CN114269910A - 新型二磷酸腺苷核糖环化酶及其抑制剂 - Google Patents
新型二磷酸腺苷核糖环化酶及其抑制剂 Download PDFInfo
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- CN114269910A CN114269910A CN202080053161.0A CN202080053161A CN114269910A CN 114269910 A CN114269910 A CN 114269910A CN 202080053161 A CN202080053161 A CN 202080053161A CN 114269910 A CN114269910 A CN 114269910A
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- adenosine diphosphate
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Abstract
本发明涉及包含新型二磷酸腺苷核糖环化酶或其自然发生的变体的表达抑制剂或活性抑制剂作为有效成分的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物。并且,本发明涉及包含检测上述二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平的制剂或者检测蛋白质水平的制剂的用于诊断二磷酸腺苷核糖环化酶介导的疾病的组合物。本发明的组合物具有抑制通过血管紧张素II的新型二磷酸腺苷核糖环化酶的表达或者活性增加引起的肾脏细胞内钙增加的效果,因此,能够有效用作二磷酸腺苷核糖环化酶介导的疾病,尤其是肾脏疾病的治疗剂。
Description
技术领域
本发明涉及将烟酰胺腺嘌呤二核苷酸(NAD+)转化为环化二磷酸腺苷核糖的新型二磷酸腺苷核糖环化酶及其抑制剂。
背景技术
二磷酸腺苷核糖环化酶(ADPRC)为从烟酰胺腺嘌呤二核苷酸(NAD+)合成环化二磷酸腺苷核糖(cyclic ADP-ribose;cADPR),从烟酰胺腺嘌呤二核苷酸磷酸(NADP+)合成烟酸胺腺嘌呤二核苷酸磷酸(nicotinic acid adenine dinucletide phosphate;NAADP)的酶,广泛存在于从植物到哺乳动物的生物中。已知上述二磷酸腺苷核糖环化酶通过从细胞内钙库向细胞质游离来调节细胞的多种功能[Berridge MJ,Bootman MD,Roderick HL.Nat RevMol Cell Biol.4,517-529,2003;Lee HC,Mol.Med.12317-323,2006]。
在稳定状态下,细胞内的钙浓度保持在10-7M以下的基础值。然而,当细胞处于激活状态时,细胞内的钙浓度增加至基础值的10倍左右,在病理状态下,钙浓度持续保持高浓度会使细胞的很多功能受到影响,其结果为细胞正常功能的消失。
在高血压或者并发高血压的糖尿病、肥胖、痴呆、局部缺血、并发细胞增殖的疾病中,细胞内的钙代谢调节异常,细胞内的钙浓度比正常高[Resnick LM.Am.J.Hypertens.6:123S-134,1993]。
作为一例,观察高血压之类慢性疾病的患者,发现因多种遗传、环境或者某种疾病的继发性病因使血管平滑肌细胞内的钙浓度持续表现出高于正常值的数值,其结果增加了诱发血管平滑肌收缩的外周血管的阻力,因此使血压持续保持在比正常血压上升的状态,从而引发高血压。
已知由此上升的血压继发性地引起血管平滑肌细胞和纤维组织的增殖和肥大,其结果,进一步增加外周血管的阻力和血压,抑制心血管系统、脑及肾脏等器官功能,甚至因心肌梗塞、心绞痛、中风及慢性心衰等引起死亡[Cowley AW Jr.Physiol Rev.72:231-300,1992]。
已知在从胰腺分泌胰岛素的过程中,通过二磷酸腺苷核糖环化酶的一种的CD38活性,即,通过环化二磷酸腺苷核糖的钙增加起到重要作用。并且,已知糖尿病的发病增加血管紧张素的生成,该肽类激素不仅诱发肾脏疾病、高血压及心脏病,还激活二磷酸腺苷核糖环化酶。
因此,二磷酸腺苷核糖环化酶存在于免疫细胞、心肌细胞、胰岛β细胞、伸肌细胞及神经细胞等,并与多种激素的受体相关,增加细胞内钙浓度及调节多种生理活动,若上述二磷酸腺苷核糖环化酶的表达或者活性调节异常,则会引起生理活动(免疫、肾脏功能、胰岛素分泌、心血管功能)调节的异常。
上述二磷酸腺苷核糖环化酶可以被多种激素激活,该酶从作为底物的烟酰胺腺嘌呤二核苷酸生成作为产物的环化二磷酸腺苷核糖,上述环化二磷酸腺苷核糖在几乎所有器官中增加细胞内的钙。并且,已知由二磷酸腺苷核糖环化酶的活性引起的钙的异常增加是胰岛素分泌(insulin secretion)[Kim BJ,Park KH,Yim CY,Takasawa S,Okamoto H,ImMJ,Kim UH.Diabetes.57:868-878,2008]、细胞肥大(hypertrophy)[Gul R,Park JH,KimSY,Jang KY,Chea JK,Ko JK,Kim UH.Cardiovasc Res.81:582-591,2009]、细胞增殖(proliferation)[Kim SY,Gul R,Rah SY,Kim SH,Park SK,Im MJ,Kwon HJ,Kim UH.Am JPhysiol Renal Physiol.294:F989-F989,2008]等多种活体病理的因素。
至今,研究得最彻底的二磷酸腺苷核糖环化酶是作为T-细胞表面抗原的CD38,该分子不仅在免疫细胞表达,还多种器官中广泛地表达。
但是,已查明在心脏、肾脏、脑中表达的是与CD38不同的二磷酸腺苷核糖环化酶[Partida-Sanchez S,Cockayne DA,Monard S,Jacobson EL,Oppenheimer N,Garvy B,Kusser K,Goodrich S,Howard M,Harmsen A,Randall TD,Lund FE.Nat Med 7:1209-16,2001]。
因此,调节组织特异性二磷酸腺苷核糖环化酶的表达将有助于治疗由细胞内钙增加诱发的疾病。并且,二磷酸腺苷核糖环化酶的活性机制尚未完全明确。
上述背景技术中的说明仅用于增进对本发明的背景的理解,不能将其认可为相当于本发明所属技术领域的普通技术人员已知的现有技术。
发明内容
技术问题
本发明人发现了不同于现有已知的哺乳动物中的二磷酸腺苷核糖环化酶(CD38、CD157)的新种类的二磷酸腺苷核糖环化酶并确认其活性,从而完成本发明。
因此,本发明的目的在于,提供新型二磷酸腺苷核糖环化酶(ADP-ribosylcyclase;ADPRC))或其自然发生的(naturally occurred)变体。
本发明的再一目的在于,提供编码上述二磷酸腺苷核糖环化酶或其自然发生的变体的核酸分子。
本发明的还有一目的在于,提供包含上述核酸分子的载体。
本发明的另一目的在于,提供包含上述载体的宿主细胞。
本发明的又一目的在于,提供将烟酰胺腺嘌呤二核苷酸转化为环化二磷酸腺苷核糖的催化剂组合物,包含:上述二磷酸腺苷核糖环化酶或其自然发生的变体、编码其的核酸分子或包含上述核酸分子的载体。
本发明的又一目的在于,提供用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,包含上述二磷酸腺苷核糖环化酶或其自然发生的变体的表达抑制剂或活性抑制剂作为有效成分。
本发明的又一目的在于,提供用于预防或改善二磷酸腺苷核糖环化酶介导的疾病的食品组合物,包含上述二磷酸腺苷核糖环化酶或其自然发生的变体的表达抑制剂或活性抑制剂作为有效成分。
本发明的又一目的在于,提供缺失上述二磷酸腺苷核糖环化酶或其自然发生的变体的异型基因的动物模型。
本发明的又一目的在于,提供有关二磷酸腺苷核糖环化酶介导的疾病诊断的信息提供方法。
本发明的又一目的在于,提供用于诊断二磷酸腺苷核糖环化酶介导的疾病的组合物,包含检测上述二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平的制剂或者检测蛋白质水平的制剂。
本发明的又一目的在于,提供二磷酸腺苷核糖环化酶介导的疾病的诊断试剂盒,包含检测上述二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平的制剂或者检测蛋白质水平的制剂。
本发明的又一目的在于,提供预防或治疗上述二磷酸腺苷核糖环化酶介导的疾病的物质的筛选方法。
本发明的其他目的及优点将通过下述本发明的详细说明、发明要求保护范围及附图得以进一步明确。
解决问题的方案
根据本发明的一实施方式,本发明提供二磷酸腺苷核糖环化酶或其自然发生的变体,包含序列表中序列1的氨基酸序列。
本发明人致力于发掘将烟酰胺腺嘌呤二核苷酸转化为环化二磷酸腺苷核糖的酶,即,有别于现有已知的二磷酸腺苷核糖环化酶的新型二磷酸腺苷核糖环化酶,从而完成本发明。
在本说明书中,术语“二磷酸腺苷核糖环化酶”或“ADP-ribosyl cyclase(ADPRC)”是指将烟酰胺腺嘌呤二核苷酸转化为环化二磷酸腺苷核糖的酶。
本说明书中,术语“二磷酸腺苷核糖环化酶的变体”是指天然或人为地取代、缺失、添加上述二磷酸腺苷核糖环化酶的一部分氨基酸序列的变体,是指保有将烟酰胺腺嘌呤二核苷酸转化为环化二磷酸腺苷核糖的催化剂活性的二磷酸腺苷核糖环化酶的变体。
在本说明书中,术语“二磷酸腺苷核糖环化酶的自然发生的(naturallyoccurred)变体”为包含上述序列表中序列1的氨基酸序列的二磷酸腺苷核糖环化酶的自然发生的变体,是指保有将烟酰胺腺嘌呤二核苷酸转化为环化二磷酸腺苷核糖的催化剂活性的二磷酸腺苷核糖环化酶的变体。
根据本发明的优选实例,本发明的二磷酸腺苷核糖环化酶的自然发生的变体为选自由种间变体(species variants)、种内同源物(species homologs)、异构体(isoforms)、等位基因变体(allelic variants)、构象变体(conformation variants)、剪接变体(splice variants)及点突变变体(point mutant variants)组成的组中的自然发生的变体。
优选地,本发明的二磷酸腺苷核糖环化酶的自然发生的变体与包含序列表中序列1的氨基酸序列的二磷酸腺苷核糖环化酶具有50%以上的同源性,更优选地,具有60%以上的同源性,更加优选地,具有70%以上的同源性,进一步更优选地,具有80%以上的同源性,最优选地,具有90%以上的同源性。
根据本发明的优选实例,本发明的二磷酸腺苷核糖环化酶的自然发生的变体发生于选自由哺乳动物、鸟类、爬虫类、两栖动物及鱼类组成的组中的生物中。
根据本发明的一实施例,确认到本发明的二磷酸腺苷核糖环化酶的自然发生的变体与包含序列表中序列1的氨基酸序列的二磷酸腺苷核糖环化酶相比,在哺乳动物的情况下,具有70%以上的同源性,在鸟类、爬虫类及两栖动物的情况下,具有60%以上的同源性,在鱼类的情况下,具有50%以上的同源性。
根据本发明的一实施例,本发明的二磷酸腺苷核糖环化酶的自然发生的变体与包含序列表中序列1的氨基酸序列的二磷酸腺苷核糖环化酶相比,人类及大鼠显出96%的同源性,黑猩猩显出93%的同源性、豚鼠及马显出91%的同源性,狗、山羊及绵羊显出90%的同源性,兔显出89%的同源性,猪显出88%的同源性、牛显出78%的同源性,鸡显出70%的同源性,蛙显出63%的同源性,火鸡显出62%的同源性,均显出高同源性,由此确认其为种间保守序列很高的酶(图4)。
根据本发明的优选实例,本发明的二磷酸腺苷核糖环化酶的自然发生的变体包含选自由序列表中序列2至序列21组成的组中氨基酸序列。
根据本发明的再一实施方式,本发明提供编码上述二磷酸腺苷核糖环化酶或其自然发生的变体的核酸分子、包含上述核酸分子的载体或包含上述载体的宿主细胞。
本发明的核酸分子可以为分离的或重组的,不仅包括单链及双链形式的脱氧核糖核酸(DNA)及核糖核酸(RNA),还包括对应的互补序列。在“分离的核酸”为从自然源中分离出来的核酸的情况下,该核酸为从存在于分离出核酸的个体的基因组中的周围基因序列中分离的核酸。在从模板通过酶促或化学方法合成的核酸,例如聚合酶链式反应(PCR)产物、互补DNA(cDNA)分子或寡核苷酸的情况下,经过这种过程生成的核酸也可以理解为分离的核酸分子。分离的核酸分子为以单独片段的形式或作为更大的核酸构建体的成分显现的核酸分子。当核酸与其他核酸序列形成功能关系时,形成“可操作地连接”。例如,若前序列或分泌前导序列(leader)的DNA表达为分泌多肽之前的形式的前蛋白(preprotein),则与多肽的DNA可操作地连接,若启动子或增强子给多肽序列的转录带来影响,则与编码序列可操作地连接,或者当核糖体结合位点为促进转译而配置时,与编码序列可操作地连接。通常,“可操作地连接”是指连接的DNA序列相邻配置,在分泌前导序列的情况下,是指相邻且存在于同一阅读框内的情况。但增强子没必要相邻配置。连接使通过在方便的限制酶位点连接来实现的。若不存在这样的位点,可以根据通常的方法使用合成寡核苷酸接头或衔接物。
根据本发明的优选实例,上述核酸分子为互补DNA。
在本说明书中,术语“载体”是指可以为了导入能够复制核酸序列的细胞而插入核酸序列的传递体。核酸序列可以为外源的(exogenous)或异源的(heterologous)。载体可以为质粒、粘粒及病毒(例如噬菌体),但不限定于此。本发明所属技术领域的普通技术人员可以通过标准的重组技术构建载体(Maniatis,et al.,Molecular Cloning,A LaboratoryManual,Cold Spring Harbor Press,Cold Spring Harbor,N.Y.,1988;及Ausubel etal.,In:Current Protocols in Molecular Biology,John,Wiley&Sons,Inc,NY,1994等)。
在本说明书中,术语“表达载体”是指包含编码转录的基因产物中至少一部分的核酸序列的载体。在部分情况下,之后RNA分子被转译为蛋白质、多肽或肽。表达载体可以包含多种调控序列。同样调节转录及转译的调控序列一起,载体及表达载体中还可以包含提供其他功能的核酸序列。
在本说明书中,术语“宿主细胞”包括真核生物及原核生物,是指能够复制上述载体或能够表达通过载体编码的基因的任意的可转化的生物。宿主细胞可以通过上述载体转染(transfected)或转化(transformed),这是指外源性的核酸分子传递或导入宿主细胞内的过程。
优选地,本发明的宿主细胞可以为细菌(bacteria)细胞、酵母菌(yeast)、动物或人类细胞(中国仓鼠卵巢(CHO)细胞、海拉(HeLa)细胞、HEK293细胞、MES13细胞、BHK-21细胞、COS7细胞、COP5细胞、A549细胞、NIH3T3细胞等),但不限定于此。
根据本发明的还有一实施方式,本发明提供将烟酰胺腺嘌呤二核苷酸转化为环化二磷酸腺苷核糖的催化剂组合物,包含:上述二磷酸腺苷核糖环化酶或其自然发生的变体、编码其的核酸分子或包含上述核酸分子的载体。
本发明的催化剂组合物有效催化将烟酰胺腺嘌呤二核苷酸转化为环化二磷酸腺苷核糖的过程。
根据本发明的另一实施方式,本发明提供包含上述二磷酸腺苷核糖环化酶或其自然发生的变体的表达抑制剂或活性抑制剂的组合物。
根据本发明的优选实例,本发明的组合物为用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物。
本发明的药物组合物可以包含:(a)上述表达抑制剂或活性抑制剂;以及(b)药剂学上可接受的载体。
根据本发明的优选实例,本发明的组合物为用于预防或改善二磷酸腺苷核糖环化酶介导的疾病的食品组合物。
根据本发明的又一实施方式,本发明提供二磷酸腺苷核糖环化酶介导的疾病的预防或治疗方法,包括向对象(subject)给药药剂学有效量的上述药物组合物的步骤。
根据本发明的又一实施方式,本发明提供用于治疗用途(for use in therapy)的上述二磷酸腺苷核糖环化酶或其自然发生的变体的表达抑制剂或活性抑制剂。
本发明所要预防或治疗的二磷酸腺苷核糖环化酶介导的疾病的种类不受限制,优选为糖尿病或肾脏疾病,更优选为肾衰竭(renal failure)、肾病(nephropathy)、肾炎(nephritis)、肾纤维化(renal fibrosis)或肾硬化(nephrosclerosis)。
根据本发明的优选实例,上述肾衰竭为慢性肾衰竭(Chronic Renal Failure)、急性肾衰竭(Acute Renal Failure)或透析前的轻度肾衰竭。
根据本发明的优选实例,上述肾病为肾病综合征(Nephropathy Syndrome)、类脂性肾病(Lipoid Nephropathy)、糖尿病肾病(Diabetic Nephropathy)、免疫球蛋白A肾病(IgA Nephropathy)、镇痛剂肾病(Analgesic Nephropathy)或高血压肾病(HypertensiveNephropathy)。
根据本发明的一实施例,本发明的组合物通过肾脏重量相对于体重的显著减少、肌酸酐清除率的显著增加、尿白蛋白量的显著减少来确认作为包括慢性肾衰竭或糖尿病肾病在内的肾脏疾病治疗剂的候补的可能性(图6);并且,将二磷酸腺苷核糖环化酶活性及环化二磷酸腺苷核糖的浓度降至正常水平(图7);将转化生长因子-β1(TGF-β1)、纤连蛋白(Fibronectin)、胶原蛋白IV(Collagen IV)的表达量降至正常水平(图8);还保有通过使肾小球肥大、炎症细胞的浸润、移行上皮细胞的形成恢复至正常水平来恢复肾脏的组织病理学变化的能力(图9);在高血压模型中也通过使肌酸酐清除率的显著增加来确认适用于高血压肾病的可能性(图11b),具有作为因肾脏功能异常或损伤引起的多种肾脏疾病的治疗剂的可能性。
在本说明书中,术语“表达抑制剂”是指抑制上述二磷酸腺苷核糖环化酶的表达的物质,本发明所属技术领域的普通技术人员可以根据上述二磷酸腺苷核糖环化酶的结构及功能轻易制备。
优选地,本发明的表达抑制剂为选自由与上述二磷酸腺苷核糖环化酶或其自然发生的变体基因的信使RNA(mRNA)互补结合的反义寡核苷酸(antisense oligonucleotide)、小干扰RNA(siRNA)、短发夹RNA(shRNA)、微小RNA(miRNA)、核酶(ribozyme)、脱氧核酶(DNAzyme)及肽核酸(PNA,protein nucleic acid)组成的组中的一种,但不限定于此。
根据本发明的优选实例,上述小干扰RNA(siRNA)包含序列表中序列22的核苷酸序列。
在本说明书中,术语“活性抑制剂”是指抑制上述表达的二磷酸腺苷核糖环化酶蛋白质的活性的物质,优选地,为选自由与上述二磷酸腺苷核糖环化酶或其自然发生的变体蛋白质特异性结合的化合物、肽、肽类似物(mimetics)、适配体及抗体组成的组中的一种。
根据本发明的优选实例,上述化合物为选自由4,4’-二羟基偶氮苯(4,4'-dihydroxyazobenzene)、2-(1,3-苯并恶唑-2-基氨基)-1-甲基喹唑啉-4(1H)-酮(2-(1,3-benzoxazol-2-ylamino)-1-methylquinazoline-4(1H)-one)及二咖啡酰奎宁酸(Dicaffeoylquinic acid,DCQA)组成的组中的化合物。
优选地,本发明的4,4’-二羟基偶氮苯可以由下述化学式1表示。
化学式1
优选地,本发明的2-(1,3-苯并恶唑-2-基氨基)-1-甲基喹唑啉-4(1H)-酮可以由下述化学式2表示。
化学式2
本发明的二咖啡酰奎宁酸可以为由选自由下述化学式3至化学式8(1,4-DCQA、3,4-DCQA、3,5-DCQA、4,5-DCQA、1,3-DCQA及1,5-DCQA)组成的组中的化学式表示的化合物。
化学式3
化学式4
化学式5
化学式6
化学式7
化学式8
根据本发明的一实施例,确认到本发明的新型二磷酸腺苷核糖环化酶的表达抑制剂或活性抑制剂通过调节二磷酸腺苷核糖环化酶的表达或活性的机制来在肾脏疾病的抑制中起作用。
因此,本发明的新型二磷酸腺苷核糖环化酶的表达抑制剂或活性抑制剂可以在临床上有效用作各不同细胞的选择性抑制剂,进而可以用作肾脏内疾病的预防、改善和/或治疗剂。
本发明的组合物不仅可以使用作为有效成分的新型二磷酸腺苷核糖环化酶的表达抑制剂或活性抑制剂,还可以与现有公知的二磷酸腺苷核糖环化酶相关疾病的治疗剂一同使用。
本发明的药物组合物可以与药剂学上可接受的载体一同配制为适当形式。“药剂学上可接受的载体”是指生理学上可接受并在向人类给药时通常不引起消化道障碍、眩晕等过敏反应或者与之相似的反应的载体。
本发明的药物组合物所包含的药剂学上可接受的载体可以为制剂时通常利用的载体,包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁及矿物油,但不限定于此。除上述成分以外,本发明的药物组合物还可以包含润滑剂、湿润剂、甜味剂、香味剂、乳化剂、悬浮剂、保存剂等。适当的药剂学上可接受的载体及制剂详细记载于Remington's Pharmaceutical Sciences(19th ed.,1995)中。
本发明的药物组合物可以口服或胃肠外给药,优选地,可以胃肠外给药,例如,可以通过静脉内注射、局部注射及腹腔注射等方式给药。
本发明的药物组合物的适当给药量可以根据配制方法、给药方式、患者的年龄、体重、性别、疾病状态、饮食、给药时间、给药途径、代谢速度及反应敏感性之类的因素而多种多样,可以通过具有通常熟练度的医生轻易决定或者处方所希望治疗或预防的有效给药量。根据本发明的优选实例,本发明的药物组合物的1日给药量为0.0001mg/kg~100mg/kg。
本发明的药物组合物可以根据本发明所属技术领域的普通技术人员易于实施的方法利用药剂学上可接受的载体和/或赋形剂配制为单剂量形式或者装入多剂量容器内来制备。在此情况下,剂型可以为油或水性溶剂中的溶液、悬浮液或乳化液形式,还可以为提取剂、粉末剂、颗粒剂、片剂或胶囊剂形式,还可以包含分散剂或稳定剂。
在将本发明的组合物制备为食品组合物的情况下,不仅包含作为有效成分的上述二磷酸腺苷核糖环化酶的表达抑制剂或活性抑制剂,还包含制备食品时通常添加的成分,例如蛋白质、碳水化合物、脂肪、营养素、调味剂及香味剂。上述碳水化合物的例有:单糖,例如葡萄糖、果糖等;二糖,例如乳糖、蔗糖、寡糖等;以及多糖,例如麦芽糊精、环糊精等通常的糖以及山梨糖醇、赤藓糖醇等糖醇。香味剂可以使用天然香味剂(索马甜、甜菊叶提取物(例如莱包迪苷A、甘草酸等))以及合成香味剂(糖精、阿巴斯甜等)。
例如,在将本发明的食品组合物制备为饮剂的情况下,除本发明的二磷酸腺苷核糖环化酶的表达抑制剂或活性抑制剂以外,还可以包含柠檬酸、液态果糖、砂糖、葡萄糖、醋酸、苹果酸、果汁、杜仲提取液、大枣提取液、甘草提取液等。
本发明的食品组合物通过调节肾脏相关的多种病理形式的相关因子的调节(肾脏重量相对于体重的显著减少、肌酸酐清除率的显著增加、尿白蛋白量的显著减少;将转化生长因子-β1、纤连蛋白、胶原蛋白IV的表达量降至正常水平;使肾小球肥大、炎症细胞的浸润、移行上皮细胞的形成恢复至正常水平)来在肾脏疾病的改善中起到非常优秀的作用。
根据本发明的又一实施方式,本发明提供缺失二磷酸腺苷核糖环化酶或其自然发生的变体的异型基因的动物模型。
根据本发明的优选实例,上述动物为除人类以外的哺乳动物、鸟类、爬虫类、两栖动物或鱼类。
根据本发明的又一实施方式,本发明提供包括如下步骤的二磷酸腺苷核糖环化酶介导的疾病的鉴定方法:步骤(a),向上述缺失二磷酸腺苷核糖环化酶或其自然发生的变体的异型基因的动物模型和野生型(wild-type)动物模型诱导特定疾病;以及步骤(b),确认上述动物模型之间的差异。
在利用上述动物模型时,可以利用上述动物模型之间的差异(例如体重、肾脏重量、血压、肌酸酐清除率、血糖、炎症、噬菌体的肥厚程度等的差异)来确认特定疾病(例如糖尿病、肾脏疾病、高血压、肥胖等)是因二磷酸腺苷核糖环化酶的介导发病还是与二磷酸腺苷核糖环化酶无关地发病的。
根据本发明的又一实施方式,本发明提供有关二磷酸腺苷核糖环化酶介导的疾病诊断的信息提供方法,包括:步骤1),检测从对象分离的试样内包含序列表中序列1的氨基酸序列的二磷酸腺苷核糖环化酶或其自然发生的变体的表达或活性水平;以及步骤2),通过将上述步骤1)的二磷酸腺苷核糖环化酶或其自然发生的变体的表达或活性水平与正常对照组比较来判断个体是否具有患环化酶介导的疾病的风险。
在本说明书中,术语“诊断”是指确认病理状态的存在或特征的行为。就本发明的目的来说,诊断是指确认与二磷酸腺苷核糖环化酶相关或由其介导的疾病已发病或发病的可能性的行为。
二磷酸腺苷核糖环化酶由多种激素激活,该酶从作为底物的烟酰胺腺嘌呤二核苷酸生成作为产物的环化二磷酸腺苷核糖,该环化二磷酸腺苷核糖在几乎所有器官中增加细胞内的钙。并且,已知由二磷酸腺苷核糖环化酶的活性引起的钙的异常增加是胰岛素分泌(insulin secretion)、细胞肥大(hypertrophy)、细胞增殖等多种活体病理的因素。因此,可以通过检测上述二磷酸腺苷核糖环化酶的表达或活性水平来为由细胞内钙增加引发的二磷酸腺苷核糖环化酶介导的疾病的诊断提供有用的信息。
根据本发明的又一实施方式,本发明提供用于诊断二磷酸腺苷核糖环化酶介导的疾病的组合物,包含检测二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平的制剂或者检测蛋白质水平的制剂,上述二磷酸腺苷核糖环化酶或其自然发生的变体包含序列表中序列1的氨基酸序列。
根据本发明的优选实例,本发明的基因表达水平的制剂为与编码二磷酸腺苷核糖环化酶或其自然发生的变体的基因特异性结合的引物或探针。
根据本发明的优选实例,本发明的检测蛋白质水平的制剂为与二磷酸腺苷核糖环化酶或其自然发生的变体特异性结合的抗体或其抗原结合片段。
由于上述抗体或其抗原结合片段与二磷酸腺苷核糖环化酶或其自然发生的变体特异性结合,因此利用其能够准确检测样品中所包含的二磷酸腺苷核糖环化酶或其自然发生的变体的量。
若利用本发明的诊断用组合物,则可以通过抗原抗体结合反应分析对上述抗体的抗原,从而可以定量二磷酸腺苷核糖环化酶或其自然发生的变体的量,优选地,上述抗原抗体结合反应选自由通常的酶联免疫吸附测定(ELISA,Enzyme-linked immunosorbentassay)、放射免疫分析(RIA,Radioimmnoassay)、夹心分析法(Sandwich assay)、聚丙烯酰胺凝胶蛋白印迹法(Western Blot)、免疫印迹分析(Immunoblot assay)及免疫组织化学染色方法(Immnohistochemical staining)组成的组中,但不限定于此。
用于抗原-抗体结合反应的固定体可以使用选自由硝化纤维膜、聚偏氟乙烯(PVDF)膜、由聚乙烯(Polyvinyl)树脂或聚苯乙烯(Polystyrene)树脂合成的孔板(Wellplate)及玻璃制成的载玻片(Slide glass)组成的组中的固定体,但不限定于此。
优选地,使用发生显色反应的通常的显色剂标记第二抗体,可以使用选自由辣根过氧化物酶(HRP,Horseradish peroxidase)、碱性磷酸酶(Alkaline phosphatase)、胶体金(Coloid gold)、聚L-赖氨酸-异硫氰酸荧光素(FITC,Poly L-lysine-fluoresceinisothiocyanate)、罗丹明-B-异硫氰酸荧光素(RITC,Rhodamine-B-isothiocyanate)等荧光物质及色素(Dye)组成的组中的一种标记体。优选地,诱导显色的底物根据发生显色反应的标记物来使用,优选地,使用选自由3,3',5,5'-四甲基联苯胺(TMB,3,3',5,5'-tetramethyl bezidine)、2,2'-联氮-双-(3-乙基苯并噻唑啉-6-磺酸)(ABTS,2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)及邻苯二胺(OPD,ophenylenediamine)组成的组中的一种,但不限定于此。
根据本发明的又一实施方式,本发明提供二磷酸腺苷核糖环化酶介导的疾病的诊断试剂盒,包含检测二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平的制剂或者检测蛋白质水平的制剂,上述二磷酸腺苷核糖环化酶或其自然发生的变体包含序列表中序列1的氨基酸序列。
本发明的诊断试剂盒还可以包括适于分析方法的一种或一种以上的其他结构成分组合物、溶液或装置、或者有关此的使用说明书。
根据本发明的又一实施方式,本发明提供预防或治疗二磷酸腺苷核糖环化酶介导的疾病的物质的筛选方法:步骤1),使用候补物质处理表达包含序列表中序列1的氨基酸序列的二磷酸腺苷核糖环化酶或其自然发生的变体的细胞;步骤2),通过上述候补物质的处理来检测上述二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平或蛋白质水平;以及步骤3),将上述基因表达水平或蛋白质水平与未使用候补物质处理的对照组比较,若减少,则将上述候补物质筛选为预防或治疗二磷酸腺苷核糖环化酶介导的疾病的物质。
优选地,上述二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平的检测通过选自由免疫沉淀法(immunoprecipitation)、放射免疫分析法(RIA)、酶联免疫吸附测定法(ELISA)、免疫组织化学、实时聚合酶链式反应(RT-PCR)、蛋白印迹法(WesternBlotting)及流式细胞荧光分选(FACS)组成的组中的一种以上的方法来检测,但不限定于此。
优选地,上述二磷酸腺苷核糖环化酶或其自然发生的变体的蛋白质水平的检测通过选自由SDS聚丙烯酰胺凝胶电泳(SDS-PAGE)、免疫荧光法、酶联免疫吸附测定法、质量分析及蛋白质芯片组成的组中的一种以上的方法来检测,但不限定于此。
发明的效果
本发明的特征及优点概括如下:
(i)本发明提供包含新型二磷酸腺苷核糖环化酶或其自然发生的变体的表达抑制剂或活性抑制剂作为有效成分的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物。
(ii)并且,本发明提供包含检测上述二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平的制剂或者检测蛋白质水平的制剂的用于诊断二磷酸腺苷核糖环化酶介导的疾病的组合物。
(iii)本发明的组合物具有抑制通过血管紧张素II的新型二磷酸腺苷核糖环化酶的表达或者活性增加引起的肾脏细胞内钙增加的效果,因此,能够有效用作二磷酸腺苷核糖环化酶介导的疾病,尤其是肾脏疾病的治疗剂。
附图说明
图1为在HEK293细胞和MES13细胞中检测新型二磷酸腺苷核糖环化酶的烟酰胺腺嘌呤二核苷酸糖苷酶(NADase)活性的图。
图2为评估纯化的FLAG-二磷酸腺苷核糖环化酶(FLAG-ADPRC)的环化二磷酸腺苷核糖合成能力的图。
图3为在MES13细胞中检测当使用血管紧张素II刺激时通过新型二磷酸腺苷核糖环化酶在细胞内生成的环化二磷酸腺苷核糖的图。
图4为通过序列对比来比较本发明的二磷酸腺苷核糖环化酶的种间序列的同源性的结果(以小鼠为基准,人类(96%),大鼠(96%),狗(90%),猪(88%),兔(89%)、绵羊(90%),鸡(70%),牛(78%),黑猩猩(93%),马(91%),蛙(63%),山羊(90%),火鸡(62%),豚鼠(91%),细粒棘球绦虫(27%),埃及血吸虫(22%),旋毛虫(22%),果蝇(19%),斑马鱼(56%))。
图5为检测抑制新型二磷酸腺苷核糖环化酶的烟酰胺腺嘌呤二核苷酸糖苷酶活性的新型抑制剂的效果的图。
图6a至图6d为在糖尿病肾病小鼠模型中检测检测二咖啡酰奎宁对血糖(图6a)、肾脏重量(kidney weight)与体重(body weight)的比例(图6b)、肌酐清除率(图6c)及尿白蛋白量(图6d)的效果的图。
图7为在糖尿病肾病小鼠模型的肾脏组织中检测二咖啡酰奎宁酸对二磷酸腺苷核糖环化酶的活性(图7的a部分)及环化二磷酸腺苷核糖浓度(图7的b部分)的效果的图。
图8为在糖尿病肾病小鼠模型的肾脏组织中检测二咖啡酰奎宁酸对转化生长因子-β1、纤连蛋白、胶原蛋白IV的表达变化的效果的图。
图9为在糖尿病肾病小鼠模型的肾脏组织中通过苏木精伊红(Hematoxylin andEosin,H&E)染色来观察组织病理学变化的图。
图10为检测正常小鼠与ADPRC hetero(ADPRC(+/-))小鼠的糖尿病肾病模型的血糖(图10a)、肾脏重量与体重的比例(图10b)及肌酐清除率(图10c)的图。
图11a至图11b为在正常小鼠与高血压小鼠模型中检测二咖啡酰奎宁酸对血压(图11a)及肌酐清除率(图11b)的效果的图。
具体实施方式
以下,通过实施例更为详细地说明本发明。这些实施例仅用于更为具体地说明本发明,本发明所属技术领域的普通技术人员应该明了的是,根据本发明的要旨,本发明的范围并不限定于这些实施例。
实施例
实施例1.新型二磷酸腺苷核糖环化酶的烟酰胺腺嘌呤二核苷酸糖苷酶的酶活性
为了确认序列表中序列1的二磷酸腺苷核糖环化酶的活性,将编码上述二磷酸腺苷核糖环化酶的互补DNA序列连接于FLAG-CMV-2载体来制备FLAG-ADPRC质粒,使用转染试剂(transfection reagent)使其在HEK293细胞或MES13细胞中诱导新型二磷酸腺苷核糖环化酶的过表达。使用裂解缓冲液(lysis buffer)裂解上述过表达的二磷酸腺苷核糖环化酶。向45μl的裂解的试样处理5μl的2mM的ε-NAD(烟酰胺1,N6-乙烯腺嘌呤二核苷酸(Nicotinamide 1,N6-ethenoadenine dinucleotide)),在37℃的温度下反应1小时。反应后使用50μl的10%的三氯乙酸(Trichloroacetic acid)处理来停止酶-底物反应。通过10分钟的离心分离,将80μl的上清液加入720μl的0.1M的磷酸钠缓冲液(sodium phosphatebuffer)后,在激发波长(excitation)为297nm、发射波长(emission)为410nm的条件下,使用荧光分析仪测量吸光度。结果如图1所示。
实施例2.评估新型二磷酸腺苷核糖环化酶的环化二磷酸腺苷核糖合成能力
上述二磷酸腺苷核糖环化酶的环化二磷酸腺苷核糖合成能力的评估是通过Graeff R et al[Graeff R,Lee HC.Biochem.J.361:379-384,2002]报告的方法来实施的。
具体地,使用转染试剂在HEK293细胞中过表达FLAG-ADPRC质粒后,使用裂解缓冲液裂解。利用FLAG-agarose色谱柱将裂解的试样纯化过表达的FLAG-ADPRC。使用100μM的β-NAD处理纯化的试样后,在37℃的温度下反应1小时。反应后,使用三氯乙酸处理以使最终浓度为0.6M来提取环化二磷酸腺苷核糖后,向0.1ml的提取物和0.1ml的环化二磷酸腺苷核糖标准溶液中加入50μl的二磷酸腺苷核糖环化酶(ADPR cyclase)(0.3μg/ml)、烟酰胺(nicotinaminde,30mM)、磷酸钠(sodium phosphate,100mM)混合溶液,在常温下反应30分钟。
向该混合液中加入乙醇(ethanol,2%)、醇脱氢酶(alcohol dehydrogenase,100μg/ml)、刃天青(resazurin,20μM)、心肌黄酶(diaphorase,10μg/ml)、黄素单核苷酸(FMN,10μM)、烟酰胺(10mM)、牛血清白蛋白(BSA,0.1mg/ml)、磷酸钠(100mM),反应2小时至4小时。使用544nm和590nm之间的荧光分光光度计测量反应物的吸光度。结果如图2所示。
实施例3.在MES13细胞中通过二磷酸腺苷核糖环化酶的细胞内环化二磷酸腺苷核糖浓度的变化
上述细胞内通过二磷酸腺苷核糖环化酶的细胞内环化二磷酸腺苷核糖浓度的变化是通过Graeff R et al[Graeff R,Lee HC.Biochem.J.361:379-384,2002]报告的方法实施的。
具体地,使用新型二磷酸腺苷核糖环化酶的小干扰RNA(small interfering RNA,序列表中序列22)作为转染试剂来抑制二磷酸腺苷核糖环化酶在MES13细胞中的表达。使用150nM的血管紧张素II处理二磷酸腺苷核糖环化酶的表达被抑制的细胞60秒钟后,利用0.6M的三氯乙酸提取环化二磷酸腺苷核糖后,向0.1ml的提取物和0.1ml的环化二磷酸腺苷核糖标准溶液中加入50μl的二磷酸腺苷核糖环化酶(0.3μg/ml)、烟酰胺、磷酸钠混合溶液,在常温下反应30分钟。
向该混合液中加入乙醇(2%)、醇脱氢酶(100μg/ml)、刃天青(20μM)、心肌黄酶(10μg/ml)、黄素单核苷酸(10μM)、烟酰胺(10mM)、牛血清白蛋白(0.1mg/ml)、磷酸钠(100mM),反应2小时至4小时。使用544nm和590nm之间的荧光分光光度计测量反应物的吸光度。结果如图3所示。
实施例4.抑制新型二磷酸腺苷核糖环化酶的烟酰胺腺嘌呤二核苷酸糖苷酶活性的新型抑制剂的效果
为了寻找抑制序列表中序列1的新型二磷酸腺苷核糖环化酶的活性的抑制剂,将通过4,4'-二羟基偶氮苯(4,4'-dihydroxyazobenzene,4-DHAB,TCI公司(日本))、2,2'-二羟基偶氮苯(2,2'-dihydroxyazobenzene,2-DAB,Sigma-Aldrich公司(美国))、2-(3,4-二羟基苯基)-3,5,7-三羟基-4H-色烯-4-酮(2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one,槲皮素(Quercetin),Sigma-Aldrich公司(美国))、San4825(kannt A et al[Kannt A,Sicka K,Kroll K,Kadereit D,Gogelein H.Naunyn.Schmiedebergs.Arch.Pharmacol.385:717-727,2012],合成(中国))和化合物筛选新发现的2-(1,3-苯并恶唑-2-基氨基)-1-甲基喹唑啉-4(1H)-酮(2-(1,3-benzoxazol-2-ylamino)-1-methylquinazoline-4(1H)-one,2-BMQ,合成(中国))、1,4-二咖啡酰奎宁酸(1,4-Dicaffeoylquinic acid,1,4-DCQA,普瑞法公司(Biopurify)(中国),以下称DCQA)与40μl的新型二磷酸腺苷核糖环化酶(ADPRC)和5μl抑制剂在冰水中反应15分钟。反应后,使用5μl的2mM的ε-NAD处理,在37℃的温度下反应1小时。反应后使用50μl的10%的三氯乙酸处理来停止酶-底物反应。通过10分钟的离心分离,将80μl的上清液加入720μl的0.1M的磷酸钠缓冲液后,在激发波长为297nm、发射波长为410nm的条件下,使用荧光分析仪测量吸光度。结果如图5所示。如图5所示,可以确认相对于Control组,4-DHAB以42.40%的比例,2-BMQ以36.49%的比例,还有DCQA以惊人的79.64%的比例抑制了烟酰胺腺嘌呤二核苷酸糖苷酶的活性。
实施例5.DCQA在肾病小鼠模型的血糖、肾脏重量与体重的比例、肌酸酐清除率及尿白蛋白量中的效果
肾病小鼠模型中的血糖、肾脏与体重的比例、肌酐清除率及尿白蛋白量的检测是通过Kim SY et al[Kim SY,Park KH,Gul R,Jang KY,Kim UH.Am.J.Physiol.RenalPhysiol.296:F291-F297,2009]报告的方法实施的。
具体地,分为向每只C57BL/6J小鼠腹腔注射0.2ml的50mM的柠檬酸盐缓冲液(citrate buffer,pH 4.8)的组(Control组和DCQA组)和以5mg/ml的浓度在50mM的柠檬酸盐缓冲液中溶解链脲佐菌素(Streptozotocin(STZ,Sigma-Aldrich公司(美国)))后向每只腹腔注射200μl的组(STZ组和STZ+DCQA组)。注射STZ后,从第2天开始测量血糖,将血糖数值为300mg/dL的小鼠分为STZ组及STZ+DCQA组后来使用。将上述实施例5中对新型二磷酸腺苷核糖环化酶的抑制效果最突出的DCQA溶于二甲基亚砜(Dimethyl Sulfoxide)中使浓度为9mg/ml后,使用生理盐水稀释为9μg/ml的浓度后向血糖上升的小鼠在6周内每日腹腔注射100μl。在6周的最后一天将小鼠放入代谢笼中接取尿液24小时。
接取尿液24小时后,测量小鼠的体重并检测血糖(图6a)。并且,为了确认作为肾脏疾病治疗剂的可能性,使用麻醉剂实施安乐死后获得血清并摘出肾脏。利用摘出的肾脏测量肾脏重量与体重的比例后(图6b),将部分肾脏放入10%的福尔马林溶液中固定以用于荧光染色及苏木精伊红染色,剩下的肾脏分为多块来检测二磷酸腺苷核糖环化酶的活性及环化二磷酸腺苷核糖的浓度。利用肌酐检测试剂盒(BioAssay System公司,美国)检测尿液和血清的肌酐来计算肌酐清除率(图6c),利用白蛋白检测试剂盒(BioAssay System公司,美国)检测尿白蛋白量(图6d)。结果如图6所示。
如上述图6所示,在通过STZ诱发的糖尿病小鼠模型中,在STZ+DCQA组的情况下,相对于对照组(STZ),血糖没有减少(图6a),但通过肾脏重量与体重的比例的显著减少(图6b),肌酸酐清除率的显著增加(图6c),尿白蛋白量的显著减少(图6d)确认到可以作为慢性肾衰竭或糖尿病肾病之类的肾脏疾病治疗剂的候补的可能性。
实施例6.肾病小鼠模型肾脏组织中DCQA对二磷酸腺苷核糖环化酶(ADPRC)的活性及环化二磷酸腺苷核糖浓度的效果
肾病小鼠模型的肾脏组织中的二磷酸腺苷核糖环化酶活性和环化二磷酸腺苷核糖浓度检测是通过Kim SY et al[Kim SY,Park KH,Gul R,Jang KY,KimUH.Am.J.Physiol.Renal Physiol.296:F291-F297,2009]报告的方法实施的。
具体地,分为向每只C57BL/6J小鼠腹腔注射0.2ml的50mM的柠檬酸盐缓冲液(pH4.8)的组(Control组和DCQA组)和以5mg/ml的浓度在50mM的柠檬酸盐缓冲液中溶解链脲佐菌素(Sigma-Aldrich公司(美国))后向每只腹腔注射200μl的组(STZ组和STZ+DCQA组)。注射STZ后,从第2天开始测量血糖,将血糖数值为300mg/dL的小鼠分为STZ组及STZ+DCQA组后来使用。将上述实施例5中对新型二磷酸腺苷核糖环化酶的抑制效果最突出的DCQA溶于二甲基亚砜中使浓度为9mg/ml后,使用生理盐水稀释为9μg/ml的浓度后向血糖上升的小鼠在6周内每日腹腔注射100μl。为了确认作为肾脏疾病治疗剂的可能性,使用麻醉剂实施安乐死后获得血清并摘出肾脏。
使用裂解缓冲液裂解各组摘出的肾组织的一部分后,向45μl的裂解的试样处理5μl的2mM的烟酰胺鸟嘌呤二核苷酸(NGD,Nicotinamide guanine dinucleotide),在37℃的温度下反应1小时。反应后使用50μl的10%的三氯乙酸(Trichloroacetic acid)处理来停止酶-底物反应。通过10分钟的离心分离,将80μl的上清液加入720μl的0.1M的磷酸钠缓冲液后,在激发波长为297nm、发射波长为410nm的条件下,使用荧光分析仪测量吸光度。
并且,使用0.2ml的0.6M的三氯乙酸处理各组摘出的肾脏组织的一部分来提取环化二磷酸腺苷核糖后,向0.1ml的提取物和0.1ml的环化二磷酸腺苷核糖标准溶液中加入50μl的二磷酸腺苷核糖环化酶(0.3μg/ml)、烟酰胺(30mM)、磷酸钠(100mM)混合溶液,在常温下反应30分钟。向该混合液加入乙醇(2%)、醇脱氢酶(100μg/ml)、刃天青(20μM)、心肌黄酶(10μg/ml)、黄素单核苷酸(10μM)、烟酰胺(10mM)、牛血清白蛋白(0.1mg/ml)、磷酸钠(100mM),反应2小时至4小时。使用544nm和590nm之间的荧光分光光度计测量反应物的吸光度。结果如图7所示。
如图7的a部分所示,本发明的DCQA将通过STZ增加的二磷酸腺苷核糖环化酶(ADP-ribosyl cyclase)的活性降至对照组(control)水平以下,如图7的b部分所示,本发明的DCQA将通过STZ增加的环化二磷酸腺苷核糖的浓度降至对照组(control)水平,从而确认到DCQA具有降低由与肾脏疾病相关的肾脏功能异常或者损伤引起的二磷酸腺苷核糖环化酶的活性和环化二磷酸腺苷核糖的浓度的能力。
实施例7.1,4-DCQA在肾病小鼠模型的肾脏组织中对转化生长因子-β1、纤连蛋白、胶原蛋白IV的表达变化的效果
肾病小鼠模型的肾脏组织中转化生长因子-β1、纤连蛋白、胶原蛋白IV的表达变化是通过Kim SY et al[Kim SY,Park KH,Gul R,Jang KY,Kim UH.Am.J.Physiol.RenalPhysiol.296:F291-F297,2009]报告的方法检测的。
具体地,分为向每只C57BL/6J小鼠腹腔注射0.2ml的50mM的柠檬酸盐缓冲液(pH4.8)的组(Control组和DCQA组)和以5mg/ml的浓度在50mM的柠檬酸盐缓冲液中溶解链脲佐菌素(Sigma-Aldrich公司(美国))后向每只腹腔注射200μl的组(STZ组和STZ+DCQA组)。注射STZ后,从第2天开始测量血糖,将血糖数值为300mg/dL的小鼠分为STZ组及STZ+DCQA组后来使用。将上述实施例5中对新型二磷酸腺苷核糖环化酶的抑制效果最突出的DCQA溶于二甲基亚砜中使浓度为9mg/ml后,使用生理盐水稀释为9μg/ml的浓度后向血糖上升的小鼠在6周内每日腹腔注射100μl。为了确认作为肾脏疾病治疗剂的可能性,使用麻醉剂实施安乐死后获得血清并摘出肾脏。将摘出的肾脏的一部分放入10%的福尔马林溶液中固定。利用冷冻组织切片机将使用10%的福尔马林溶液固定的肾脏组织切成肾脏组织切片并放置在载玻片上,使用TTBS(Tris缓冲盐溶液(Tris-buffered saline,TBS)和0.1%的吐温(Tween)20)缓冲液洗涤后,使用含有1%的牛血清白蛋白(BSA)的TTBS缓冲液反应1小时。使用含有1%的牛血清白蛋白的TTBS缓冲液将第一抗体(转化生长因子-β1(Santa Cruz公司,美国)、纤连蛋白(Santa Cruz公司,美国)、胶原蛋白IV(Abcam公司,英国))稀释为1∶200后在4℃的温度下反应12小时以上。使用TTBS缓冲液将与第一抗体反应的组织洗涤3次后,将附着有聚L-赖氨酸-异硫氰酸荧光素的第二抗体以1∶200的比例稀释于TTBS缓冲液后在避光的场所中在室温下反应1小时。在第二抗体反应后使用TTBS缓冲液洗涤3次后,利用封固溶液粘合盖玻片。使用以绿色荧光观察的荧光显微镜(Carl Zeiss公司,德国)观察染色的肾脏在组织。结果如图8所示。
如图8所示,本发明的DCQA将通过STZ增加的转化生长因子-β1、纤连蛋白、胶原蛋白IV的表达量降至对照组(control)水平,从而确认到DCQA具有降低由与肾脏疾病相关的肾脏功能异常或损伤引起的转化生长因子-β1、纤连蛋白、胶原蛋白IV的表达量的能力。
实施例8.肾病小鼠模型肾脏组织中通过苏木精伊红染色的组织病理学变化
肾病小鼠模型中的肾脏组织的组织病理学变化是通过Shu B et al[Shu B,FengY,Gui Y,Lu Q,Wei W,Xue X,Sun X,He W,Yang J,Dai C.Cell.Signal.42:249-258,2018]报告的方法检测的。
具体地,分为向每只C57BL/6J小鼠腹腔注射0.2ml的50mM的柠檬酸盐缓冲液(pH4.8)的组(Control组和DCQA组)和以5mg/ml的浓度在50mM的柠檬酸盐缓冲液中溶解链脲佐菌素(Sigma-Aldrich公司(美国))后向每只腹腔注射200μl的组(STZ组和STZ+DCQA组)。注射STZ后,从第2天开始测量血糖,将血糖数值为300mg/dL的小鼠分为STZ组及STZ+DCQA组后来使用。将上述实施例5中对新型二磷酸腺苷核糖环化酶的抑制效果最突出的DCQA溶于二甲基亚砜中使浓度为9mg/ml后,使用生理盐水稀释为9μg/ml的浓度后向血糖上升的小鼠在6周内每日腹腔注射100μl。为了确认作为肾脏疾病治疗剂的可能性,使用麻醉剂实施安乐死后获得血清并摘出肾脏。将摘出的肾脏的一部分放入10%的福尔马林溶液中固定。利用冷冻组织切片机将使用10%的福尔马林溶液固定的肾脏组织切成肾脏组织切片并放置在载玻片上,用流水冲洗5分钟后,使用苏木精(Hematoxylin)染色5分钟。染色后,用流水冲洗5分钟后,在157mM的盐酸快速浸泡2次并拿出后,用流水冲洗5分钟。在0.25%的氨水中快速浸泡1次并拿出后,再次用流水冲洗5分钟,使用伊红(Eosin)染色约30秒钟后,分别在70%的乙醇反应30秒钟,在80%的乙醇中反应30秒钟,在90%的乙醇中反应30秒钟,在100%的乙醇中第一次反应30秒钟,在100%的乙醇中第二次反应30秒钟,在100%的乙醇中第三次反应30秒钟。最后在二甲苯(Xylene)中第一次反应5分钟后,在二甲苯中第二次反应5分钟以上后,使用封固溶液粘合盖玻片。使用光学显微镜(Lieca公司,德国)观察染色的肾脏组织。结果如图9所示。
如图9所示,本发明的DCQA使通过STZ增加的肾小球肥大、炎症细胞的浸润、移行上皮细胞的形成恢复至与对照组(control)相似的水平,从而确认到DCQA具有恢复由与肾脏疾病相关的肾脏的功能异常或损伤引起的肾脏的组织病理学变化的能力。
实施例9.比较正常小鼠与ADPRC hetero(ADPRC(+/-))小鼠肾脏疾病模型的血糖、肾脏与体重的比例及肌酐清除率
肾病小鼠模型中的血糖、肾脏与体重的比例及肌酸酐清除率的检测是通过Kim SYet al[Kim SY,Park KH,Gul R,Jang KY,Kim UH.Am.J.Physiol.Renal Physiol.296:F291-F297,2009]报告的方法实施的。
具体地,将链脲佐菌素溶于50mM的柠檬酸盐缓冲液(pH4.8)中使浓度为5mg/ml后向每只129S1/SvImJ小鼠(野生型(wild type,WT))和在The Jackson Laboratory公司(美国)制备的敲除(knockout)ADPRC hetero的(ADPRC(+/-))小鼠腹腔注射200μl。注射后从第2天开始测量血糖,使用血糖数值为300mg/dL的小鼠。从血糖上升开始6周后,将小鼠放入代谢笼中接取尿液24小时。
接取尿液24小时后,测量小鼠的体重,检测血糖(图10a)。使用麻醉剂实施安乐死后获得血清并摘出肾脏。利用摘出的肾脏测量肾脏重量及体重的比例(图10b)。利用肌酐检测试剂盒(BioAssay System公司美国)检测尿液和血清的肌酐来计算肌酐清除率(图10c)。结果如图10所示。
如图10所示,在通过STZ诱发糖尿病的小鼠模型中,相对于对照组,在ADPRC(+/-)中血糖虽然没有减少(图10a),本发明的ADPRC(+/-)+STZ组的肾脏重量与体重的比例比WT+STZ组显著减少(图10b)。并且,通过STZ的肌酐清除率的减少在ADPRC(+/-)+STZ组中并未减少(图10c),从而确认新型二磷酸腺苷核糖环化酶在慢性肾衰竭活着糖尿病肾病之类的肾脏疾病中的重要程度。
实施例10.DCQA在正常小鼠与高血压小鼠模型的血压及肌酐清除率中的效果
高血压小鼠模型的血压及肌酐清除率的检测是通过Allagnat et al[AllagnatF,Haefliger JA,Lambelet M,Longchamp A,Berard X,Mazzolai L,Corpataux JM,Deglise S.Eur.J.Vasc.Endovasc.Surg.51:733-742,2016]和Kim SY et al[Kim SY,ParkKH,Gul R,Jang KY,Kim UH.Am.J.Physiol.Renal Physiol.296:F291-F297,2009]报告的方法实施的。
具体地,将8mg的L-NAME(Nω亚硝基左旋精氨酸甲酯(Nω-nitro-l-arginine-methyl-ester),Sigma-Aldrich公司,美国)溶于1ml的生理盐水后每天向每只C57BL/6J小鼠口服给药0.2ml。在口服给药的第7天和第14天在小鼠的尾部测量血压,确认血压升高之后,将上述实施例5中对新型二磷酸腺苷核糖环化酶的抑制效果最突出的DCQA溶于二甲基亚砜中使浓度为9mg/ml后,使用生理盐水稀释为9μg/ml的浓度后在7天内每日腹腔注射100μl并口服给药L-NAME。使用DCQA处理6天后,将小鼠装入代谢笼中接取尿液24小时。
接取尿液24小时后测量小鼠的血压(图11a)。利用麻醉剂实施安乐死后获取血清。
利用肌酐检测试剂盒(BioAssay System公司,美国)检测尿液和血清的肌酐来计算肌酐清除率(图11b)。结果如图11a和图11b所示。
如图11a所示,确认到DCQA在高血压模型中没有降低血压的效果。但肌酐清除率在DCQA的作用下增加,从而确认其具有作为高血压肾病之类的肾脏疾病的治疗剂的候补的可能性(图11b)。
参考文献
1.Berridge MJ,Bootman MD,Roderick HL.Calcium signalling:dynamics,homeostasis and remodelling.Nat Rev Mol Cell Biol.4:517-529,2003.
2.Lee HC.Structure and enzymatic functions of human CD38.Mol Med.12:317-323,2006.
3.Resnick LM.Ionic basis of hypertension,insulin resistance,vasculardisease,and related disorders.The mechanism of“Syndrome X”.Am.J.Hypertens.6:123S-134S,1993.
4.Cowley AW Jr.Long-term control of arterial bloodpressure.Physiol.Rev.72:231-300,1992.
5.Kim BJ,Park KH,Yim CY,Takasawa S,Okamoto H,Im MJ,Kim UH.Generationof nicotininc acid adenine dinucleotide phosphate and cyclic ADP-ribose byglucagon-like peptide-1evokes Ca2+signal that is essential for insulinesecreation in mouse pancreatic islets.Diabetes.57:868-878,2008.
6.Gul R,Park JH,Kim SY,Jang KY,Chea JK,Ko JK,Kim UH.Inhibition ofADP-ribosyl cyclase attenuates antiotensin II-induced cardiachypertrophy.Cardiovasc.Res.81:582-591,2009.
7.Kim SY,Gul R,Rah SY,Kim SH,Park SK,Im MJ,Kwon HJ,Kim UH.Molecularmechanism of ADP-ribosyl cyclase activation in angiotensin II signaling inmurine mesangial cells.Am.J.Physiol.Renal.Physiol.294:F989-F989,2008.
8.Partida-Sanchez S,Cockayne DA,Monard S,Jacobson EL,Oppenheimer N,Garvy B,Kusser K,Goodrich S,Howard M,Harmsen A,Randall TD,Lund FE.Cyclic ADP-ribose production by CD38 regulates intracellular calcium release,extracellular calcium influx and chemotaxis in neutrophils and is requiredfor bacterial clearance in vivo.Nat Med7:1209-1216,2001.
9.Graeff R,Lee HC.A novel cycling assay for cellular cADP-ribose withnanomolar sensitivity.Biochem.J.361:379-384,2002.
10.Kim SY,Park KH,Gul R,Jang KY,Kim UH.Role of kidney ADP-ribosylcyclase in diabetic nephropathy.Am.J.Physiol.Renal Physiol.296:F291-F297,2009.
11.Shu B,Feng Y,Gui Y,Lu Q,Wei W,Xue X,Sun X,He W,Yang J,DaiC.Blockade of CD38 diminishes lipopolysaccharide-induced macrophage classicalactivation and acute kidney injury involving NF-κBsignalingsuppression.Cell.Signal.42:249-258,2018.
12.Allagnat F,Haefliger JA,Lambelet M,Longchamp A,Berard X,MazzolaiL,Corpataux JM,Deglise S.Nitric oxide deficit drives intimal hyperplasia inmouse models ofhypertension.Eur.J.Vasc.Endovasc.Surg.51:733-742,2016.
13.Kannt A,Sicka K,Kroll K,Kadereit D,Gogelein H.Naunyn.Schmiedebergs.Arch.Pharmacol.385:717-727,2012.
以上详细描述了本发明的特定部分,但本发明所属技术领域的普通技术人员应该明白的是,这些详细描述只是优选的实例,而非要以此来限制本发明的范围。因此,本发明的实质范围应通过随附的发明要求保护范围的等价物来定义。
<110> 全北大学校产学协力团
<120> 新型二磷酸腺苷核糖环化酶及其抑制剂
<130> PCT696
<150> KR 10-2019-0076979
<151> 2019-06-27
<150> KR 10-2020-0076635
<151> 2020-06-23
<160> 22
<170> KoPatentIn 3.0
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<223> Mouse ADP-ribosyl Cyclase
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Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Leu
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ser Phe Arg Pro Asn Asp Pro Lys
85 90 95
Ser Tyr Glu Ala Tyr Val Leu Asn Ile Ile Arg Phe Leu Glu Lys Tyr
100 105 110
Lys Asp Ser Ala Gln Lys Asp Asp Met Ile Phe Glu Asp Cys Gly Asn
115 120 125
Val Pro Ser Glu Pro Lys Glu Arg Gly Asp Ile Asn His Glu Arg Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Lys Leu Asp Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Leu Asn Asp Asp Ser Tyr Gly Tyr Arg Glu Gly Lys Pro Cys Ile
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Glu Ser Leu Glu Thr Tyr Pro Leu Met Met Lys Tyr Asn Pro Asn
195 200 205
Val Leu Pro Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Lys Asp Lys
210 215 220
Val Gly Asn Ile Glu Tyr Phe Gly Met Gly Gly Tyr Tyr Gly Phe Pro
225 230 235 240
Leu Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu
245 250 255
Gln Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Val Asp Thr Glu
260 265 270
Ile Arg Val Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Glu
275 280 285
Lys Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Ile Lys Ser
290 295 300
<210> 2
<211> 303
<212> PRT
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<220>
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<400> 2
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Phe
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ser Phe Arg Pro Asn Asp Pro Lys
85 90 95
Ser Tyr Glu Ala Tyr Val Leu Asn Ile Val Arg Phe Leu Glu Lys Tyr
100 105 110
Lys Asp Ser Ala Gln Arg Asp Asp Met Ile Phe Glu Asp Cys Gly Asp
115 120 125
Val Pro Ser Glu Pro Lys Glu Arg Gly Asp Phe Asn His Glu Arg Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Lys Leu Glu Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Leu Asn Asp Glu Thr Tyr Gly Tyr Lys Glu Gly Lys Pro Cys Ile
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Glu Ser Leu Glu Thr Tyr Pro Val Met Lys Tyr Asn Pro Asn Val
195 200 205
Leu Pro Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Lys Asp Lys Val
210 215 220
Gly Asn Val Glu Tyr Phe Gly Leu Gly Asn Ser Pro Gly Phe Pro Leu
225 230 235 240
Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu Gln
245 250 255
Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Met Asp Thr Glu Ile
260 265 270
Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Glu Lys
275 280 285
Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val Lys Ser
290 295 300
<210> 3
<211> 304
<212> PRT
<213> Artificial Sequence
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<223> Rat ADP-ribosyl Cyclase
<400> 3
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Leu
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ser Phe Arg Pro Asn Asp Pro Lys
85 90 95
Ser Tyr Glu Ala Tyr Val Leu Asn Ile Ile Arg Phe Leu Glu Lys Tyr
100 105 110
Lys Asp Ser Ala Gln Lys Asp Asp Met Ile Phe Glu Asp Cys Gly Ser
115 120 125
Met Pro Ser Glu Pro Lys Glu Arg Gly Glu Phe Asn His Glu Arg Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Lys Leu Asp Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Leu Asn Asp Glu Ser Tyr Gly Tyr Lys Glu Gly Lys Pro Cys Ile
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Glu Ser Leu Glu Thr Tyr Pro Leu Thr Met Lys Tyr Asn Pro Asn
195 200 205
Val Leu Pro Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Lys Asp Lys
210 215 220
Val Gly Asn Ile Glu Tyr Phe Gly Met Gly Gly Phe Tyr Gly Phe Pro
225 230 235 240
Leu Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu
245 250 255
Gln Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Leu Asp Thr Glu
260 265 270
Ile Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Glu
275 280 285
Lys Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val Lys Ser
290 295 300
<210> 4
<211> 303
<212> PRT
<213> Artificial Sequence
<220>
<223> Dog ADP-ribosyl Cyclase
<400> 4
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Phe
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ser Phe Arg Pro Asn Asp Pro Lys
85 90 95
Ser Tyr Glu Glu Tyr Val Arg Asn Ile Val Arg Phe Leu Glu Lys Tyr
100 105 110
Lys Asp Ser Ala Gln Lys Asp Glu Met Ile Phe Glu Asp Cys Gly Asn
115 120 125
Met Pro Ser Glu Ile Lys Glu Arg Gly Glu Phe Asn Asn Glu Arg Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Lys Leu Glu Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Ile Asn Asp Glu Thr Tyr Gly Tyr Arg Asp Gly Lys Pro Cys Val
165 170 175
Leu Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Glu Ser Leu Glu Ala Tyr Pro Val Met Lys Tyr Asn Pro Tyr Val
195 200 205
Leu Pro Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Lys Asp Arg Ile
210 215 220
Gly Asn Val Glu Tyr Phe Gly Leu Gly Gly Tyr Pro Gly Phe Pro Leu
225 230 235 240
Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu Gln
245 250 255
Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Met Asp Thr Glu Ile
260 265 270
Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Glu Lys
275 280 285
Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val Lys Ser
290 295 300
<210> 5
<211> 303
<212> PRT
<213> Artificial Sequence
<220>
<223> Pig ADP-ribosyl Cyclase
<400> 5
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Leu Met
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Phe
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ser Gln Lys Thr Glu Ile Ser Phe Arg Pro Asn Asp Pro Gln
85 90 95
Ser Tyr Glu Ser Tyr Val Val Ser Ile Val Arg Phe Leu Glu Lys Tyr
100 105 110
Lys Asp Leu Ala Gln Lys Asp Asp Met Ile Phe Glu Asp Cys Gly Asn
115 120 125
Val Pro Ser Glu Leu Lys Glu Arg Gly Glu Tyr Asn Asn Glu Arg Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Arg Leu Glu Trp Leu Gly Asn Ser Ser
145 150 155 160
Gly Leu Asn Asp Glu Thr Tyr Gly Tyr Lys Asp Gly Lys Pro Cys Val
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Glu Ser Leu Glu Thr Tyr Pro Val Met Lys Tyr Asn Pro Tyr Val
195 200 205
Leu Pro Val His Cys Thr Gly Lys Arg Asp Glu Asp Lys Glu Lys Val
210 215 220
Gly Thr Met Glu Tyr Phe Gly Leu Gly Gly Tyr Pro Gly Phe Pro Leu
225 230 235 240
Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu Gln
245 250 255
Pro Leu Met Ala Val Gln Phe Thr Asn Leu Thr Met Asp Thr Glu Ile
260 265 270
Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Glu Lys
275 280 285
Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val Lys Ser
290 295 300
<210> 6
<211> 303
<212> PRT
<213> Artificial Sequence
<220>
<223> Rabbit ADP-ribosyl Cyclase
<400> 6
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Phe
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Val
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ala Phe Arg Pro Ser Asp Pro Lys
85 90 95
Ser Tyr Glu Glu Tyr Val Val Asn Ile Val Arg Phe Leu Glu Lys Tyr
100 105 110
Lys Asp Ser Ala Gln Lys Asp Asp Met Val Phe Glu Asp Cys Gly Asp
115 120 125
Val Pro Ser Glu Pro Lys Glu Arg Gly Glu Phe Asn Asn Glu Arg Gly
130 135 140
Gln Arg Lys Val Cys Arg Phe Lys Leu Asn Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Ile Asp Asp Glu Thr Tyr Gly Tyr Lys Asp Gly Lys Pro Cys Ile
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Asp Ser Leu Glu Phe Ser Pro Gly Thr Lys Tyr Asn Pro Asn Val
195 200 205
Leu Pro Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Lys Glu Lys Val
210 215 220
Gly Ser Met Glu Tyr Phe Gly Met Gly Asp Tyr Ala Gly Phe Pro Leu
225 230 235 240
Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu Gln
245 250 255
Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Met Asp Thr Glu Ile
260 265 270
Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Glu Lys
275 280 285
Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val Lys Ser
290 295 300
<210> 7
<211> 303
<212> PRT
<213> Artificial Sequence
<220>
<223> Sheep ADP-ribosyl Cyclase
<400> 7
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Phe
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ala Phe Arg Pro Asn Asp Pro Lys
85 90 95
Ser Tyr Met Thr Tyr Val Asp Asn Ile Asp Asn Phe Leu Lys Lys Tyr
100 105 110
Arg Asp Ser Ala Gln Lys Asp Asp Met Ile Phe Glu Asp Cys Gly Asn
115 120 125
Val Pro Ser Glu Leu Lys Asp Arg Gly Glu Phe Asn Asn Glu Gln Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Lys Leu Glu Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Ile Asn Asp Glu Thr Tyr Gly Tyr Lys Glu Gly Lys Pro Cys Val
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Glu Ser Leu Glu Thr Tyr Pro Val Met Lys Tyr Asn Pro Tyr Val
195 200 205
Leu Pro Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Lys Glu Lys Val
210 215 220
Gly Ser Ile Glu Tyr Phe Gly Leu Gly Gly Tyr Pro Gly Phe Pro Leu
225 230 235 240
Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu Gln
245 250 255
Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Met Asp Thr Glu Ile
260 265 270
Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Glu Lys
275 280 285
Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val Lys Ser
290 295 300
<210> 8
<211> 305
<212> PRT
<213> Artificial Sequence
<220>
<223> Chicken ADP-ribosyl Cyclase
<400> 8
Met Ala Arg Gly Lys Ala Asn Asp Gly Asp Gly Asn Trp Lys Lys Phe
1 5 10 15
Ile Trp Asn Ser Glu Lys Lys Glu Leu Leu Gly Arg Thr Gly Gly Ser
20 25 30
Trp Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala
35 40 45
Gly Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Val Ser Glu
50 55 60
Phe Glu Pro Lys Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln
65 70 75 80
Val Pro Gln Val Gln Lys Thr Glu Ile Ser Phe Thr Val Asn Asp Pro
85 90 95
Lys Ser Tyr Asp Pro Tyr Val Lys Asn Leu Glu Gly Phe Leu Asn Lys
100 105 110
Tyr Ser Ala Gly Glu Gln Thr Asp Asn Ile Val Phe Gln Asp Cys Gly
115 120 125
Asp Ile Pro Thr Asp Tyr Lys Glu Arg Gly Pro Tyr Asn Asp Ala Gln
130 135 140
Gly Gln Lys Lys Val Cys Lys Phe Lys Arg Glu Trp Leu Glu Asn Cys
145 150 155 160
Ser Gly Leu Gln Asp Asn Thr Phe Gly Tyr Lys Asp Gly Lys Pro Cys
165 170 175
Ile Leu Val Lys Leu Asn Arg Ile Ile Gly Phe Lys Pro Lys Ala Pro
180 185 190
Glu Asn Glu Ser Leu Pro Ser Asp Leu Ala Gly Lys Tyr Asn Pro Tyr
195 200 205
Leu Ile Pro Val His Cys Val Ala Lys Arg Asp Glu Asp Ala Asp Lys
210 215 220
Ile Gly Met Val Glu Tyr Tyr Gly Met Gly Gly Tyr Pro Gly Phe Ala
225 230 235 240
Leu Gln Tyr Tyr Pro Tyr Tyr Gly Arg Leu Leu Gln Pro Gln Tyr Leu
245 250 255
Gln Pro Leu Val Ala Val Gln Phe Thr Asn Leu Thr Tyr Asp Val Glu
260 265 270
Val Arg Val Glu Cys Lys Glu Tyr Gly Gln Asn Ile Gln Tyr Ser Asp
275 280 285
Lys Asp Arg Phe Gln Gly Arg Phe Asp Ile Lys Phe Asp Ile Lys Ser
290 295 300
Ser
305
<210> 9
<211> 133
<212> PRT
<213> Artificial Sequence
<220>
<223> Cattle ADP-ribosyl Cyclase
<400> 9
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Phe
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ala Phe Arg Pro Asn Asp Pro Lys
85 90 95
Ser Tyr Met Thr Tyr Val Asp Asn Ile Asp Asn Phe Leu Lys Lys Tyr
100 105 110
Ser Ala Leu Val Asp Leu Val Phe Ser Gln Val Lys Thr Met Asp Asn
115 120 125
Lys Arg Met Asn Thr
130
<210> 10
<211> 303
<212> PRT
<213> Artificial Sequence
<220>
<223> Chimpanzee ADP-ribosyl Cyclase
<400> 10
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Phe
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ser Phe Arg Pro Asn Asp Pro Lys
85 90 95
Ser Tyr Glu Ala Tyr Val Leu Asn Ile Val Arg Phe Leu Glu Lys Tyr
100 105 110
Lys Asp Ser Ala Gln Arg Asp Asp Met Ile Phe Glu Asp Cys Gly Asp
115 120 125
Val Pro Ser Glu Pro Lys Glu Arg Gly Asp Phe Asn His Glu Arg Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Lys Leu Glu Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Leu Asn Asp Glu Thr Tyr Gly Tyr Lys Glu Gly Lys Pro Cys Ile
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Glu Ser Leu Glu Thr Tyr Pro Val Met Lys Tyr Asn Pro Asn Val
195 200 205
Leu Pro Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Lys Asp Lys Ile
210 215 220
Gly Asn Val Glu Tyr Phe Gly Leu Gly Asn Ser Pro Gly Phe Pro Leu
225 230 235 240
Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu Gln
245 250 255
Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Met Asp Thr Glu Ile
260 265 270
Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Glu Lys
275 280 285
Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val Lys Ser
290 295 300
<210> 11
<211> 303
<212> PRT
<213> Artificial Sequence
<220>
<223> Horse ADP-ribosyl Cyclase
<400> 11
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Phe
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ser Phe Arg Pro Asn Asp Pro Lys
85 90 95
Ser Tyr Glu Ala Tyr Val Leu Asn Ile Val Arg Phe Leu Glu Lys Tyr
100 105 110
Lys Asp Ser Ala Gln Lys Asp Asp Met Ile Phe Glu Glu Cys Gly Ser
115 120 125
Val Pro Ser Glu Leu Lys Glu Arg Gly Glu Phe Asn Asn Glu Arg Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Lys Leu Glu Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Ile Asn Asp Glu Thr Tyr Gly Tyr Lys Glu Gly Lys Pro Cys Val
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Glu Ser Leu Glu Thr Tyr Pro Val Met Lys Tyr Ser Pro Tyr Val
195 200 205
Leu Pro Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Lys Glu Lys Ile
210 215 220
Gly Asn Val Glu Tyr Phe Gly Leu Gly Gly Tyr Pro Gly Phe Pro Leu
225 230 235 240
Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu Gln
245 250 255
Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Met Asp Thr Glu Ile
260 265 270
Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Asp Lys
275 280 285
Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val Lys Ser
290 295 300
<210> 12
<211> 304
<212> PRT
<213> Artificial Sequence
<220>
<223> Frog ADP-ribosyl Cyclase
<400> 12
Met Ala Arg Asp Lys Ala Lys Glu Thr Asp Gly Gly Trp Arg Lys Phe
1 5 10 15
Ile Trp Asn Pro Asp Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser
20 25 30
Trp Phe Lys Ile Leu Leu Phe Tyr Leu Ile Phe Tyr Gly Cys Leu Ala
35 40 45
Gly Ile Phe Ile Gly Thr Ile Gln Val Leu Leu Leu Thr Ile Ser Glu
50 55 60
Tyr Glu Pro Lys Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln
65 70 75 80
Val Pro Lys Ala Val Lys Thr Glu Ile Asn Phe Ser Pro Asn Asp Pro
85 90 95
Asp Ser Tyr Asn Asp Tyr Val Gln Ser Met Glu Lys Phe Ile Ser Lys
100 105 110
Tyr Ser Asn Glu Asn Gln Val Ser Asp Lys Phe Glu Asp Cys Gly Thr
115 120 125
Met Pro Gly Gln Tyr Arg Glu Arg Gly Gly Leu Asn Lys Asp Gly Gly
130 135 140
Gln Lys Lys Ser Cys Val Phe Arg Arg Gln Trp Leu Gln Asn Cys Ser
145 150 155 160
Gly Ile Asp Asp Gln Thr Phe Gly Phe Ala Glu Gly Lys Pro Cys Val
165 170 175
Ile Val Lys Leu Asn Arg Ile Val Ala Phe Lys Pro Val Pro Pro Gln
180 185 190
Asn Asn Ser Leu Pro Pro Glu Met Thr Ala Asn Tyr Asn Pro Tyr Val
195 200 205
Ile Pro Ile His Cys Gln Gly Lys Arg Asp Glu Asp Ile Pro Asn Ile
210 215 220
Arg Glu Val Lys Tyr Tyr Gly Met Gly Gly Phe Ala Gly Phe Pro Leu
225 230 235 240
Asn Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Glu Tyr Leu Gln
245 250 255
Pro Leu Ile Ala Val Gln Phe Thr Asn Leu Thr Phe Asn Thr Glu Ile
260 265 270
Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Asp Tyr His Asp Lys
275 280 285
Asp Arg Phe Gln Gly Arg Phe Asp Ile Lys Phe Asp Ile Lys Ser Ser
290 295 300
<210> 13
<211> 303
<212> PRT
<213> Artificial Sequence
<220>
<223> Goat ADP-ribosyl Cyclase
<400> 13
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Phe
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ala Phe Arg Pro Asn Asp Pro Lys
85 90 95
Ser Tyr Met Thr Tyr Val Asp Asn Ile Asp Asn Phe Leu Lys Lys Tyr
100 105 110
Arg Asp Ser Ala Gln Lys Asp Asp Met Ile Phe Glu Asp Cys Gly Asn
115 120 125
Val Pro Ser Glu Leu Lys Asp Arg Gly Glu Phe Asn Asn Glu Gln Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Lys Leu Glu Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Ile Asn Asp Glu Thr Tyr Gly Tyr Arg Glu Gly Lys Pro Cys Val
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Glu Ser Leu Glu Thr Tyr Pro Val Met Lys Tyr Asn Pro Tyr Val
195 200 205
Leu Pro Val Gln Cys Thr Gly Lys Arg Asp Glu Asp Lys Glu Lys Val
210 215 220
Gly Ser Ile Glu Tyr Phe Gly Leu Gly Gly Tyr Pro Gly Phe Pro Leu
225 230 235 240
Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys Tyr Leu Gln
245 250 255
Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Met Asp Thr Glu Ile
260 265 270
Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr Ser Glu Lys
275 280 285
Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val Lys Ser
290 295 300
<210> 14
<211> 319
<212> PRT
<213> Artificial Sequence
<220>
<223> Turkey ADP-ribosyl Cyclase
<400> 14
Met Thr Val Leu Trp Lys Lys Phe Pro Asn Ala Ser Asp Val Thr Ala
1 5 10 15
Ile Gly Phe Thr Leu Pro Gly Tyr Gln Arg Val Phe Phe Asn Ser Trp
20 25 30
Arg Thr Ala Leu Leu His Gln Ala Leu Pro Ala Ser Pro Gly Cys Val
35 40 45
Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly Ile
50 55 60
Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Val Ser Glu Phe Glu
65 70 75 80
Pro Lys Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Val Pro
85 90 95
Gln Val Gln Lys Thr Glu Ile Ser Phe Thr Val Ser Asp Pro Lys Ser
100 105 110
Tyr Asp Pro Tyr Val Lys Asn Leu Glu Gly Phe Leu Ser Lys Tyr Ser
115 120 125
Ala Gly Glu Gln Thr Asp Asn Ile Val Phe Gln Asp Cys Gly Asp Val
130 135 140
Pro Met Asp Tyr Lys Glu Arg Gly Pro Tyr Asn Asp Asp Gln Gly Gln
145 150 155 160
Lys Lys Val Cys Lys Phe Lys Arg Glu Trp Leu Glu Asn Cys Ser Gly
165 170 175
Leu Gln Asp Asn Thr Phe Gly Tyr Lys Glu Gly Lys Pro Cys Ile Leu
180 185 190
Val Lys Leu Asn Arg Ile Ile Gly Phe Lys Pro Lys Ala Pro Glu Asn
195 200 205
Glu Ser Leu Pro Leu Gly Leu Ala Gly Lys Tyr Asn Pro Phe Leu Ile
210 215 220
Pro Val His Cys Val Ala Lys Arg Asp Glu Asp Ser Asp Lys Ile Gly
225 230 235 240
Thr Val Glu Tyr Tyr Gly Met Gly Gly Tyr Pro Gly Phe Ala Leu Gln
245 250 255
Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro His Tyr Leu Gln Pro
260 265 270
Leu Val Ala Val Gln Phe Thr Asn Leu Thr Tyr Asp Val Glu Val Arg
275 280 285
Val Glu Cys Arg Ala Tyr Gly Gln Asn Ile Gln Tyr Ser Asp Lys Asp
290 295 300
Arg Phe Gln Gly Arg Phe Asp Ile Lys Phe Asp Ile Arg Ser Ser
305 310 315
<210> 15
<211> 306
<212> PRT
<213> Artificial Sequence
<220>
<223> Guinea Pig ADP-ribosyl Cyclase
<400> 15
Met Ala Arg Gly Lys Ala Lys Glu Glu Gly Ser Trp Lys Lys Phe Ile
1 5 10 15
Trp Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp
20 25 30
Phe Lys Ile Leu Leu Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly
35 40 45
Ile Phe Ile Gly Thr Ile Gln Val Met Leu Leu Thr Ile Ser Glu Leu
50 55 60
Lys Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Thr Gln Ile
65 70 75 80
Pro Gln Ile Gln Lys Thr Glu Ile Ser Phe Arg Pro Ala Asp Pro Lys
85 90 95
Ser Tyr Glu Ala Tyr Val Leu Asn Ile Tyr Arg Phe Leu Glu Lys Tyr
100 105 110
Lys Asp Ala Ala Gln Lys Asp Asp Met Ile Phe Glu Asp Cys Ser Thr
115 120 125
Val Pro Ser Glu Pro Lys Glu Arg Gly Asp Phe Asn His Glu Arg Gly
130 135 140
Glu Arg Lys Val Cys Arg Phe Lys Leu Glu Trp Leu Gly Asn Cys Ser
145 150 155 160
Gly Gln Asn Asp Asp Ser Tyr Gly Tyr Arg Asp Gly Lys Pro Cys Ile
165 170 175
Ile Ile Lys Leu Asn Arg Val Leu Gly Phe Lys Pro Lys Pro Pro Lys
180 185 190
Asn Asp Ser Ser Glu Thr Val Glu Ile Tyr Ser Thr Met Lys Tyr Asn
195 200 205
Pro Tyr Val Leu Pro Val Gln Cys Thr Gly Lys Arg Glu Glu Asp Lys
210 215 220
Asp Lys Ile Gly Ser Val Glu Tyr Phe Gly Leu Gly Gly Tyr Ala Gly
225 230 235 240
Phe Pro Leu Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Lys
245 250 255
Tyr Leu Gln Pro Leu Leu Ala Val Gln Phe Thr Asn Leu Thr Thr Asp
260 265 270
Thr Glu Val Arg Ile Glu Cys Lys Ala Tyr Gly Glu Asn Ile Gly Tyr
275 280 285
Ser Glu Lys Asp Arg Phe Gln Gly Arg Phe Asp Val Lys Ile Glu Val
290 295 300
Lys Ser
305
<210> 16
<211> 280
<212> PRT
<213> Artificial Sequence
<220>
<223> E.granulos ADP-ribosyl Cyclase
<400> 16
Met Val Arg Cys Ser Glu Arg Tyr Arg Asn Leu Gly Leu Ala Ile Phe
1 5 10 15
Asn Pro Lys Glu Lys Lys Phe Cys Gly Arg Thr Cys Arg Ser Trp Ala
20 25 30
Leu Ile Phe Val Tyr Tyr Leu Ile Phe Tyr Ser Cys Leu Ala Gly Phe
35 40 45
Trp Ile Gly Met Leu Ser Val Leu Ile Phe Ala Met Ile Asp Thr Thr
50 55 60
Val Pro Ser Leu Thr Gly Met Gln Ser Leu Leu Lys Leu Asn Pro Gly
65 70 75 80
Leu Gly Ile Leu Pro Pro Val Asp Ser Glu Gly Thr Leu Ile Gln Leu
85 90 95
Thr Leu Phe Asp Ser Lys Gln Lys Gln Asp Tyr Leu Asn Phe Met Gln
100 105 110
Ser Tyr Leu Met Gly Tyr Ser Asn Ile Ser Thr Asn Cys Asp Phe Glu
115 120 125
Asn Gly Thr Arg Ile Asn Ser Ser Ile Leu Glu Pro Cys Glu Phe Pro
130 135 140
Leu Ser Leu Leu Gly Pro Cys Ala Asp Pro Ala Asp Tyr Ile Asn Ser
145 150 155 160
His Asn Asn Phe Cys Phe Tyr Leu Lys Leu Asn Lys Ile Tyr Gly Tyr
165 170 175
Leu Pro Asp Ile Glu Gly Asn Lys Ile Pro Ile Gln Cys Gly Pro Ala
180 185 190
Asn Ser Phe Asp Gly Ala Asn Leu Gly Gln Pro Val Tyr Tyr Pro Ser
195 200 205
Val Arg Thr Ala Asn Gly Thr Phe Gly Tyr Phe Ser Ser Val Ala Phe
210 215 220
Pro Tyr Leu Asn Gln Pro His Tyr Gln Val Pro Leu Leu Ala Val Thr
225 230 235 240
Phe Pro Asp Ile Lys Pro Asn Thr Val Val Met Val Ser Cys Ala Val
245 250 255
Leu Asn Val Lys Asp Gln Glu Pro Phe Arg Phe Asp Leu Ala Ile Asp
260 265 270
Met Asp Arg Pro Ile Ala Leu Thr
275 280
<210> 17
<211> 232
<212> PRT
<213> Artificial Sequence
<220>
<223> S.haematob ADP-ribosyl Cyclase
<400> 17
Met Gly Met Leu Ile Ile Ile Thr Gln Leu Ile Ile Ser Asn Asp Gln
1 5 10 15
Pro Tyr Ile Thr Gly Met Asp Ser Pro Leu Ala Leu Ser Pro Gly Leu
20 25 30
Gly Met Arg Pro Arg Asn Asp Phe Lys Thr Thr Leu Ile Ala Tyr Ala
35 40 45
Ser Ser Asp Pro Gln Thr Tyr Met Pro Phe Val Gln Asp Ile Arg Thr
50 55 60
Phe Leu Tyr Phe Tyr Glu Glu Val Asn Ile Gln Pro Gln Asp Gly Phe
65 70 75 80
Ala Thr Cys Asp Lys Ile Lys Ser Pro Asp Asp Val Asp Leu Val Cys
85 90 95
Lys Phe Tyr Pro His Asp Met Gly Val Cys Val Lys Glu Asn Asn Phe
100 105 110
Gly Tyr Asp Arg Ser Gln Pro Cys Val Ile Met Lys Ile Asn Lys Val
115 120 125
Tyr Gly Trp Leu Pro Asp Ile Val Asn Lys Thr Leu Ser Asn Asn Pro
130 135 140
Leu Val Arg Cys His Gly Gln Asn Pro Gln Asp Leu Glu Asn Phe Gly
145 150 155 160
Gln Val Leu Tyr Phe Pro Asn Ile Thr Val Asp Gly Lys Thr Tyr Gly
165 170 175
Tyr Phe Ser His Leu Tyr Phe Pro Tyr Leu Met Gln Val Ala Tyr Arg
180 185 190
Ser Pro Leu Val Ala Val Gln Phe Ala Ser Pro Lys Arg His Val Leu
195 200 205
Leu Met Val Arg Cys Glu Leu Phe Asn Val Arg Asn Pro Gly Asp Pro
210 215 220
Met Asp Phe Glu Ile Leu Val Asp
225 230
<210> 18
<211> 190
<212> PRT
<213> Artificial Sequence
<220>
<223> T.spiralis ADP-ribosyl Cyclase
<400> 18
Met Gly Tyr Gln Pro Trp Leu Arg Asp Asp Pro Glu Ser Thr Leu Ile
1 5 10 15
Tyr Phe Asn Arg Ser Glu Pro Ser Thr Tyr Lys Asn Asn Ser Ser Asn
20 25 30
Arg Glu Asn Thr His Ile Ala Cys Ala Phe Asp Leu Ile Glu His Phe
35 40 45
Glu Ser Gln Gly Cys Gly Glu Lys Asp Asp Phe Gly Phe Lys Asn Ala
50 55 60
Thr Pro Cys Ile Val Leu Thr Leu Asn Lys Leu Ile Gly Trp Glu Pro
65 70 75 80
Val Ala Tyr Pro Lys Asp Ser Ala Pro Asp Ala Ile Lys Asp His Tyr
85 90 95
Asn Tyr Ser Thr Pro Asp Val Ala Ile Ala Cys Glu Gly Glu Phe Pro
100 105 110
Val Asp Gln Glu His Ile Gly Pro Leu Gln Tyr Ile Pro Pro Thr Gly
115 120 125
Ile Pro His Lys Phe Phe Pro Tyr Arg Val Met Pro Asn Tyr His Gln
130 135 140
Pro Phe Ala Leu Val Lys Phe Val Gly Pro Pro Lys Gly Ile Leu Ile
145 150 155 160
Glu Val Glu Cys Lys Ala Tyr Ala Tyr Asn Ile Met His Asp Arg Ser
165 170 175
Tyr Arg Leu Gly Met Val His Phe Glu Leu Leu Ile Asp Ser
180 185 190
<210> 19
<211> 345
<212> PRT
<213> Artificial Sequence
<220>
<223> Drosophila ADP-ribosyl Cyclase
<400> 19
Met Pro Glu Asp Val Met Val Pro Ser Gly Asn Tyr Lys Val Arg Lys
1 5 10 15
Arg Phe Arg Asn Glu Glu His Arg Arg Ser Lys Lys Asp Met Pro Trp
20 25 30
Thr Lys Gln Ile Leu Asp Leu Asn Glu Asn Arg Phe Phe Gly Arg Thr
35 40 45
Ala Trp Ala Trp Cys Arg Ile Val Ser Phe Tyr Leu Leu Leu Tyr Leu
50 55 60
Leu Ile Phe Leu Ile Leu Leu Cys Leu Tyr Leu Ile Phe Arg Phe Tyr
65 70 75 80
Phe Ile Gln Lys Asp Arg Pro Ser Ile Leu Lys Glu Ala Pro Gly Leu
85 90 95
Ser Ile Val Pro Arg Asn Glu Ser Thr Ile Thr Phe Tyr Tyr Asn Gln
100 105 110
Met Pro Asp Ile Tyr Pro Leu Cys Asp Arg Ile Asp Glu Phe Leu Glu
115 120 125
Lys Leu Asp Asp Glu Ala Phe Glu Tyr Phe His Glu Cys Asn Gly Asp
130 135 140
Lys Leu Trp Gly Tyr Asn Glu Lys Lys Pro Cys Val Phe Val Lys Leu
145 150 155 160
Asn Lys Ile Phe Gly Phe Lys Pro Glu Val Tyr Thr Ser Pro Thr Glu
165 170 175
Leu Pro Ser Glu Ala Pro Pro Glu Leu Thr Thr Ile Met Gly Lys Phe
180 185 190
Lys Gly His Asp Arg Ile Trp Leu Thr Cys Glu Leu Ser Gln Gly Lys
195 200 205
Leu Pro Lys Ile Val Tyr Ile Pro Gly Pro Tyr Phe Asp Thr Glu Glu
210 215 220
Leu Ala Gly Val Ser Arg Val Val Ala Leu Gln Leu Thr Glu Met Pro
225 230 235 240
Glu Asn Lys Glu Ile Phe Val Ser Cys Arg Val Trp Ala Lys Asn Ile
245 250 255
Lys Ile Asp Leu Lys Gln Thr Gly Arg Gly Asn Ala Lys Phe Ser Met
260 265 270
Lys Met Lys Val Lys Lys Ser Asn Asn Asn Pro Pro Asp Asn Leu Glu
275 280 285
Thr Arg Pro Thr Lys Phe Lys Val Trp Lys Pro Asn Gln Asp Gln Gln
290 295 300
Arg Ile Phe Tyr Asp Glu Asp Leu Gln Leu Pro Asp Val Pro Asp Leu
305 310 315 320
Glu Ala Glu Asp Asp Gly Val Lys Thr Asp Thr Arg Ser Ala Ile Pro
325 330 335
Thr Glu Pro Pro Asp Lys Leu Lys Arg
340 345
<210> 20
<211> 306
<212> PRT
<213> Artificial Sequence
<220>
<223> Zebrafish Type A ADP-ribosyl Cyclase
<400> 20
Met Pro Ala Asn Lys Asp Gly Asp Gly Gly Trp Lys Ser Phe Ile Trp
1 5 10 15
Asn Ser Asp Lys Lys Glu Phe Leu Gly Arg Thr Gly Cys Ser Trp Leu
20 25 30
Lys Ile Phe Ile Phe Tyr Val Ile Phe Tyr Gly Cys Leu Ala Gly Ile
35 40 45
Phe Ile Gly Thr Ile Gln Ala Met Leu Leu Thr Leu Ser Asn Tyr Lys
50 55 60
Pro Thr Tyr Gln Asp Arg Val Ala Pro Pro Gly Leu Ser His Ser Pro
65 70 75 80
Arg Pro Asp Lys Ala Glu Ile Asn Tyr Asn Ile Asn Asp Glu Ser Thr
85 90 95
Tyr Leu Pro Tyr Val Asn His Ile Asp Ala Phe Leu Lys Ala Tyr Asn
100 105 110
Glu Asp Val Gln Lys Asp Asp Thr Lys Phe Glu Glu Cys Gly Asp Lys
115 120 125
Pro Gln Phe Tyr Thr Asp Arg Gly Glu Leu Glu Ser Asp Asn Gly Val
130 135 140
Arg Lys Ala Cys Arg Phe Arg Arg Glu Trp Leu Gly Glu Cys Ser Gly
145 150 155 160
Gln Lys Asp Glu Lys Leu Lys Asn Tyr Gly Phe Asp Asp Gly Gln Pro
165 170 175
Cys Leu Ile Val Lys Leu Asn Arg Ile Val Asn Phe Met Pro Arg Pro
180 185 190
Pro Ala Ser Asn Asp Ser Ile Pro Glu Ala Val Arg Pro Lys Leu Gln
195 200 205
Gly Asn Val Ile Pro Ile His Cys Ser Ser Lys Arg Glu Glu Glu Ala
210 215 220
Asn Leu Leu Gly Gln Ile Lys Tyr Phe Gly Leu Gly Thr Gly Phe Pro
225 230 235 240
Leu Gln Tyr Tyr Pro Tyr Tyr Gly Lys Leu Leu Gln Pro Gln Tyr Leu
245 250 255
Gln Pro Leu Val Ala Ile Lys Phe Tyr Asn Ile Thr Thr Asp Val Asp
260 265 270
Val Arg Val Glu Cys Lys Val Tyr Gly Glu Asn Ile Asp Tyr Ser Glu
275 280 285
Lys Asp Arg Ser Gln Gly Arg Phe Asp Ile Lys Phe Thr Ile Lys Thr
290 295 300
Lys Ser
305
<210> 21
<211> 302
<212> PRT
<213> Artificial Sequence
<220>
<223> Zebrafish Type B ADP-ribosyl Cyclase
<400> 21
Met Pro Ala Gln Asn Lys Asp Asp Gly Gly Trp Lys Lys Phe Val Trp
1 5 10 15
Asn Ser Glu Lys Lys Glu Phe Leu Gly Arg Thr Gly Gly Ser Trp Ala
20 25 30
Lys Ile Phe Leu Phe Tyr Leu Ile Phe Tyr Gly Cys Leu Ala Gly Ile
35 40 45
Phe Ile Gly Thr Ile Gln Ile Leu Leu Leu Thr Leu Ser Asp Tyr Lys
50 55 60
Pro Thr Trp Gln Asp Arg Val Ala Pro Pro Gly Leu Thr His Phe Pro
65 70 75 80
Arg Ser Asp Lys Ser Glu Ile Ala Ile Asn Leu Asp Asp Glu Val Ser
85 90 95
Phe Leu Asn Tyr Val Lys Val Met Arg Glu Phe Leu Thr Ser Tyr Asp
100 105 110
Gln Glu Lys Gln Leu Asp Asn Met Gln Phe Glu Asn Cys Gly Glu Ser
115 120 125
Pro Leu Asp Tyr Lys Asn Arg Gly Asp Leu Glu Ser Asp Val Gly Val
130 135 140
Arg Arg Ala Cys Gln Phe Ser Arg Glu Trp Leu Gly Pro Cys Ser Gly
145 150 155 160
Leu Asp Asp Pro Tyr Phe Gly Phe Lys Glu Gly Lys Pro Cys Leu Ile
165 170 175
Ala Lys Leu Asn Arg Ile Val Asn Phe Arg Pro Lys Pro Pro Val Ser
180 185 190
Asn Glu Ser Ile Pro Glu Glu Val Gln His Lys Val Gln Pro Tyr Leu
195 200 205
Ile Pro Ile His Cys Thr Asn Lys Lys Glu Glu Asp Ala Gly Lys Leu
210 215 220
Gly Glu Val Arg Tyr Tyr Gly Phe Gly Gly Gly Phe Pro Leu Gln Tyr
225 230 235 240
Tyr Pro Tyr Tyr Gly Lys Leu Leu His Pro Gln Tyr Leu Gln Pro Leu
245 250 255
Val Ala Ile Gln Phe Leu Asn Ile Thr Pro Asn Thr Asp Met Arg Ile
260 265 270
Glu Cys Lys Val Tyr Gly Glu Asn Ile Tyr Tyr His Asp Lys Asp Arg
275 280 285
Tyr Gln Gly Arg Phe Asp Val Lys Phe Asn Ile Lys Lys Ser
290 295 300
<210> 22
<211> 25
<212> RNA
<213> Artificial Sequence
<220>
<223> ADPRC siRNA
<400> 22
cccaagaaug aauccuugga gacuu 25
Claims (25)
1.一种二磷酸腺苷核糖环化酶或其自然发生的变体,其特征在于,包含序列表中序列1的氨基酸序列。
2.根据权利要求1所述的二磷酸腺苷核糖环化酶或其自然发生的变体,其特征在于,上述二磷酸腺苷核糖环化酶的自然发生的变体为选自由种间变体、种内同源物、异构体、等位基因变体、构象变体、剪接变体及点突变变体组成的组中的自然发生的变体。
3.根据权利要求1所述的二磷酸腺苷核糖环化酶或其自然发生的变体,其特征在于,上述二磷酸腺苷核糖环化酶的自然发生的变体在选自由哺乳动物、鸟类、爬虫类、两栖动物及鱼类组成的组中的生物中发生。
4.根据权利要求1所述的二磷酸腺苷核糖环化酶或其自然发生的变体,其特征在于,上述二磷酸腺苷核糖环化酶的自然发生的变体包含选自由序列表中序列2至序列21组成的组中的氨基酸序列。
5.根据权利要求1所述的二磷酸腺苷核糖环化酶或其自然发生的变体,其特征在于,上述二磷酸腺苷核糖环化酶或其变体将烟酰胺腺嘌呤二核苷酸转化为环化二磷酸腺苷核糖。
6.一种核酸分子,其特征在于,编码权利要求1所述的二磷酸腺苷核糖环化酶或其自然发生的变体。
7.一种载体,其特征在于,包含权利要求6所述的核酸分子。
8.一种宿主细胞,其特征在于,包含权利要求7所述的载体。
9.一种将烟酰胺腺嘌呤二核苷酸转化为环化二磷酸腺苷核糖的催化剂组合物,其特征在于,包含权利要求1所述的二磷酸腺苷核糖环化酶或其自然发生的变体、权利要求6所述的核酸分子或权利要求7所述的载体。
10.一种用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,其特征在于,包含二磷酸腺苷核糖环化酶或其自然发生的变体的表达抑制剂或活性抑制剂作为有效成分,上述二磷酸腺苷核糖环化酶或其自然发生的变体包含序列表中序列1的氨基酸序列。
11.根据权利要求10所述的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,其特征在于,上述二磷酸腺苷核糖环化酶或其自然发生的变体的表达抑制剂选自由反义寡核苷酸、小干扰RNA、短发夹RNA、微小RNA、核酶、脱氧核酶及肽核酸组成的组中。
12.根据权利要求11所述的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,其特征在于,上述小干扰RNA包含序列表中序列22的核苷酸序列。
13.根据权利要求10所述的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,其特征在于,上述二磷酸腺苷核糖环化酶或其自然发生的变体的活性抑制剂选自由化合物、肽、肽类似物、适配体及抗体组成的组中。
14.根据权利要求13所述的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,其特征在于,上述化合物选自由4,4’-二羟基偶氮苯、2-(1,3-苯并恶唑-2-基氨基)-1-甲基喹唑啉-4(1H)-酮及二咖啡酰奎宁酸组成的组中。
15.根据权利要求10所述的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,其特征在于,上述二磷酸腺苷核糖环化酶介导的疾病为肾脏疾病。
16.根据权利要求15所述的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,其特征在于,上述肾脏疾病为肾衰竭、肾病、肾炎、肾纤维化或肾硬化。
17.根据权利要求16所述的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,其特征在于,上述肾衰竭为慢性肾衰竭、急性肾衰竭或透析前的轻度肾衰竭。
18.根据权利要求16所述的用于预防或治疗二磷酸腺苷核糖环化酶介导的疾病的药物组合物,其特征在于,上述肾病为肾病综合征、类脂性肾病、糖尿病肾病、免疫球蛋白A肾病、镇痛剂肾病或高血压肾病。
19.一种用于预防或改善二磷酸腺苷核糖环化酶介导的疾病的食品组合物,其特征在于,包含二磷酸腺苷核糖环化酶或其自然发生的变体的表达抑制剂或活性抑制剂作为有效成分,上述二磷酸腺苷核糖环化酶或其自然发生的变体包含序列表中序列1的氨基酸序列。
20.一种非人动物模型,其特征在于,缺失权利要求1所述的二磷酸腺苷核糖环化酶或其自然发生的变体的异型基因。
21.一种二磷酸腺苷核糖环化酶介导的疾病的鉴定方法,其特征在于,包括:
步骤(a),向权利要求20所述的动物模型和野生型动物模型诱导特定疾病;以及
步骤(b),确认上述动物模型之间的差异。
22.一种有关二磷酸腺苷核糖环化酶介导的疾病诊断的信息提供方法,其特征在于,包括:
步骤1),检测从对象分离的试样内包含序列表中序列1的氨基酸序列的二磷酸腺苷核糖环化酶或其自然发生的变体的表达或活性水平;以及
步骤2),通过将上述步骤1)的二磷酸腺苷核糖环化酶或其自然发生的变体的表达或活性水平与正常对照组比较来判断个体是否具有患环化酶介导的疾病的风险。
23.一种用于诊断二磷酸腺苷核糖环化酶介导的疾病的组合物,其特征在于,包含检测二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平的制剂或者检测蛋白质水平的制剂,上述二磷酸腺苷核糖环化酶或其自然发生的变体包含上述序列表中序列1的氨基酸序列。
24.一种二磷酸腺苷核糖环化酶介导的疾病的诊断试剂盒,其特征在于,包含检测二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平的制剂或者检测蛋白质水平的制剂,上述二磷酸腺苷核糖环化酶或其自然发生的变体包含上述序列表中序列1的氨基酸序列。
25.一种预防或治疗二磷酸腺苷核糖环化酶介导的疾病的物质的筛选方法,其特征在于,包括:
步骤1),使用候补物质处理表达包含序列表中序列1的氨基酸序列的二磷酸腺苷核糖环化酶或其自然发生的变体的细胞;
步骤2),通过上述候补物质的处理来检测上述二磷酸腺苷核糖环化酶或其自然发生的变体的基因表达水平或蛋白质水平;以及
步骤3),将上述基因表达水平或蛋白质水平与未使用候补物质处理的对照组比较,若减少,则将上述候补物质筛选为预防或治疗二磷酸腺苷核糖环化酶介导的疾病的物质。
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