn Phe(2)SEQ ID NO:2的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:2:
Ala Val Ser Glu Ile Gln Phe Met His Asn Leu Gly Lys His Leu Ser
1 5 10 15
Ser Met Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30
Asn Phe(2)SEQ ID NO:3的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:3:
Ser Val Ser Glu Ile Gln Leu Met His Asn Leu Gly Lys His Leu Ser
1 5 10 15
Ser Leu Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30
Asn Phe(2)SEQ ID NO:4的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:4:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gin
1 5 10 15
Asp Leu Arg Arg Arg Phe Phe Leu His His Leu Ile Ala Glu Ile His
20 25 30
Thr Ala(2)SEQ ID NO:5的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:5:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gin
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Arg Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:6的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:6:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:7的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:7:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:8的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:34
(D)其它信息:/注=″Xaa34=高丝氨酸″
(xi)序列描述:SEQ ID NO:8:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Xaa(2)SEQ ID NO:9的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:34
(D)其它信息:/注=″Xaa34=高丝氨酸内酯″
(xi)序列描述:SEQ ID NO:9:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Xaa(2)SEQ ID NO:10的信息:
(i)序列特征:
(A)长度:37个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(xi)序列描述:SEQ ID NO:10:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala Gly Arg Arg
35(2)SEQ ID NO:11的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:11:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu Lys
20 25 30
Glu Leu(2)SEQ ID NO:12的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:12:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Ala Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:13的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:13:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Ala Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:14的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:14:
Ala Val Ser Glu Ala Gln Leu Leu His Asp Leu Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Ala Leu(2)SEQ ID NO:15的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:15:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His
20 25 30
Thr Ala(2)SEQ ID NO:16的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:16:
Ala Val Ser Glu His Gln Leu Leu His Asp Arg Gly Arg Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His
20 25 30
Thr Ala(2)SEQ ID NO:17的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:17:
Ala Val Ser Glu His Gln Leu Leu His Asp Arg Gly Arg Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Lys Arg Leu His
20 25 30
Thr Ala(2)SEQ ID NO:18的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:29
(D)其它信息:/注=″Xaa29=赖氨酸-(OCCH2(OCH2CH2)2OCH3)″
(xi)序列描述:SEQ ID NO:18:
Ala Val Ser Glu His Gln Leu Leu His Asp Arg GlY Arg Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Xaa Arg Leu His
20 25 30
Thr Ala(2)SEQ ID NO:19的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:29
(D)其它信息:/注=″Xaa29=赖氨酸-(OCCH2(OCH2CH2)110OCH3″
(xi)序列描述:SEQ ID NO:19:
Ala Val Ser Glu His Gln Leu Leu His Asp Arg Gly Arg Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Xaa Arg Leu His
20 25 30
Thr Ala(2)SEQ ID NO:20的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:20:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Ala Leu Ala Glu Ala Leu Ala Glu Ala Leu His
20 25 30
Thr Ala(2)SEQ ID NO:21的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:21:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Ser Leu Leu Ser Ser Leu Leu Ser Ser Leu His
20 25 30
Thr Ala(2)SEQ ID NO:22的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:22:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:23的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:8
(D)其它信息:/注=″Xaa8=正亮氨酸″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:18
(D)其它信息:/注=″Xaa18=正亮氨酸″
(xi)序列描述:SEQ ID NO:23:
Ala Val Ser Glu Ile Gln Phe Xaa His Asn Leu Gly Lys His Leu Ser
1 5 10 15
Ser Xaa Glu Arg Val Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Asn Tyr(2)SEQ ID NO:24的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:8
(D)其它信息:/注=″Xaa8=正亮氨酸″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:18
(D)其它信息:/注=″Xaa18=正亮氨酸″
(xi)序列描述:SEQ ID NO:24:
Ala Val Ser Glu Ile Gln Phe Xaa His Asn Leu Gly Lys His Leu Ser
1 5 10 15
Ser Xaa Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Asn Tyr(2)SEQ ID NO:25的信息:
(i)序列特征:
(A)长度:35个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:25:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Met Ala
35(2)SEQ ID NO:26的信息:
(i)序列特征:
(A)长度:10个氨基酸
(B)类型:氨基酸
(D)拓扑结构:螺旋状
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:内
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:8
(D)其它信息:/注=″Xaa8=谷氨酸或精氨酸″
(ix)特征:
(A)名称/关键词:区
(B)位置:1..10
(D)其它信息:/注=″序列26位于序列5、6、7、8、9、10、
11、12、13和14的22到31位″
(xi)序列描述:SEQ ID NO:26:
Glu Leu Leu Glu Lys Leu Leu Xaa Lys Leu
1 5 10(2)SEQ ID NO:27的信息:
(i)序列特征:
(A)长度:10个氨基酸
(B)类型:氨基酸
(D)拓扑结构:螺旋状
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:内
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:8
(D)其它信息:/注=″Xaa8=谷氨酸、赖氨酸
或赖氨酸-OCCH2PEGX)″
(ix)特征:
(A)名称/关键词:区
(B)位置:1..10
(D)其它信息:/注=″序列27位于序列15、16、17、18和19
的22到31位″
(xi)序列描述:SEQ ID NO:27:
Glu Leu Leu Glu Arg Leu Leu Xaa Arg Leu
1 5 10(2)SEQ ID NO:28的信息:
(i)序列特征:
(A)长度:10个氨基酸
(B)类型:氨基酸
(D)拓扑结构:螺旋状
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:内
(ix)特征:
(A)名称/关键词:肽
(B)位置:1..10
(D)其它信息:/注=″序列28位于序列20的22到31位″
(xi)序列描述:SEQ ID NO:28:
Ala Leu Ala Glu Ala Leu Ala Glu Ala Leu
1 5 10(2)SEQ ID NO:29的信息:
(i)序列特征:
(A)长度:10个氨基酸
(B)类型:氨基酸
(D)拓扑结构:螺旋状
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:内
(ix)特征:
(A)名称/关键词:肽
(B)位置:1..10
(D)其它信息:/注=″序列29位于序列21的22到31位.″
(xi)序列描述:SEQ ID NO:29:
Ser Leu Leu Ser Ser Leu Leu Ser Ser Leu
1 5 10(2)SEQ ID NO:30的信息:
(i)序列特征:
(A)长度:10个氨基酸
(B)类型:氨基酸
(D)拓扑结构:螺旋状
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:内
(ix)特征:
(A)名称/关键词:肽
(B)位置:1..10
(D)其它信息:/注=″序列30位于序列22的22到31位上″
(xi)序列描述:SEQ ID NO:30:
Ala Phe Tyr Asp Lys Val Ala Glu Lys Leu
1 5 10(2)SEQ ID NO:31的信息:
(i)序列特征:
(A)长度:88个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:cDNA
(iii)假设:否
(iv)反义:否
(xi)序列描述:SEQ ID NO:31:CCTCTAGATC TCCGCGGCGC TAGCATGGCT GTTTCTGAAC ATCAGCTGCT TCATGACAAAGGTAAATCGA TTCAAGATCT GAGACGTC 88(2)SEQ ID NO:32的信息:
(i)序列特征:
(A)长度:90个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:cDNA
(iii)假设:否
(iv)反义:是
(xi)序列描述:SEQ ID NO:32:CCTCGAAGCT TATGCATCAT TATCTAGACA TAGTATGCAG CTTTTCAAGC AGTTTCTCCAGCAGCTCGCG ACGTCTCAGA TCTTGAATCG 90(2)SEQ ID NO:33的信息:
(i)序列特征:
(A)长度:23个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:cDNA
(iii)假设:否
(iv)反义:否
(xi)序列描述:SEQ ID NO:33:CCTCTAGATC TCCGCGCGCT AGC 23(2)SEQ ID NO:34的信息:
(i)序列特征:
(A)长度:24个碱基对
(B)类型:核酸
(C)链型:单链
(D)拓扑结构:线性
(ii)分子类型:cDNA
(iii)假设:否
(iv)反义:是
(xi)序列描述:SEQ ID NO:34:CCTCGAAGCT TATGCATCAT TATC 24(2)SEQ ID NO:35的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:35:
Ala Val Ser Glu Ile Gln Phe Leu His Asn Leu Gly Lys His Leu Ser
1 5 10 15
Ser Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Asn Tyr(2)SEQ ID NO:36的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:34
(D)其它信息:/注=″Xaa是高丝氨酸″
(xi)序列描述:SEQ ID NO:36:
Ala Val Ser Glu Ile Gln Phe Leu His Asn Leu Gly Lys His Leu Ser
1 5 10 15
Ser Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Asn Xaa(2)SEQ ID NO:37的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:34
(D)其它信息:/注=″Xaa是高丝氨酸″
(xi)序列描述:SEQ ID NO:37:
Ala Val Ser Glu Ile Gln Phe Leu His Asn Lys Gly Lys His Leu Ser
1 5 10 15
Ser Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Asn Xaa(2)SEQ ID NO:38的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:38:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Lys Leu Lys Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:39的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:39:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His
20 25 30
Thr Ala(2)SEQ ID NO:40的信息:
(i)序列特征:
(A)长度:35个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:40:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His
20 25 30
Thr Ala Pro
35(2)SEQ ID NO:41的信息:
(i)序列特征:
(A)长度:37个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:41:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His
20 25 30
Thr Ala Gly Arg Arg
35(2)SEQ ID NO:42的信息:
(i)序列特征:
(A)长度:38个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:38
(D)其它信息:/注=″Xaa是高丝氨酸″
(xi)序列描述:SEQ ID NO:42:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His
20 25 30
Thr Ala Gly Arg Arg Xaa
35(2)SEQ ID NO:43的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:43:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu,Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Tyr(2)SEQ ID NO:44的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:44:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Tyr Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:45的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:45:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Cys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:46的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:13
(D)其它信息:/注=″Xaa是Cys(CH-2CONH(CH-2)-2NH(生物素基))″
(xi)序列描述:SEQ ID NO:46:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Xaa Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:47的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:13
(D)其它信息:/注=″Xaa是Lys(7-二甲氨基-2-氧代
-2H-1-苯并吡喃-4-乙酰基)
(xi)序列描述:SEQ ID NO:47:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Xaa Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:48的信息:
(i)序列特征:
(A)长度:35个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:48:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala Gly
35
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:4
(D)其它信息:/注=″Xaa4是Glu(OCH-3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:10
(D)其它信息:/注=″Xaa10是Asp(OCH-3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:17
(D)其它信息:/注=″Xaa17是Asp(OCH-3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:22
(D)其它信息:/注=″Xaa22是Glu(OCH3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:25
(D)其它信息:/注=″Xaa25是Glu(OCH-3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:29
(D)其它信息:/注=″Xaa29是Glu(OCH-3)″
(xi)序列描述:SEQ ID NO:49:
Ala Val Ser Xaa His Gln Leu Leu His Xaa Lys Gly Lys Ser Ile Gln
1 5 10 15
Xaa Leu Arg Arg Arg Xaa Leu Leu Xaa Lys Leu Leu Xaa Lys Leu His
20 25 30
Ala(2)SEQ ID NO:50的信息:
(i)序列特征:
(A)长度:33个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:4
(D)其它信息:/注=″Xaa4是Glu(OCH-3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:10
(D)其它信息:/注=″Xaa10是Asp(OCH-3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:17
(D)其它信息:/注=″Xaa17是Asp(OCH-3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:22
(D)其它信息:/注=″Xaa22是Glu(OCH-3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:25
(D)其它信息:/注=″Xaa25是Glu(OCH-3)″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:29
(D)其它信息:/注=″Xaa29是Glu(OCH-3)″
(xi)序列描述:SEQ ID NO:50:
Ala Val Ser Xaa His Gln Leu Leu His Xaa Lys Gly Lys Ser Ile Gln
1 5 10 15
Xaa Leu Arg Arg Arg Xaa Leu Leu Xaa Lys Leu Leu Xaa Lys Leu His
20 25 30
Ala(2)SEQ ID NO:51的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:34
(D)其它信息:/注=″Xaa是高丝氨酸″
(xi)序列描述:SEQ ID NO:51:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Xaa(2)SEQ ID NO:52的信息:
(i)序列特征:
(A)长度:35个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:52:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala Pro
35(2)SEQ ID NO:53的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:53:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Pro(2)SEQ ID NO:54的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:54:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Pro(2)SEQ ID NO:55的信息:
(i)序列特征:
(A)长度:33个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:55:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Pro(2)SEQ ID NO:56的信息:
(i)序列特征:
(A)长度:32个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:56:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu Pro
20 25 30(2)SEQ ID NO:57的信息:(i)序列特征:
(A)长度:37个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:57:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Arg Ser Ala Trp
35(2)SEQ ID NO:58的信息:
(i)序列特征:
(A)长度:42个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:58:
Ala Val Ser Glu His Gln Leu Leu His Asp Arg Gly Arg Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His
20 25 30
Thr Ala Gly Arg Arg Thr Arg Ser Ala Trp
35 40(2)SEQ ID NO:59的信息:
(i)序列特征:
(A)长度:42个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:59:
Ala Val Ser Glu His Gln Leu Leu His Asp Arg Gly Arg Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His
20 25 30
Thr Arg Gly Arg Arg Thr Arg Ser Ala Trp
35 40(2)SEQ ID NO:60的信息:
(i)序列特征:
(A)长度:42个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:13
(D)其它信息:/注=″Xaa13是Lys(二氢肉桂酰基)″
(xi)序列描述:SEQ ID NO:60:
Ala Val Ser Glu His Gln Leu Leu His Asp Arg Gly Xaa Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His
20 25 30
Thr Arg Gly Arg Arg Thr Arg Ser Ala Trp
35 40(2)SEQ ID NO:61的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:8
(D)其它信息:/注=″Leu8是正亮氨酸″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:18
(D)其它信息:/注=″Leu18是正亮氨酸″
(xi)序列描述:SEQ ID NO:61:
Ala Val Ser Glu Ile Gln Phe Leu His Asn Leu Gly Lys His Leu Ser
1 5 10 15
Ser Leu Thr Arg Ser Ala Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30
Asn Tyr(2)SEQ ID NO:62的信息:
(i)序列特征:
(A)长度:35个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:62:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Met Ala
35(2)SEQ ID NO:63的信息:
(i)序列特征:
(A)长度:33个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:33
(D)其它信息:/注=″Xaa是Thr
1,4-二氨基丁酰内酰胺″
(xi)序列描述:SEQ ID NO:63:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Xaa(2)SEQ ID NO:64的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:64:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Phe Phe Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:65的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:65:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu His Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:66的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:66:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu His Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:67的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:67:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Ile Ala Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:68的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:68:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Glu Ile His
20 25 30
Thr Ala(2)SEQ ID NO:69的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:34
(D)其它信息:/注=″Xaa是高丝氨酸″
(xi)序列描述:SEQ ID NO:69:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Xaa(2)SEQ ID NO:70的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:34
(D)其它信息:/注=″Xaa是高丝氨酸″
(xi)序列描述:SEQ ID NO:70:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Xaa(2)SEQ ID NO:71的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:两者
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:71:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala(2)SEQ ID NO:72的信息:
(i)序列特征:
(A)长度:37个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:72:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Arg Ser Ala Trp
35(2)SEQ ID NO:73的信息:
(i)序列特征:
(A)长度:36个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:36
(D)其它信息:/注=″Xaa是Ala
3-(2-萘基)-L-丙氨酸″
(xi)序列描述:SEQ ID NO:73:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Arg Ser Xaa
35(2)SEQ ID NO:74的信息:
(i)序列特征:
(A)长度:37个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:74:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala Ser Ala Trp
35(2)SEQ ID NO:75的信息:
(i)序列特征:
(A)长度:38个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:75:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala Glu Ile Arg Ala
35(2)SEQ ID NO:76的信息:
(i)序列特征:
(A)长度:37个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:76:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala Glu Ile Arg
35(2)SEQ ID NO:77的信息:
(i)序列特征:
(A)长度:36个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:77:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala Glu Ile
35(2)SEQ ID NO:78的信息:
(i)序列特征:
(A)长度:35个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:N-末端
(xi)序列描述:SEQ ID NO:78:
Ala Val Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln
1 5 10 15
Asp Leu Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His
20 25 30
Thr Ala Glu
35(2)SEQ ID NO:79的信息:
(i)序列特征:
(A)长度:34个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:N-末端
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:8
(D)其它信息:/注=″Leu8是正亮氨酸″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:18
(D)其它信息:/注=″Leu18是正亮氨酸″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:34
(D)其它信息:/注=″Xaa是高丝氨酸内酯″
(xi)序列描述:SEQ ID NO:79:
Ala Val Ser Glu Ile Gln Phe Leu His Asn Lys Gly Lys His Leu Ser
1 5 10 15
Ser Leu Glu Arg Val Glu Trp Leu Arg Lys Lys Leu Gln Asp Val His
20 25 30
Asn Xaa(2)SEQ ID NO:80的信息:
(i)序列特征:
(A)长度:32个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:内
(xi)序列描述:SEQ ID NO:80:
Ser Glu His Gln Leu Leu His Asp Lys Gly Lys Ser Ile Gln Asp Leu
1 5 10 15
Arg Arg Arg Glu Leu Leu Glu Lys Leu Leu Glu Lys Leu His Thr Ala
20 25 30(2)SEQ ID NO:81的信息:
(i)序列特征:
(A)长度:28个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:内
(xi)序列描述:SEQ ID NO:81:
Leu Leu His Asp Lys Gly Lys Ser Ile Gln Asp Leu Arg Arg Arg Glu
1 5 10 15
Leu Leu Glu Lys Leu Leu Glu Lys Leu His Thr Ala
20 25(2)SEQ ID NO:82的信息:
(i)序列特征:
(A)长度:27个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:内
(xi)序列描述:SEQ ID NO:82:
Leu His Asp Lys Gly Lys Ser Ile Gln Asp Leu Arg Arg Arg Glu Leu
1 5 10 15
Leu Glu Lys Leu Leu Glu Lys Leu His Thr Ala
20 25(2)SEQ ID NO:83的信息:
(i)序列特征:
(A)长度:41个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:内
(xi)序列描述:SEQ ID NO:83:
Ser Glu His Gln Leu Leu His Asp Arg Gly Arg Ser Ile Gln Asp Leu
1 5 10 15
Arg Arg Arg Glu Leu Leu Glu Arg Leu Leu Glu Arg Leu His Leu His
20 25 30
Arg Gly Arg Arg Thr Arg Ser Ala Trp
35 40(2)SEQ ID NO:84的信息:
(i)序列特征:
(A)长度:35个氨基酸
(B)类型:氨基酸
(D)拓扑结构:线性
(ii)分子类型:蛋白质
(iii)假设:否
(v)片段类型:内
(xi)序列描述:SEQ ID NO:84:
Leu Leu His Asp Arg Gly Arg Ser Ile Gln Asp Leu Arg Arg Arg Glu
1 5 10 15
Leu Leu Glu Arg Leu Leu Glu Arg Leu His Ala Gly Arg Arg Thr Arg
20 25 30
Ser Ala Trp
35(2)SEQ ID NO:85的信息:
(i)序列特征:
(A)长度:10个氨基酸
(B)类型:氨基酸
(D)拓扑结构:螺旋状
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:内
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:1和4
(D)其它信息:/注=″Xaa1和Xaa4=Glu、Glu(OCH3)、His或Phe″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:2
(D)其它信息:/注=″Xaa2=Leu或Phe″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:5
(D)其它信息:/注=″Xaa5=Lys或His″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:7 and 10
(D)其它信息:/注=″Xaa7和Xaa10=Leu或Ile″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:8
(D)其它信息:/注=″Xaa8=Ala、Arg或Glu″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:9
(D)其它信息:/注=″Xaa9=Lys或Glu″
(xi)序列描述:SEQ ID NO:85:
Xaa Xaa Leu Xaa Xaa Leu Xaa Xaa Xaa Xaa
1 5 10(2)SEQ ID NO:86的信息:
(i)序列特征:
(A)长度:10个氨基酸
(B)类型:氨基酸
(D)拓扑结构:螺旋状
(ii)分子类型:肽
(iii)假设:否
(v)片段类型:内
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:1和4
(D)其它信息:/注=″Xaa1和Xaa4=Glu、Glu(OCH3)、His或Phe″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:2
(D)其它信息:/注=″Xaa2=Leu或Phe ″
(ix)特征:
(A)名称/关键词:修饰的位点
(B)位置:8
(D)其它信息:/注=Xaa8=Glu、Lys或Lys(COCH2PEGX)
(xi)序列描述:SEQ ID NO:86:
Xaa Xaa Leu Xaa Arg Leu Leu Xaa Arg Leu
1 5 10
Claims (8)
1.一种合成甲状旁腺素(PTH)或甲状旁腺素相关肽(PTHrP)类似物或其盐的方法,在所述类似物和其盐中,选自SEQ ID NO:85、86、26、27和29的氨基酸残基22-31形成一个两亲性α-螺旋,该方法包括:
a)分别合成三个前体肽片段:N-末端片段、中部片段和C-末端片段,其中N-末端片段具有C-末端甘氨酸,中部片段具有C-末端亮氨酸或C-末端谷氨酸,并且C-末端片段具有N-末端亮氨酸;
b)从它们各自的树脂支持物上切下N-末端片段和中部片段;
c)使所说的切下的前体肽片段依次与树脂结合的C-末端肽片段缩合,形成所需的多肽产物;
d)除去侧链保护基;和
e)从树脂支持物上切下所述的多肽产物;
其中最终的多肽产物包括具有下式的PTH或PTHrP类似物和其药学上可接受的盐:
Xaa1 Xaa2 Xaa3 Xaa4 Xaa5 Xaa6 Xaa7 Leu His Asp Xaa11 Gly Xaa13 Ser Ile GlnAsp Leu Xaa19 Xaa20 Xaa21 Xaa22-31 Xaa32 Xaa33 Xaa34 Xaa35 Xaa36 Xaa37 Xaa38Term,其中:
Xaa1不存在或者是Ala;
Xaa2不存在或者是Val;
Xaa3不存在或者是Ser;
Xaa4不存在或者是Glu或Glu(OCH3);
Xaa5不存在或者是His或Ala;
Xaa6不存在或者是Gln;
Xaa7不存在或者是Leu;
Xaa11是Lys、Arg或Leu;
Xaa13是Lys、Arg、Tyr、Cys、Leu、Cys(CH2CONH(CH2)2NH(生物素基))、Lys(7-二甲氨基-2-氧代-2H-1-苯并吡喃-4-乙酰基)或Lys(二氢肉桂酰基);
Xaa20是Arg或Leu;
Xaa19和Xaa21独立地为Lys、Ala或Arg;
Xaa22-31选自SEQ ID NO:85、86、26、27或29;
Xaa32是His、Pro或Lys;
Xaa33不存在或者是Pro、Thr、Glu或Ala;
Xaa34不存在或者是Pro、Arg、Met、Ala、hSer、hSer内酯、Tyr或Leu;
Xaa35不存在或者是Pro、Glu、Ser、Ala或Gly;
Xaa36不存在或者是Ala、Arg或Ile;
Xaa37不存在或者是Arg、Trp或3-(-2-萘基)-L-丙氨酸;
Xaa38不存在或者是Ala或hSer或者Xaa38-42是Thr Arg Ser Ala Trp;
并且Term是OR或NR2,这里各R独立地为H、(C1-C4)烷基或苯基(C1-C4)烷基;
或者,其中所说的PTH或PTHrP的多肽类似物包括具有下式的物质和其药学上可接受的盐:
Xaa1 Val Ser Glu Ile Gln Xaa7 Xaa8 His Asn Xaa11 Gly Lys His Leu Xaa16 SerXaa18 Xaa19 Arg Xaa21 Xaa22-31 His Asn Xaa34 Term,其中:
Xaa1是Ser或Ala;
Xaa7是Leu或Phe;
Xaa8是Leu、Met或Nle;
Xaa11是Leu或Lys;
Xaa16是Asn或Ser;
Xaa18是Leu、Met或Nle;
Xaa19是Glu、Thr或Arg;
Xaa21是Val、Ser或Arg;
Xaa22-31选自SEQ ID NO:26、27或29;
Xaa34是Phe、hSer或Tyr;
Term是OR或NR2、这里R是H或(C1-C4)烷基。
2.权利要求1的方法,其中所说的PTH或PTHrP类似物选自:
AVSEHQLLHDKGKSIQDLRRRELLEKLLEKLHTA-NH2(SEQ ID NO:7)
AVSEHQLLHDKGKSIQDLRRRELLEKLLEKLHTA-OH(SEQ ID NO:6)
AVSEHQLLHDKGKSIQDLRRRELLERLLERLHTA-OH(SEQ ID NO:15)
AVSEHQLLHDRGRSIQDLRRRELLERLLERLHTA-OH(SEQ ID NO:16)
AVSEHQLLHDRGRSIQDLRRRELLERLLKRLHTA-OH(SEQ ID NO:17)
AVSEHQLLHDKGKSIQDLRRRELLEKLLRKLHTA-OH(SEQ ID NO:5)
AVSEHQLLHDKGKSIQDLRRRELLEKLLEKLHTAGRR-OH(SEQ ID NO:10)
AVSEAQLLHDLGKSIQDLRRRELLEKLLEKLHAL-OH(SEQ ID NO:14)
AVSEHQLLHDKGKSIQDLRRRELLEKLLELLKE L-NH2(SEQ ID NO:11)
AVSEIQFXHNLGKHLSSXERVELLEKLLEKLHNY-NH2(X=Nle,SEQ ID NO:23)
AVSEIQFXHNLGKHLSSXRRRELLEKLLEKLHNY-NH2(X=Nle,SEQ ID NO:24)
AVSEHQLLHDKGKSIQDLARRELLEKLLEKLHTA-NH2(SEQ ID NO:12)
AVSEHQLLHDKGKSIQDLRRAELLEKLLEKLHTA-NH2(SEQ ID NO:13)
AVSEHQLLHDKGKSIQDLRRRSLLSSLLSSLHTA-NH2(SEQ ID NO:21)
AVSEIQFLHN LGKHLSSLRR RELLEKLLEK LHNY-NH2(SEQ ID NO:35)
AVSEHQLLHD KGKSIQDLKL KELLEKLLEK LHTA-NH2(SEQ ID NO:38)
AVSEHQLLHD KGKSIQDLRR RELLERLLER LHTA-NH2(SEQ ID NO:39)
AVSEHQLLHD KGKSIQDLRR RELLERLLER LHTAP-OH(SEQ ID NO:40)
AVSEHQLLHD KGKSIQDLRR RELLERLLER LHTAGRR-OH(SEQ ID NO:41)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTY-NH2(SEQ ID NO:43)
AVSEHQLLHD KGYSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:44)
AVSEHQLLHD KGCSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:45)
AVSEHQLLHD KGXSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:46)(X=Cys(CH2CONH(CH2)2NH(生物素基)))
AVSEHQLLHD KGXSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:47)(X=Lys(7-二甲氨基-2-氧代-2H-1-苯并吡喃-4-乙酰基))
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAG-OH(SEQ ID NO:48)
AVSX1HQLLHX2 KGKSIQX2LRR RX1LLX1KLLX1K LHA-OH(SEQ ID NO:49)(X1=Glu(OCH3);X2=Asp(OCH3))
AVSX1HQLLHX2 KGKSIQX2LRR RX1LLX1KLLX1K LHA-OCH3(SEQ ID NO:50)(X1=Glu(OCH3);X2=Asp(OCH3))
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAP-OH(SEQ ID NO:52)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTP-OH(SEQ ID NO:53)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTP-NH2(SEQ ID NO:54)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHP-NH2(SEQ ID NO:55)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LP-NH2(SEQ ID NO:56)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTRSAW-OH(SEQ ID NO:57)
AVSEHQLLHD RGRSIQDLRR RELLERLLER LHTAGRRTRSAW-OH(SEQ IDNO:58)
AVSEHQLLHD RGRSIQDLRR RELLERLLER LHTAGRRTRSAW-NH2(SEQ IDNO:59)
AVSEHQLLHD RGXSIQDLRR RELLERLLER LHTAGRRTRSAW-OH(SEQ IDNO:60)(X=Lys(二氢肉桂酰基))
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTMA-NH2(SEQ ID NO:62)
AVSEHQLLHD KGKSIQDLRR RFFLEKLLEK LHTA-NH2(SEQ ID NO:64)
AVSEHQLLHD KGKSIQDLRR RELLHKLLEK LHTA-NH2(SEQ ID NO:65)
AVSEHQLLHD KGKSIQDLRR RELLEHLLEK LHTA-NH2(SEQ ID NO:66)
AVSEHQLLHD KGKSIQDLRR RELLEKLIAK LHTA-NH2(SEQ ID NO:67)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEE IHTA-NH2(SEQ ID NO:68)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTRSAW-NH2(SEQ ID NO:72)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTRSAX-OH(SEQ ID NO:73)(X=Na1(2)=3-(2-萘基)-L-丙氨酸)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTASAW-OH(SEQ ID NO:74)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAEIRA-OH(SEQ ID NO:75)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAEIR-OH(SEQ ID NO:76)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAEI-OH(SEQ ID NO:77)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTAE-OH(SEQ ID NO:78)
SEHQLLHD KGKSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:80)
LLHD KGKSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:81)
LHD KGKSIQDLRR RELLEKLLEK LHTA-NH2(SEQ ID NO:82)
SEHQLLHD RGRSIQDLRR RELLERLLER LHAGRRTRSAW-OH(SEQ ID NO:83)
LLHD RGRSIQDLRR RELLERLLER LHAGRRTRSAW-OH(SEQ ID NO:84)
AVSEHQLLHDKGKSIQDLRR RELLEKLLEKLHTX(X=hSerlac,SEQ ID NO:9)
AVSEHQLLHDKGKSIQDLRR RELLEKLLEKLHTX-NH2(X=hSer,SEQ ID NO:8)
AVSEIQFLHN LGKLSSLRR RELLEKLLEK LHNX-NH2(SEQ ID NO:36)(X=高丝氨酸)
AVSEIQFLHN KGKHLSSLRR RELLEKLLEK LHNX-NH2(SEQ ID NO:37)(X=高丝氨酸)
AVSEHQLLHD KGKSIQDLRR RELLERLLER LHTAGRRX-NH2(SEQ ID NO:42)(X=高丝氨酸)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTX-NHCH2CH3(SEQ ID NO:69)(X=高丝氨酸)
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTX-NHCH2CH2C6H5(SEQ IDNO:70)(X=高丝氨酸),和
AVSEHQLLHD KGKSIQDLRR RELLEKLLEK LHTX-OH(SEQ ID NO:51)(X=高丝氨酸)。
3.权利要求1或2的方法,其中所说的PTH或PTHrP类似物是SEQ ID NO:7的多肽:AVSEHQLLHDKGKSIQDLRRRELLEKLLEKLHTA-NH2。
4.权利要求3的方法,其中所说的N-末端片段由AVSEHQLLHDKG组成,所说的中部片段由KSIQDLRREL组成,所说的C-末端片段由LEKLLEKLHTA组成。
5.权利要求4的方法,其中所说的C-末端片段是由LEKL,LEKL和HTA缩合形成的。
6.权利要求3的方法,其中所说的N-末端片段由AVSEHQLLHDKG组成,所说的中部片段由KSIQDLRRRE组成,所说的C-末端片段由LLEKLLEKLHTA组成。
7.权利要求6的方法,其中所说的C-末端片段是由LLEK,LLEK和LHTA缩合形成的。
8.一种制备药物组合物的方法,其特征在于,实施如权利要求1至7中任一项所述的制备PTH或PTHrP类似物的方法,并且将所获得的PTHrP类似物与一种或多种药学上可接受的添加剂混合。
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US2332296P | 1996-07-30 | 1996-07-30 | |
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CN101355959B (zh) * | 2005-11-10 | 2013-02-27 | 密歇根理工大学管理委员会 | 黑熊甲状旁腺素和使用黑熊甲状旁腺素的方法 |
EP1979370B1 (en) * | 2006-01-17 | 2010-03-17 | N.V. Organon | SELECTIVE ENZYMATIC HYDROLYSIS OF C-TERMINAL tert-BUTYL ESTERS OF PEPTIDES |
PT2957278T (pt) | 2006-10-03 | 2017-08-23 | Ipsen Pharma Sas | Uma composição estável compreendendo pthrp e utilizações da mesma |
USRE49444E1 (en) | 2006-10-03 | 2023-03-07 | Radius Health, Inc. | Method of treating osteoporosis comprising administration of PTHrP analog |
US7803770B2 (en) | 2006-10-03 | 2010-09-28 | Radius Health, Inc. | Method of treating osteoporosis comprising administration of PTHrP analog |
CN102448482A (zh) | 2009-03-27 | 2012-05-09 | 范安德尔研究所 | 甲状旁腺素肽和甲状旁腺素相关蛋白肽及使用方法 |
CA2782640A1 (en) | 2009-12-07 | 2011-06-16 | Michigan Technological University | Black bear parathyroid hormone and methods of using black bear parathyroid hormone |
CN102731643A (zh) * | 2012-06-26 | 2012-10-17 | 深圳翰宇药业股份有限公司 | 一种治疗骨质疏松多肽的制备方法 |
CN102993293B (zh) * | 2012-12-05 | 2014-05-07 | 深圳翰宇药业股份有限公司 | 一种特立帕肽醋酸盐的纯化方法 |
HUE034308T2 (en) | 2013-03-21 | 2018-02-28 | Sanofi Aventis Deutschland | Preparation of hydantoin-containing peptide products |
US10450343B2 (en) | 2013-03-21 | 2019-10-22 | Sanofi-Aventis Deutschland Gmbh | Synthesis of cyclic imide containing peptide products |
CN104530198B (zh) * | 2014-12-09 | 2017-09-15 | 兰州大学 | 一种片段缩合制备醋酸去氨加压素的方法 |
IL297369B1 (en) | 2015-04-29 | 2024-02-01 | Radius Pharmaceuticals Inc | RAD for use in a method to treat mutant estrogen receptor positive breast cancer or mutant estrogen receptor positive ovarian cancer |
KR102322802B1 (ko) | 2017-01-05 | 2021-11-04 | 래디어스 파마슈티컬스, 인코포레이티드 | Rad1901-2hcl의 다형 형태 |
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EP3765488A1 (en) * | 2018-03-12 | 2021-01-20 | Fresenius Kabi iPSUM S.r.l. | Process for the manufacture of pthrp analogue |
US11643385B2 (en) | 2018-07-04 | 2023-05-09 | Radius Pharmaceuticals, Inc. | Polymorphic forms of RAD1901-2HCl |
CN111057139B (zh) * | 2018-10-17 | 2023-12-22 | 南京华威医药科技集团有限公司 | 一种制备特立帕肽的新工艺 |
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