CN101203238A - 用于药物用途的蛋白酶 - Google Patents
用于药物用途的蛋白酶 Download PDFInfo
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- CN101203238A CN101203238A CNA200680022643XA CN200680022643A CN101203238A CN 101203238 A CN101203238 A CN 101203238A CN A200680022643X A CNA200680022643X A CN A200680022643XA CN 200680022643 A CN200680022643 A CN 200680022643A CN 101203238 A CN101203238 A CN 101203238A
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- C12N9/54—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea bacteria being Bacillus
Abstract
涉及SEQIDNO:2的氨基酸1-274的蛋白酶,即源自地衣芽孢杆菌的丝氨酸蛋白酶的药物用途,所述蛋白酶也称作枯草杆菌蛋白酶Carlsberg,在所述用途中将该蛋白酶任选地与脂肪酶和/或淀粉酶组合。医学适应症的实例是:治疗消化性病症、胰腺外分泌机能不全(PEI)、胰腺炎、囊性纤维化、I型糖尿病和/或II型糖尿病。
Description
技术领域
本发明涉及蛋白酶的药物用途,所述蛋白酶涉及源自地衣芽孢杆菌(Bacillus licheniformis)的丝氨酸蛋白酶(SEQ ID NO:2的氨基酸1-274),在所述用途中任选地将该蛋白酶与脂肪酶和/或淀粉酶组合。医学适应症(medicalindication)的实例是:治疗消化性病症(digestive disorder)、胰腺外分泌机能不全(pancreatic exocrine insufficiency)(PEI)、胰腺炎、囊性纤维化、I型糖尿病和/或II型糖尿病。
背景技术
已知几种以胰酶补充剂形式存在的商业药物用于治疗胰腺外分泌机能不全。这些产品的活性组分是消化酶,主要为淀粉酶、脂肪酶和蛋白酶,其通常产生于胰腺并分泌至小肠上部(十二指肠)。这些药物中使用的酶源自牛或猪的胰腺,然而市场也存在含有微生物酶的产品,例如产品其包含来自米根霉(Rhizopus oryzae)的脂肪酶、来自米曲霉(Aspergillus oryzae)的蛋白酶和来自米曲霉的淀粉酶。
US 5614189(EP 600868)描述源自疏棉状腐质霉(Humicola lanuginosa)的脂肪酶在胰酶替代疗法中的用途,例如在对患有囊性纤维化的患者的治疗中。所述脂肪酶来自疏棉状腐质霉DSM 4109,具有SEQ ID NO:14的氨基酸1-269的氨基酸序列。
WO 00/54799描述在治疗I型和II型糖尿病中,有脂肪分解、蛋白水解和淀粉分解活性的、生理上可以接受的酶混合物的用途。
WO 02/060474描述来自德氏根霉(Rhizopus delemar)的浓缩脂肪酶、来自蜂蜜曲霉(Aspergillus melleus)的中性蛋白酶和来自米曲霉的淀粉酶在对消化不良的治疗中的用途。
WO 01/62280描述在哺乳动物中治疗或预防胃肠病症时,与多功能交联剂交联的特定的非真菌脂肪酶晶体、蛋白酶和淀粉酶的用途,其中所述脂肪酶晶体在从约2.0至9.0的pH范围内具有活性。优选的脂肪酶来自假单胞菌属(Pseudomonas),优选的淀粉酶来自芽孢杆菌属(Bacillus)或曲霉菌(Aspergillus),优选的蛋白酶是菠萝蛋白酶、木瓜蛋白酶或无花果蛋白酶。
EP 0828509描述在对外分泌胰腺机能不全的治疗中,特定的酸稳定性淀粉酶的用途,任选地可与特定的酸稳定性脂肪酶和/或蛋白酶组合。优选的淀粉酶来自黑曲霉(Aspergillus niger),优选的脂肪酶来自少根根霉(Rhizopusarrhizus)或爪哇根霉(Rhizopus javanicus)。
WO 91/00345描述许多用于洗涤剂组合物中的丝氨酸枯草杆菌蛋白酶(serine subtilisin protease)及其改进的变体。
WO 2005/115445(在本申请的优先权日后公布)描述蛋白酶的药物用途,所述蛋白酶涉及源自拟诺卡氏菌属菌种(Nocardiopsis sp.)NRRL 18262的蛋白酶(该蛋白酶具有本引用文献中SEQ ID NO:1的氨基酸1-188的氨基酸序列),任选地将所述蛋白酶与脂肪酶和/或淀粉酶组合。医学适应症和本发明中相同。
WO 02/077187公开具有改变的T-细胞表位的解淀粉芽孢杆菌(Bacillusamyloliquefaciens)枯草杆菌蛋白酶及其各种用途。对药物组合物提出权利要求。
WO 01/12795公开蛋白水解酶组合物的药物用途。优选的蛋白酶来自米曲霉、黑曲霉、酱油曲霉(Aspergillus sojae)、黄曲霉(Aspergillus falvus)、泡盛曲霉(Aspergillus awamori)或枯草芽孢杆菌(Bacillus subtilis)。
WO 2004/078773公开如何将蛋白酶如枯草杆菌蛋白酶保持在非活性状态,所述非活性状态能够在外部信号的请求时激活。在其它用途中公开原枯草杆菌蛋白酶(pro-subtilisin)在伤口清洁制剂中的用途,和如何引发活性枯草杆菌蛋白酶的形成。优选的蛋白酶是ProD-枯草杆菌蛋白酶或ProD-负载枯草杆菌蛋白酶(ProD-loaded subtilisin)(Yabuta等,J.Biol.Chem.278:15246-51,2003)。
US 2002/0081703公开用于降低非人蛋白质变应原性的方法,其中用人枯草杆菌蛋白酶中的类似区域(analogous region)鉴定和代替表位。对包含人枯草杆菌蛋白酶的药物组合物提出权利要求。
在本领域中需要可供选择的,优选改进的酶,所述酶用于药物用途,特别用于上述医学适应症(medical indication)。
发明简述
本发明提供可供选择的,优选改进的酶,所述酶用于医疗用途,特别用于治疗消化性病症、胰腺外分泌机能不全(PEI)、胰腺炎、囊性纤维化、I型糖尿病和/或II型糖尿病。所述新酶是蛋白酶、淀粉酶和脂肪酶。优选地,用于本发明的用途的酶在体内和/或体外有改进的效能;改进的pH稳定性分布;改进的pH活性分布;对蛋白酶的降解稳定;在胆汁盐存在时稳定;和/或具有降低的变应原性。
本发明涉及用作药物的蛋白酶,其中所述蛋白酶与SEQ ID NO:2的氨基酸1-274有至少50%同一性,任选地将该蛋白酶与脂肪酶和/或淀粉酶组合。
本发明还涉及这些蛋白酶在生产药物中的用途,所述药物用来治疗消化性病症、PEI、胰腺炎(急性和/或慢性)、囊性纤维化、I型糖尿病和/或II型糖尿病,这些用途任选地还包含脂肪酶和/或淀粉酶的用途。
此外本发明还涉及药物组合物,其包含这样的蛋白酶,以及至少一种可药用的辅助材料,任选地包括脂肪酶和/或淀粉酶。
本发明还涉及消化性病症、PEI、胰腺炎(急性和/或慢性)、囊性纤维化、I型糖尿病和/或II型糖尿病的治疗方法,其通过施用治疗上有效量的这样的蛋白酶,任选地与脂肪酶和/或淀粉酶一起施用。
发明详述
酶
本发明涉及蛋白酶的药物用途,所述蛋白酶与SEQ ID NO:2的氨基酸1-274的蛋白酶具有至少50%的同一性,所述蛋白酶是源自地衣芽孢杆菌的丝氨酸蛋白酶,也称作枯草芽孢杆菌蛋白酶Carlsberg。本发明还涉及这些蛋白酶用于产生药物的用途,所述药物用来治疗消化性病症、PEI、胰腺炎、囊性纤维化、I型糖尿病和/或II型糖尿病。本发明还涉及药物组合物,其包含这样的脂肪酶,和至少一种可药用的辅助材料;以及通过施用治疗上有效量的这样的蛋白酶治疗上述疾病的方法。
在下文中,用于本发明的组合物、方法和用途中的蛋白酶称作“本发明的蛋白酶”。
在优选实施方案中,本发明的蛋白酶与SEQ ID NO:2的氨基酸1-274具有至少51%、52%、53%、54%、55%、56%、57%、58%、59%或至少60%的同一性程度。在其它优选实施方案中,本发明的蛋白酶与SEQ ID NO:2的氨基酸1-274具有至少61%、62%、63%、64%、65%、66%、67%、68%、69%或至少70%的同一性程度。在更进一步优选的实施方案中,本发明的蛋白酶与SEQ ID NO:2的氨基酸1-274具有至少71%、72%、73%、74%、75%、76%、77%、78%、79%或至少80%的同一性程度。在其它优选的实施方案中,本发明的蛋白酶与SEQ ID NO:2的氨基酸1-274具有至少81%、82%、83%、84%、85%、86%、87%、88%、89%或至少90%的同一性程度。在最优选的实施方案中,本发明的蛋白酶与SEQ ID NO:2的氨基酸1-274具有至少91%、92%、93%、94%、95%、96%、97%、98%或至少99%的同一性程度。
在本文中,术语“蛋白酶”定义为水解肽键的酶。它包括任何属于EC 3.4酶组的酶(包括其中全部十三个亚类,这些酶在下文中称作“属于EC 3.4.-.-组”)。EC号参考NC-IUBMB,Academic Press,San Diego,California的EnzymeNomenclature 1992,包括分别在Eur.J.Biochem.1994,223,1-5;Eur.J.Biochem.1995,232,1-6;Eur.J.Biochem.1996,237,1-5;Eur.J.Biochem.1997,250,1-6;and Eur.J.Biochem.1999,264,610-650中公布的补充材料1-5。所述命名法经常性地补充和更新;参见,例如环球网http://www.chem.qmw.ac.uk/iubmb/enzyme/index.html。
根据蛋白酶的催化机制将它们分成下述组:丝氨酸蛋白酶(S)、半胱氨酸蛋白酶(C)、天冬氨酸蛋白酶(A)、金属蛋白酶(M),和未知的或尚未分类的蛋白酶(U),参见Handbook of Proteolytic Enzymes,A.J.Barrett,N.D.Rawlings,J.F.Woessner(eds),Academic Press(1998)(在下文中称作“手册”),特别是简介部分。
在另一个实施方案中,本发明的蛋白酶是丝氨酸蛋白酶。术语丝氨酸蛋白酶指丝氨酸肽酶和它们的同族异种体(clan),如手册所定义,具体参见1-175章。丝氨酸蛋白酶是肽酶,其中的催化机制依赖于作为攻击肽键的亲核试剂发挥作用的丝氨酸残基的羟基。
在更进一步的实施方案中,本发明的蛋白酶是枯草杆菌蛋白酶和/或源自枯草杆菌蛋白酶家族。术语枯草杆菌蛋白酶或枯草杆菌蛋白酶家族包括所有SB族(Clan SB)丝氨酸蛋白酶,特别是其S8家族(Family SB)(手册中第93章介绍SB族)。为了测定指定的蛋白酶是否是枯草杆菌蛋白酶,参考手册和其中说明的原理。这种测量能够针对所有类型的蛋白酶进行,所述蛋白酶可以是天然存在的或野生型蛋白酶;或者基因工程或合成蛋白酶。在具体实施方案中,本发明的蛋白酶中催化三联体(catalytic triad)的顺序是Asp-His-Ser。在另一个具体实施方案中,本发明的蛋白酶的三级结构包括α-螺旋和β-折叠。SB族包括内肽酶和外肽酶。在更进一步具体的实施方案中,本发明的蛋白酶是内肽酶。内肽酶表现出对N-和C-末端阻断的肽底物的活性,所述底物与所述蛋白酶的特异性相关。
在具体实施方案中,本发明的蛋白酶不是ProD-枯草杆菌蛋白酶或ProD-负载的枯草杆菌蛋白酶(Yabuta等,J.Biol.Chem.278:15246-51,2003)。在另一个具体实施方案中,本发明的蛋白酶不是野生型枯草芽孢杆菌的枯草杆菌蛋白酶,和/或不源自枯草芽孢杆菌。
因此,在第一方面,本发明的蛋白酶选自下组:(a)属于EC 3.4.-.-酶组的蛋白酶;(b)丝氨酸蛋白酶;(c)肽酶SB族的枯草杆菌蛋白酶;和(d)S8家族的枯草杆菌蛋白酶。
在第二方面,本发明的蛋白酶源自微生物,例如源自真菌,或源自细菌。细菌的实例是芽孢杆菌属的菌株,如嗜碱芽孢杆菌(Bacillus alkalophilus)、解淀粉芽孢杆菌、短芽孢杆菌(Bacillus brevis)、克劳氏芽孢杆菌(Bacillus clausii)、环状芽孢杆菌(Bacillus circulans)、凝结芽孢杆菌(Bacillus coagulans)、灿烂芽孢杆菌(Bacillus lautus)、迟缓芽孢杆菌(Bacillus lentus)、地衣芽孢杆菌、巨大芽孢杆菌(Bacillus megaterium)、肠膜芽孢杆菌(Bacillus mesentericus)、纳豆芽孢杆菌(Bacillus natto)、短小芽孢杆菌(Bacillus pumilus)、芽孢杆菌属菌种(Bacillus sp.)、嗜热脂肪芽孢杆菌(Bacillus stearothermophilus)、枯草芽孢杆菌、枯草芽孢杆菌纳豆变种(Bacillus subtilis var natto)或苏云金芽孢杆菌(Bacillusthuringiensis)的菌株;特别是解淀粉芽孢杆菌、克劳氏芽孢杆菌、迟缓芽孢杆菌、地衣芽孢杆菌、肠膜芽孢杆菌、纳豆芽孢杆菌、短小芽孢杆菌、芽孢杆菌属菌种、嗜热脂肪芽孢杆菌、枯草芽孢杆菌或枯草芽孢杆菌纳豆变种的菌株;优选地衣芽孢杆菌菌株。在本上下文中,术语“源自”包括可从或已从野生型菌株获得的酶;以及,优选地,具有至少一个取代、插入和/或缺失至少一个氨基酸残基的所述酶的变体。术语变体还包括改组的(shufflant)、杂合的、嵌合的酶和共有酶(consensus enzyme)。变体可以用本领域任何已知方法产生,如定点诱变(site-directed mutagenesis)、随机突变、共有衍生方法(consensusderivation processes)(EP 897985)和基因改组(gene shuffling)(WO 95/22625、WO 96/00343)等。
下述为本发明的蛋白酶的实例,其源自芽孢杆菌属的菌株并且涉及下述蛋白酶:SEQ ID NO:2的氨基酸1-274的蛋白酶:Swissprot subt_bacli登录号P00780(源自地衣芽孢杆菌,SEQ ID NO:5的氨基酸1-274);Swissprotsubn_bacna登录号P35835(源自纳豆芽孢杆菌,SEQ ID NO:6的氨基酸1-275);Swissprot subt_bacpu登录号P07518(源自短小芽孢杆菌,SEQ ID NO:7的氨基酸1-275);Swissprot subt_bacsu登录号P04189(源自枯草芽孢杆菌,SEQ ID NO:8的氨基酸1-275);Swissprot subt_bacst登录号P29142(源自嗜热脂肪芽孢杆菌,SEQ ID NO:9的氨基酸1-275);Swissprot subt_bacam登录号P00782(源自解淀粉芽孢杆菌,SEQ ID NO:10的氨基酸1-275);Swissprotsubs_bacle登录号P29600(源自迟缓芽孢杆菌,SEQ ID NO:11的氨基酸1-269);Swissprot elya_baccs登录号P41362(源自克劳氏芽孢杆菌,SEQ ID NO:12的氨基酸1-269);和Swissprot elya_bacya登录号P20724(源自芽孢杆菌属菌种,SEQ ID NO:13的氨基酸1-268);以及它们的变体,如上所定义。
本发明的蛋白酶的其它具体实例是下述商业产品中包含的蛋白酶:Purafect MA、Purafect、Purafect Ox(变体M222S)、Purafect Prime(Y217L)、Properase(S87N+S101G+V104N)、FN3(N76D+S103A+V104I)、FN4(S101G+S103A+V104I+G159D+A232V+Q236H+Q245R+N248D+N252K)-SEQ ID NO:10的成熟部分的所有优选变体并可从Genencor/Danisco以商业方法获得;Blap(SEQ ID NO:11的成熟部分,具有S99D+S101R+S103A+V104I+G160S)、BLAP R(具有S3T+V4I+V199M+V205I+L217D的Blap),和BLAP X(具有S3T+V4I+V205I的Blap)-全部来自Henkel/Kemira;和来自Kao的KAP(A230V+S256G+S259N)。
在第三方面,本发明的蛋白酶是,或者能够被视为,SEQ ID NO:2的蛋白酶的变体,即它包含SEQ ID NO:2的氨基酸1-274中一个或多个氨基酸的取代、缺失和/或插入中的至少一个。优选地,氨基酸改变的性质是较不重要的(of a minornature),即保守的氨基酸取代或插入,其不显著影响蛋白质的折叠和/或活性;小缺失;小的氨基或羧基末端延伸,如氨基末端甲硫氨酸残基;小接头肽;或通过改变净电荷或其它功能,例如多组氨酸序列(poly-histidinetract)、抗原表位(antigenic epitope)或结合域来促进纯化的小延伸。在本文的上下文中,术语“小”独立地表明多至25个氨基酸残基。在优选实施方案中,术语“小”独立地表明多至24、23、22、21或多至20个氨基酸残基。在其它的优选实施方案中,术语“小”独立地表明多至19、18、17、16、15、14、13、12、11或多至10个氨基酸残基。在进一步优选的实施方案中,术语“小”独立地表明多至9、8、7、6、5、4、3、2或多至1个氨基酸残基。在可供选择的实施方案中,术语“小”独立地表明多至40、39、38、37、36、35、34、33、32、31、30、29、28、27或多至26个氨基酸残基。
保守取代的实例是在以下组之内:碱性氨基酸组(精氨酸、赖氨酸和组氨酸)、酸性氨基酸组(谷氨酸和天冬氨酸)、极性氨基酸组(丝氨酸、苏氨酸、谷氨酰胺和天冬酰胺)、疏水性氨基酸组(亮氨酸、异亮氨酸、缬氨酸和丙氨酸)、芳族氨基酸组(苯丙氨酸、色氨酸和酪氨酸)和小氨基酸组(甘氨酸、丙氨酸、脯氨酸、丝氨酸、苏氨酸、半胱氨酸和甲硫氨酸)。
可供选择地,保守取代的实例是在以下组之内:碱性氨基酸组(精氨酸、赖氨酸和组氨酸)、酸性氨基酸组(谷氨酸和天冬氨酸)、极性氨基酸组(谷氨酰胺和天冬酰胺)、疏水性氨基酸组(亮氨酸、异亮氨酸和缬氨酸)、芳族氨基酸组(苯丙氨酸、色氨酸和酪氨酸)和小氨基酸组(甘氨酸、丙氨酸、丝氨酸、苏氨酸和甲硫氨酸)。通常不改变比活性(specific activity)的氨基酸取代是本领域已知的,并且由例如H.Neurath and R.L.Hill,1979,In,The Proteins,AcademicPress,New York描述。最普遍发生的交换是Ala/Ser、Val/Ile、Asp/Glu、Thr/Ser、Ala/Gly、Ala/Thr、Ser/Asn、Ala/Val、Ser/Gly、Tyr/Phe、Ala/Pro、Lys/Arg、Asp/Asn、Leu/Ile、Leu/Val、Ala/Glu和Asp/Gly。
SEQ ID NO:5-13的任何成熟蛋白酶部分的优选变体,例如SEQ ID NO:13的氨基酸1-268的优选变体,包含一个或多个氨基酸的取代、缺失和/或插入中的至少一个(与亲本或祖先酶比较,例如,与SEQ ID NO:13的氨基酸1-268比较),如上述就SEQ ID NO:2的氨基酸1-274的变体所解释的。更优选这些变体具有保守氨基酸取代或插入、小缺失、小接头或具有小延伸,同样如上述就SEQ ID NO:2的氨基酸1-274的变体所解释的。本发明的蛋白酶变体的具体实例是SEQ ID NO:11的变体99aE(参见实施例4)。
在第四方面,本发明的蛋白酶具有与SEQ ID NO:2的氨基酸1-274的差异不多于25、24、23、22、21、20、19、18、17、16、15、14、13、12或不多于11个氨基酸的氨基酸序列;或者,它与SEQ ID NO:2的氨基酸1-274的差异不多于10、9、8、7、6、5、4、3、2或不多于1个氨基酸。在可供选择的实施方案中,本发明的蛋白酶具有与SEQ ID NO:2的氨基酸1-274的差异不多于40、39、38、37、36、35、34、33、32、31、30、29、28、27或不多于26个氨基酸的氨基酸序列。
SEQ ID NO:5-13的任何成熟蛋白酶部分的优选变体,例如SEQ ID NO:7的氨基酸1-275的优选变体,具有与SEQ ID NO:5-13中任一的成熟部分(例如SEQ ID NO:7的氨基酸1-275)的差异不多于25、24、23、22、21、20、19、18、17、16、15、14、13、12或不多于11个氨基酸的氨基酸序列;或者,它们与SEQ ID NO:5-13中任一的成熟部分(例如SEQ ID NO:7的氨基酸1-275)的差异不多于10、9、8、7、6、5、4、3、2或不多于1个氨基酸。
在第五方面,本发明的蛋白酶是SEQ ID NO:2的等位变体(优选为其成熟部分的等位变体)、SEQ ID NO:5-13中任一的等位变体(优选为它们的成熟部分中任一的等位变体)或任何这些序列的具有蛋白酶活性的片段。术语等位变体表示占据相同染色体基因座的基因的任何两种或两种以上可选形式。等位变异通过突变天然地发生,并且可导致种群内的多态性。基因突变可以是沉默的(在编码的多肽中无变化)或可以编码具有改变的氨基酸序列的多肽。多肽的等位变体是由基因的等位变体编码的多肽。术语片段在本文中定义为从SEQ ID NO:2的氨基酸1-274的氨基和/或羧基末端,或者从SEQ ID NO:5-13中任一的氨基和/或羧基末端,优选从其成熟部分,缺失一个或多个氨基酸的多肽。优选地,缺失小数目的氨基酸,小如上述所定义。更优选地,片段包含至少244、245、246、247、248、249或至少250个氨基酸。最优选地,片段包含至少251、252、253、254、255、256、257、258、259、260、261、262、263、264、265、266、267、268、269、270、271、272或至少273个氨基酸残基。
总而言之,本发明的一个实施方案涉及用于药物用途的蛋白酶,其中a)所述蛋白酶包含选自下组的氨基酸序列:SEQ ID NO:2的氨基酸1-274、SEQID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268;和/或b)所述蛋白酶是选自下组的氨基酸序列的变体:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268,其中所述变体与相应氨基酸序列的差异不多于25个氨基酸,并且其中:(i)与相应的氨基酸序列相比,所述变体包含一个或多个氨基酸的取代、缺失和/或插入中的至少一个;和/或(ii)与相应的氨基酸序列相比,所述变体包含至少一个小缺失;和/或(iii)与相应的氨基酸序列相比,所述变体包含至少一个小的N-或C-末端延伸;和/或c)所述蛋白酶是具有选自下组的氨基酸的蛋白酶的变体:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ IDNO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268;和/或d)所述蛋白酶是具有选自下组的氨基酸的蛋白酶的片段:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ IDNO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268。
具体而言,本发明涉及用于药物用途的蛋白酶,其中所述蛋白酶具有选自下组的氨基酸序列:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268。
在另一个具体实施方案中,本发明的蛋白酶可以与其它蛋白酶组合使用。其它蛋白酶的实例是哺乳动物蛋白酶,和微生物蛋白酶。优选的哺乳动物蛋白酶是胰腺提取物,例如来自猪或牛(ox),如胰酶制剂(pancreatin)。胰酶制剂可以以未包覆(未加工)产品的形式使用,或者以配方产品(formulated products)的形式(包有肠溶衣的(enteric coated)(提供对胃酸的抗性),或非功能性包覆的(包覆的,但不提供对胃酸的抗性))使用。胰酶制剂可能包含另外的酶活性组分,如胰脂肪酶、BSSL(Bile Salt Stimulated Lipase)和/或胰淀粉酶。优选的微生物蛋白酶源自细菌或真菌菌株,例如源自曲霉属菌株,如米曲霉或蜂蜜曲霉,具体而言产品Prozyme 6TM(中性、碱性蛋白酶EC 3.4.21.63),可从AmanoPharmaceuticals,Japan以商业方法获得。
任选地,将本发明的蛋白酶与脂肪酶组合使用,有或没有淀粉酶,如下文进一步解释的。
在本文的上下文中,脂肪酶指羧酸脂水解酶EC 3.1.1.-,其包括活性如EC 3.1.1.3三酰甘油脂肪酶、EC 3.1.1.4磷脂酶A1、EC 3.1.1.5溶血磷脂酶、EC 3.1.1.26半乳糖酯酶(galactolipase)、EC 3.1.1.32磷脂酶A1、EC3.1.1.73阿魏酸脂酶。在具体实施方案中,脂肪酶是EC 3.1.1.3三酰甘油脂肪酶。
在具体实施方案中,脂肪酶是哺乳动物脂肪酶,例如来自猪或牛的胰腺提取物,如胰酶制剂。胰酶制剂可以以未包覆(未加工)产品的形式使用,或者以配方产品的形式(包有肠溶衣的,或非功能性包覆的,如上所述)使用。胰酶制剂可能包含另外的酶活性组分,如胰蛋白酶、BSSL(Bile Salt StimulatedLipase),和/或胰淀粉酶。脂肪酶可以是微生物脂肪酶,例如源自细菌或真菌菌株,如芽孢杆菌属、假单胞菌属、曲霉属或根霉属(Rhizopus)。脂肪酶可以具体源自根霉属的菌株,如爪哇根霉、米根霉或德氏根霉,例如产品Lipase DAmano 2000TM(也称作Lipase D2TM),其可从Amano Pharmaceuticals,Japan以商业方法获得。
在进一步具体的实施方案中,脂肪酶是重组产生的微生物脂肪酶,例如源自真菌如腐质霉属(Humicola)或根毛霉属(Rhizomucor),源自酵母如念珠菌属(Candida),或源自细菌如假单胞菌属。在优选实施方案中,脂肪酶源自疏棉状腐质霉或米赫根毛霉(Rhizomucor miehei)的菌株。
疏棉状腐质霉(与细毛嗜热霉(Thermomyces lanuginosus)同义)脂肪酶(SEQID NO:14)在EP 305216中描述,具体的脂肪酶变体在下述文献中描述,例如WO 92/05249、WO 92/19726、WO 94/25577、WO 95/22615、WO 97/04079、WO 97/07202、WO 99/42566、WO 00/32758、WO 00/60063、WO 01/83770、WO 02/055679和WO 02/066622。优选的疏棉状腐质霉脂肪酶变体是包含SEQID NO:15的氨基酸1-269或2-269的脂肪酶,如下述:(i)SEQ ID NO:15的氨基酸+1至+269,(ii)SEQ ID NO:15的氨基酸-5至+269,(iii)SEQ ID NO:15的氨基酸-4至+269;(iv)SEQ ID NO:15的氨基酸-3至+269;(v)SEQ IDNO:15的氨基酸-2至+269;(vi)SEQ ID NO:15的氨基酸-1至+269,(vii)SEQID NO:15的氨基酸+2至+269,以及(viii)(i)-(vii)脂肪酶中的两种或更多种的任何混合物-以及它们的变体。在具体实施方案中,脂肪酶选自(i)、(ii)的脂肪酶和(i)与(ii)的任意混合物。(i)与(ii)的优选混合物包含至少5%,优选至少10%、20%、30%、40%、50%、60%、70%、80%、90%或至少95%的脂肪酶(i),百分比使用Edman方法通过N-末端测序确定,如要求DK专利申请200500929的优选权的PCT申请中实施例5所述)。其它优选混合物是:(a)包含35-75%的脂肪酶(ii),优选40-70%,更优选45-65%的脂肪酶(ii)的组合物;(b)包含20-60%,优选25-55%,更优选30-50%,最优选35-47%的脂肪酶(i)的组合物;(c)包含多至30%,优选多至25%,更优选多至20%,最优选多至16%的脂肪酶(vii)的组合物;和(d)(a)、(b)和/或(c)的任意组合,如包含45-65%的脂肪酶(ii)、35-47%的脂肪酶(i),和多至16%的脂肪酶(vii)的组合物。
SEQ ID NO:14和15的脂肪酶可例如按美国专利号5,869,438所述制备(美国专利中的SEQ ID NO:1是编码SEQ ID NO:14的脂肪酶的DNA序列)。SEQ ID NO:15的脂肪酶可例如通过在合适的宿主细胞中重组表达DNA序列而制备,所述DNA序列是美国专利的SEQ ID NO:1的修饰序列,所述修饰反映出本文的SEQ ID NO:14和15之间的氨基酸差异。这些修饰可以用定点诱变实现,如本领域所了解的。
真菌脂肪酶另外的实例是EP 785994中所述来自特异腐质霉的角质酶(cutinase),和EP 869167中所述来自尖镰孢(Fusarium oxysporum)的磷脂酶。酵母脂肪酶的实例是来自南极假丝酵母(Candida antarctica)的脂肪酶A和B,其中脂肪酶A在EP 652945中有所描述,并且脂肪酶B由例如Uppenberg等在Structure,2(1994),293中描述。细菌脂肪酶的实例是EP 214761中所述源自洋葱假单胞菌(Pseudomonas cepacia)的脂肪酶。
在优选实施方案中,脂肪酶与SEQ ID NO:15的脂肪酶是至少70%同一的,优选与SEQ ID NO:15的氨基酸1-269是至少70%同一的。在另外的优选实施方案中,对于SEQ ID NO:15的同一性程度,优选对于其氨基酸1-269的同一性程度,是至少71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%。在可选的实施方案中,对于SEQ ID NO:15的同一性程度,优选对于其氨基酸1-269的同一性程度,是至少约50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%或至少69%。
在还进一步优选的实施方案中,脂肪酶,如哺乳动物胰脂肪酶,是1,3-位特异性的脂肪酶。
任选地,本发明的蛋白酶,和或不和上述的脂肪酶一起,与淀粉酶组合使用。
在本文的上下文中,淀粉酶是催化淀粉与其它直链和支链的寡糖和多糖的内部水解(endo-hydorlysis)的酶。淀粉的直链淀粉部分富含1,4-α-糖苷键,而支链淀粉部分更支链化,不仅包含1,4-α-糖苷键,也包含1,6-α-糖苷键。在具体实施方案中,淀粉酶是属于EC 3.2.1.1组的酶。
在具体实施方案中,淀粉酶是哺乳动物淀粉酶,例如来自猪或牛的胰腺提取物,如胰酶制剂。胰酶制剂可以以未包覆(未加工)产品的形式使用,或者以配方产品的形式(包有肠溶衣的,或非功能性包覆的)使用。胰酶制剂可能还包含另外的酶活性组分,如胰蛋白酶、BSSL和/或胰脂肪酶。淀粉酶还可以是微生物淀粉酶,例如源自细菌或真菌菌株,如芽孢杆菌属、假单胞菌属、曲霉属或根霉属。
淀粉酶可以特别地源自曲霉属的菌株,如黑曲霉、米曲霉或蜂蜜曲霉,例如源自米曲霉的产品Amylase A1TM,其可从Amano Pharmaceuticals,Japan以商业方法获得,或源自蜂蜜曲霉的Amylase ECTM,其可从Extract-Chemie,Germany以商业方法获得。
真菌淀粉酶的其它实例是黑曲霉淀粉酶(SWISSPROT P56271),其也在WO 89/01969的实施例3中描述,和米曲霉淀粉酶。米曲霉淀粉酶的变体的实例在WO 01/34784中描述。
源自地衣芽孢杆菌的α-淀粉酶是细菌α-淀粉酶的实例。该淀粉酶,例如,在WO 99/19467中描述,其中还描述有其它同源的细菌α-淀粉酶,例如,源自解淀粉芽孢杆菌和嗜热脂肪芽孢杆菌的淀粉酶,以及它们的变体。其它淀粉酶变体的实例是美国专利号4,933,279、EP 722490和EP 904360中描述的那些。
优选的淀粉酶是包含下述序列的淀粉酶:SEQ ID NO:16的氨基酸1-481(如其氨基酸1-481、1-484或1-486),SEQ ID NO:17的氨基酸1-481,和/或SEQ ID NO:18的氨基酸1-483。在优选实施方案中,淀粉酶与下述的任一是至少70%同一的:(i)SEQ ID NO:16的氨基酸1-481,(ii)SEQ ID NO:17的氨基酸1-481,和/或(iii)SEQ ID NO:18的氨基酸1-483。SEQ ID NO:16-18的淀粉酶可例如按共同待审的丹麦专利申请号2005 00931所述的制备,所述申请的标题为“用作医疗用途的淀粉酶(Amylases for Pharmaceutical Use)”,由Pharmaceuticals GmbH和Novozymes A/S于2005年6月24日提出申请。
在(i)、(ii)或(iii)中任一的其它优选实施方案中,对于SEQ ID NO:16、17或18的对应部分的同一性程度是至少71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%。在可供选择的实施方案中,对于SEQ ID NO:16、17或18的对应部分的同一性程度是至少约50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%或至少69%。
就本发明而言,酶的特别优选的组合为下述:(i)SEQ ID NO:2的氨基酸1-274的蛋白酶,与包含SEQ ID NO:15的氨基酸1-269或2-269的脂肪酶组合;(ii)SEQ ID NO:2的氨基酸1-274的蛋白酶,与包含SEQ ID NO:16的氨基酸1-481(如其氨基酸1-481、1-484或1-486)的淀粉酶组合;(iii)SEQ ID NO:2的氨基酸1-274的蛋白酶,与具有SEQ ID NO:17的氨基酸1-481的淀粉酶组合;(iv)SEQ ID NO:2的氨基酸1-274的蛋白酶,与具有SEQ ID NO:18的氨基酸1-483的淀粉酶组合;(v)SEQ ID NO:2的氨基酸1-274的蛋白酶,与包含SEQ ID NO:16的氨基酸1-481(如其氨基酸1-481、1-484或1-486)的淀粉酶,和包含SEQ ID NO:15的氨基酸1-269或2-269的脂肪酶组合;(vi)SEQ ID NO:2的氨基酸1-274的蛋白酶,与具有SEQ ID NO:17的氨基酸1-481的淀粉酶,和包含SEQ ID NO:15的氨基酸1-269或2-269的脂肪酶组合;和(vii)SEQ ID NO:2的氨基酸1-274的蛋白酶,与具有SEQ ID NO:18的氨基酸1-483的淀粉酶,和包含SEQ ID NO:15的氨基酸1-269或2-269的脂肪酶组合。
因此,本发明的一个实施方案涉及与脂肪酶和/或淀粉酶组合用于药物用途的蛋白酶,其中(i)所述蛋白酶是本文定义的蛋白酶;(ii)所述脂肪酶包含SEQID NO:15的氨基酸2-2691;并且(iii)所述淀粉酶是选自下组的淀粉酶:a)包含SEQ ID NO:16的氨基酸1-481的淀粉酶,b)具有SEQ ID NO:17的氨基酸1-481的淀粉酶,和c)具有SEQ ID NO:18的氨基酸1-483的淀粉酶。
具体而言,本发明涉及与脂肪酶和/或淀粉酶组合用于药物用途的蛋白酶,其中(i)所述蛋白酶包含或优选是,或具有,SEQ ID NO:2的氨基酸1-274;(ii)所述脂肪酶包含SEQ ID NO:15的氨基酸2-269;并且(iii)所述淀粉酶是选自下组的淀粉酶:a)包含SEQ ID NO:16的氨基酸1-481的淀粉酶,b)具有SEQID NO:17的氨基酸1-481的淀粉酶,和c)具有SEQ ID NO:18的氨基酸1-483的淀粉酶。
酶的其它优选组合是下述:(i)与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的蛋白酶,和与SEQ ID NO:15的氨基酸1-269具有至少50%同一性的脂肪酶组合;(ii)与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的蛋白酶,和与SEQ ID NO:16的氨基酸1-481具有至少50%同一性的淀粉酶组合;(iii)与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的蛋白酶,和与SEQ ID NO:17的氨基酸1-481具有至少50%同一性的淀粉酶组合;(iv)与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的蛋白酶,和与SEQ IDNO:18的氨基酸1-483具有至少50%同一性的淀粉酶组合;(v)与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的蛋白酶,和与SEQ ID NO:16的氨基酸1-481具有至少50%同一性的淀粉酶,及与SEQ ID NO:15的氨基酸1-269具有至少50%同一性的脂肪酶组合;(vi)与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的蛋白酶,和与SEQ ID NO:17的氨基酸1-481具有至少50%同一性的淀粉酶,及与SEQ ID NO:15的氨基酸1-269具有至少50%同一性的脂肪酶组合;和(vii)与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的蛋白酶,和与SEQ ID NO:18的氨基酸1-483具有至少50%同一性的淀粉酶,及与SEQ ID NO:15的氨基酸1-269具有至少50%同一性的脂肪酶组合。在(i)-(vii)的优选实施方案中,每个同一性程度独立为,至少51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、69%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%、92%、93%、94%、95%、96%、97%、98%或至少99%。
因此,本发明的一个实施方案涉及与脂肪酶和/或淀粉酶组合用于药物用途的蛋白酶,其中(i)所述蛋白酶选自下组:a)与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的蛋白酶;b)包含选自下组的氨基酸序列的蛋白酶:SEQID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268;c)选自下组的氨基酸序列的变体的蛋白酶:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ IDNO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268,其中所述变体与相应氨基酸序列的差异不多于25个氨基酸,并且其中:(i)与相应的氨基酸序列相比,所述变体包含一个或多个氨基酸的取代、缺失和/或插入中的至少一种;和/或(ii)与相应的氨基酸序列相比,所述变体包含至少一个小缺失;和/或(iii)与相应的氨基酸序列相比,所述变体包含至少一个小的N-或C-末端延伸;d)蛋白酶,其是具有选自下组的氨基酸的蛋白酶的等位变体:SEQ IDNO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268;e)蛋白酶,其是具有选自下组的氨基酸的蛋白酶的片段:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ IDNO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268;和f)具有选自下组的氨基酸序列的蛋白酶:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268;(ii)所述脂肪酶与具有SEQ ID NO:15的氨基酸1-269的脂肪酶有至少70%同一性;并且(iii)所述淀粉酶与选自下组的淀粉酶有至少70%同一性:a)具有SEQ ID NO:16的氨基酸1-481的淀粉酶,b)具有SEQ ID NO:17的氨基酸1-481的淀粉酶,和c)具有SEQ ID NO:18的氨基酸1-483的淀粉酶。
通常而言,蛋白酶、脂肪酶和淀粉酶(下文称作“酶”,即本发明的酶)可以是天然或野生型酶(获得自动物,特别是哺乳动物,例如人或猪的酶;获得自植物,或获得自微生物),也可以是任何其显示期望的酶活的突变体、变体、片段等,以及合成酶,如改组、杂交或嵌合酶,和共有酶。
在特定的实施方案中,酶是低变应原性变体,将所述酶设计成当曝露于动物包括人时产生降低的免疫应答。术语免疫应答可以理解为由曝露于酶的动物的免疫系统产生的任何反应。免疫应答的一种类型是变应性应答,其导致曝露的动物中IgE的水平增加。低变应原性变体可以使用本领域已知的技术制备。例如可将酶与聚合物基团屏蔽部分(polymer moieties shielding portion)或者免疫应答涉及的酶的表位结合。与聚合物的结合可涉及聚合物对酶的体外化学偶联,例如,如WO 96/17929、WO 98/30682、WO 98/35026和/或WO99/00489所述。所述结合可以另外或可选地涉及聚合物对酶的体内偶联。这种结合可以用下述方法实现:编码酶的核酸序列的基因工程,在酶中插入编码额外糖基化位点的共有序列和在能够将酶糖基化的宿主中表达酶,参见例如WO 00/26354。提供低变应原性变体的另一种方法是:编码酶的核酸序列的基因工程,以引起酶的自寡聚,致使所述酶单体可屏蔽其它酶单体的表位,并且由此降低寡聚体的变应原性。这些产品和它们的制备在例如WO96/16177中有所描述。免疫反应涉及的表位可以由各种方法鉴定,如WO00/26230和WO 01/83559中所述的噬菌体展示方法,或EP 561907中所述的随机方法。一旦将表位鉴定,可通过已知的基因操作技术,如定向诱变(参见例如WO 00/26230、WO 00/26354和/或WO 00/22103)改变它的氨基酸序列以产生改变的酶的免疫性质,和/或可在足够接近表位处进行聚合物的结合,以使聚合物屏蔽所述表位。
在具体实施方案中,酶为(i)在pH 2-8稳定,优选也在pH 3-7稳定,更优选在pH 4-6稳定;(ii)在pH 4-9,优选4-8有活性;(iii)对胃蛋白酶和其它消化蛋白酶(如胰蛋白酶(pancreas protease),即主要为胰蛋白酶(trypsin)和胰凝乳蛋白酶)的降解稳定;和/或(iv)在胆汁盐存在下稳定和/或有活性。
优选地,本发明的蛋白酶是酸稳定的,这表示即使在持续曝露于酸性环境后,纯蛋白酶仍然保持有活性。优选地,保留活性是已知用于药物用途的比较蛋白酶的保留活性的1.1、1.2、1.3、1.5、1.6、1.8、2.0、2.5和3.0倍高。
在进一步具体的实施方案中,酸稳定性指:将纯蛋白酶稀释到相当于A280=1.0,之后在缓冲液(100mM琥珀酸、100mM HEPES、100mM CHES、100mM CABS、1mM CaCl2、150mM KCl、0.01%X-100,pH 3.5)中于37℃温育2小时,如使用WO 01/58276的实施例2C中所述试验方法测定的(底物:Suc-AAPF-pNA,pH 9.0,25℃),所述纯蛋白酶的活性是参照活性(referenceactivity)的至少40%(或至少45、50、55、60、65、70、75、80、85、90、95或至少97%)。术语参照活性指相同蛋白酶在以下处理之后的蛋白酶活性:将所述蛋白酶以纯的形式温育,稀释至A280=1.0,在缓冲液(100mM琥珀酸、100mM HEPES、100mM CHES、100mM CABS、1mM CaCl2、150mM KCl、0.01%X-100,pH 9.0)中于5℃温育2小时,其中所述酶活性用如上所述方法确定。术语A280=1.0指所述纯蛋白酶的这样的浓度(稀释度):其在1cm通径长度(path length)的比色皿中,于280nm相对于缓冲液空白产生1.0的吸光度。术语纯蛋白酶指A280/A260比率在1.70以上或等于1.70的样品(参见WO01/58276的实施例2E),并且通过扫描考马斯染色的SDS-PAGE凝胶测得所述样品在对应于所述蛋白酶的条带中具有该样品扫描密度的至少95%(参见WO 01/58276的实施例2A)。
术语“与......组合”指根据本发明的蛋白酶、脂肪酶和/或淀粉酶的组合用途。组合用途可以是同时的、重叠的或顺序的,这三个术语通常按照医师的处方来解释。
术语“同时的”指酶同时有活性的环境,例如当它们作为一种或多种单独的药物产品同时施用时,或者如果将它们在一种和同样的药物组合物中施用时。
术语“顺序的”指这样的情况,其中一种和/或两种酶先作用,而第二种和/或第三种酶随后作用。顺序的作用能够这样获得:将所述酶作为单独的药物制剂施用,中间有期望的间歇;或者作为一种药物组合物施用,其中对所述酶进行不同的配制(区分),例如为了获得不同的释放时间,提供改进的产品稳定性,或为了最优化酶剂量。
术语“重叠的”指这样的情况,其中酶活性时期既不完全是同时的,也不完全是顺序的,即存在特定的时期,其中两种酶或全部酶都有活性。
术语“一”,例如当用于本发明的酶的上下文中时,指至少一种。在具体实施方案中,“一”表示“一种或多种”或“至少一种”,其也表示一种、两种、三种、四种、五种等。
用参数“同一性”描述两个氨基酸序列之间的相关性。
对于本发明,通过使用来自EMBOSS软件包(http://emboss.org)2.8.0版的Needle程序,确定两个氨基酸序列之间的比对。Needle程序运行Needleman,S.B.and Wunsch,C.D.(1970)J.Mol.Biol.48,443-453所述的全局比对算法(global alignment algorithm)。使用的取代矩阵(substitution matrix)是BLOSUM62,缺口开放罚分(gap opening penalty)是10,缺口延伸罚分(gapextension penalty)是0.5。
本发明的氨基酸序列(“发明序列”;例如SEQ ID NO:2的氨基酸1-274)与不同的氨基酸序列(“外源序列”;例如WO 2005/115445的SEQ ID NO:1的氨基酸1-188)之间的同一性程度这样计算:将两个序列的比对中完全匹配的氨基酸数目,除以“发明序列”的长度或“外源序列”的长度中较短的一个。结果以百分比同一性表示。
当“ 发明序列”和“外源序列”在重叠中的同样位置具有同一的氨基酸残基时(在下述比对实例中用“|”表示),则发生完全匹配。序列的长度是序列中氨基酸残基的数目(例如SEQ ID NO:2的长度是274)。
在下述完全假设的比对实例中,重叠是序列1的氨基酸序列“HTWGER-NL”;或序列2的氨基酸序列“HGWGEDANL”。在所述实例中,缺口用“-”表示。
假设的比对实例:
序列1:ACMSHTWGER-NL
| ||| ||
序列2:HGWGEDANLAMNPS
因此,序列1对序列2的同一性百分比是6/12=0.5,对应于50%。
在具体实施方案中,多肽的氨基酸序列与(with),或对于(to),SEQ ID NO:2的氨基酸1-274的同一性百分比用如下方法确定:i)使用Needle程序比对两个氨基酸序列,使用BLOSUM62置换矩阵,缺口开放罚分为10,并且缺口延伸罚分为0.5;ii)计算比对中完全匹配的数目;iii)将完全匹配的数目除以两个氨基酸序列中最短序列的长度,和iv)将iii)中除法的结果转换成百分比。
或者,两个氨基酸序列的同一性程度可以用程序“比对”确定,所述程序“比对”为Needleman-Wunsch比对(即全局比对)。将序列通过所述程序比对,使用默认的记分矩阵BLOSUM50。缺口的第一个残基的罚分是12,对于缺口其它残基的罚分是2。Needleman-Wunsch算法在Needleman,S.B.and Wunsch,C.D.,(1970),Journal of Molecular Biology,48:443-453中有描述,并且所述比对程序由Myers和W.Miller在“Optimal Alignments in Linear Space”CABIOS(computer applications in the biosciences)(1988)4:11-17中描述。“比对”是FASTA软件包v20u6版的一部分(参见W.R.Pearson and D.J.Lipman(1988),“Improved Tools for Biological Sequence Analysis”,PNAS 85:2444-2448,和W.R.Pearson(1990)“Rapid and Sensitive Sequence Comparison with FASTP andFASTA”Metods in Enzymology 183:63-98)。
本发明的任何酶的样品序列或测试序列,与指定序列之间的同一性程度可以按照如下方法确定:使用程序“比对”来比对所述两个序列。确定比对中完美匹配的数目(“N-完美-匹配”)(完美匹配指比对中相同位置上为相同的氨基酸残基)。也确定两个进行比对的序列的共有长度(common length),即比对(重叠)中氨基酸的总数,包括比对产生的拖尾和前导缺口,如果存在任何这样的缺口(“N-重叠”)。将同一性程度作为“N-完美-匹配”和“N-重叠”之间的比率计算(如果要转换成同一性百分比,则乘以100)。
样品序列或测试序列与特定序列之间的同一性程度可以按照如下方法确定:使用软件“比对”来比对所述序列。确定比对中完美匹配的数目(“N-完美-匹配”)(完美匹配指比对中的相同位置上是相同的氨基酸残基)。确定样品序列的长度(氨基酸残基数)(“N-样品”)。将同一性程度作为“N-完美-匹配”和“N-样品”之间的比率计算(如果要转换成同一性百分比,则乘以100)。
样品序列或测试序列与特定序列之间的同一性程度也可以按照如下方法确定:使用软件“比对”来比对所述序列。确定比对序列中完美匹配的数目(“N-完美-匹配”)(完美匹配指比对中的相同位置上是相同的氨基酸残基)。确定指定序列的长度(氨基酸残基数)(“N-指定”)。将同一性程度作为“N-完美-匹配”和“N-指定”之间的比率计算(如果要转换成同一性百分比,则乘以100)。
优选地,重叠是指定序列的至少20%(“N-重叠”如上所定义,除以指定序列中氨基酸的数目(“N-指定”),乘以100),更优选为至少25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或至少95%。这表示当将样品序列与指定序列比对时,指定序列的氨基酸的至少20%(优选25-95%)最终包括于重叠中。
或者,重叠是指定序列的至少20%(“N-重叠”如上所定义,除以如上所定义的“N-样品”,乘以100),更优选为至少25%、30%、35%、40%、45%、50%、55%、60%、65%、70%、75%、80%、85%、90%或至少95%。这表示当与指定序列比对时,样品序列的氨基酸的至少20%(优选25-95%)最终包括于重叠中。
本发明的酶的活性能够使用任何合适的试验方法测定。通常,可使试验-pH和试验-温度适合于所述酶。试验-pH值的实例是pH 2、3、4、5、6、7、8、9、10、11或12。试验-温度的实例是30、35、37、40、45、50、55、60、65、70、80、90或95℃。优选的pH值和温度是在生理范围,如pH值4、5、6、7或8,和温度30、35、37或40℃。
例如,蛋白酶活性能够使用任何试验测定,其中使用底物,所述底物包括相应于所述蛋白酶的特异性的肽键。
实验部分包括了合适的酶试验方法的实例,具体参见实施例2。其它实例是用于脂肪酶和淀粉酶活性的FIP或Ph.Eur.试验。
药物
在本文的上下文中,术语“药物”指化合物,或化合物的混合物,其治疗、预防和/或减轻疾病的症状,优选治疗和/或减轻疾病的症状。药物可以由医师开出处方,或者可以是非处方(over-the-counter)产品。
药物组合物
本发明的酶的分离、纯化和浓缩可以通过常规方法进行。例如,它们可以通过常规方法从发酵培养液中回收,所述常规方法包括但不限于,离心、过滤、萃取、喷雾干燥、蒸发或沉淀,并用本领域已知的各种方法进一步纯化,所述方法包括但不限于,层析(例如,离子交换、亲和、疏水、色谱聚焦和尺寸排阻)、电泳方法(例如,制备型等电聚焦)、差别溶解度(例如,硫酸铵沉淀)、SDS-PAGE或萃取(参见,例如,Protein Purification,J.-C.Janson and LarsRyden,editors,VCH Publishers,New York,1989)。
本发明的纯蛋白酶的制备在本文的实施例1中描述。在这个实例中,从地衣芽孢杆菌生产菌株中,用定点诱变缺失编码所谓组分C蛋白酶(SEQ IDNO:4,由SEQ ID NO:3编码)的基因,如本领域所知。缺失这个基因的另一种方法可以是,例如,传统突变(classical mutation),例如美国专利号4,266,031所述,优选与现有技术的高通量筛选方法组合使用。
在实施例1中,表达SEQ ID NO:2的蛋白酶的细胞源自地衣芽孢杆菌的野生型菌株,即菌株ATCC 14580,其可从美国典型培养物保藏中心ATCC(American Type Culture Collection)公开获得。可以优选地将编码本发明的蛋白酶的基因的一个或多个额外拷贝插入该细胞中,所述基因例如编码SEQ IDNO:2的氨基酸1-274的基因。这可以例如按WO 02/00907所述,使用例如WO 99/43835中公开的启动子实现。
在具体实施方案中,将每个酶的浓缩固体或液体制备物单独制备。这些浓缩物也可以,至少部分地,单独进行配制,如下所详细解释的。
在进一步具体的实施方案中,将酶以固体浓缩物形式包括于本发明的药物组合物中。酶能够通过本领域已知的各种方法形成固态。例如,固态可以是结晶,其中酶分子以高度有序的形式排列;或者是沉淀物,其中酶分子排列形式有序性较低,或者是无序形式。
结晶可以例如在接近酶的pI的pH和低电导率实现,所述电导率例如10mS/cm或更低,如EP 691982所述。
各种沉淀方法在本领域已知,包括用盐沉淀,如硫酸铵,和/或硫酸钠;用有机溶剂沉淀,如乙醇,和/或异丙醇;或者用聚合物,如PEG(聚乙二醇)。或者,酶能够用本领域已知的各种方法通过去除溶剂(通常为水)而从溶液沉淀,所述方法例如冻干、蒸发(例如在减少的压力下),和/或喷雾干燥。
在进一步具体的实施方案中,酶的固体浓缩物中活性酶蛋白的含量为固体浓缩物中总蛋白含量的至少50%(重量/重量)。在还进一步具体的实施方案中,活性酶蛋白的含量相对于固体浓缩物的总蛋白含量是至少55、60、65、70、75、80、85、90或至少95%(重量/重量)。蛋白含量能够如本领域已知的进行测量,例如通过密度计扫描考马斯染色的SDS-PAGE凝胶;通过使用商业试剂盒,如Protein Assay ESL,定购号1767003,其可从Roche以商业方法获得;或根据WO 01/58276的实施例8所述的方法。
优选地,用密度计扫描考马斯染色的SDS-PAGE凝胶进行测定时,蛋白酶酶蛋白组成根据本发明使用的固体蛋白酶浓缩物的至少50%,更优选至少55、60、65、70、75、80、85、90、92、94、95、96或至少97%。
本发明的药物组合物包含酶,所述酶优选以浓缩酶制备物的形式,更优选以固体浓缩物的形式,并有至少一种可药用的辅助材料或补充(subsidiary)材料,如(i)至少一种载体和/或赋型剂;或(ii)至少一种载体、赋型剂、稀释剂,和/或佐剂。任选的其它组分的非限定性实例(全部为可药用的)是崩散剂(disintegrator)、润滑剂、缓冲剂、增湿剂、防腐剂、增香剂、溶剂、增溶剂、悬浮剂、乳化剂、稳定剂、推进剂和媒介物(vehicle)。
通常,根据所述医学适应症,可以针对本领域已知的所有施用方式来设计本发明的组合物,优选包括肠内施用(通过消化道)。因此,组合物可以为固体、半固体、液体或气体形式,如片剂、胶囊、粉剂、颗粒剂(granule)、微球(microsphere)、软膏、乳膏(cream)、泡沫、溶液、栓剂、注射剂、吸入剂、凝胶、微球、洗剂(lotion)和气溶胶。医务工作者将了解选择最合适的施用途径,并理所应当地避免潜在的危险或不利的施用途径。
下述方法和辅助材料因此也仅作为示例性而绝非用以限制。
对于固体口服制备物,所述酶能够单独使用或与合适的添加剂组合使用,以制成小丸(pellet)、微丸(micropellet)、片剂、微片剂、粉剂、颗粒剂或胶囊,例如,与常规载体组合使用,如乳糖、甘露醇、玉米淀粉或马铃薯淀粉;与赋型剂或粘合剂组合使用,如结晶状或微结晶状纤维素、纤维素衍生物、阿拉伯胶、玉米淀粉或明胶;与崩散剂组合使用,如玉米淀粉、马铃薯淀粉或羧甲基纤维素钠;与润滑剂组合使用,如巴西棕榈蜡、白蜡、虫胶、无水胶状硅石(waterless colloid silica)、从1500到20000的聚乙二醇(PEG,也称作macrogol),特别是PEG 4000、PEG 6000、PEG 8000,聚维酮,滑石,monolein或硬脂酸镁;并且如果需要,与稀释剂、佐剂、缓冲剂、润湿剂、防腐剂如对羟基苯甲酸甲酯(E218)、着色剂如二氧化钛(E171),和增香剂如蔗糖、糖精、橙油、柠檬油和香兰素组合使用。口服制备物是用于治疗PEI的医学适应症的优选制备物的实例。
还能够将所述酶非常常规地配制成液体口服制备物,通过将它们溶解、悬浮或乳化在水溶剂如水中,或非水溶剂中,如植物性或其它类似的油、合成的脂肪族酸甘油酯、高级脂肪族酸的酯、丙二醇、聚乙二醇如PEG 4000,或低级醇,如直链或支链C1-C4醇,例如2-丙醇;并且如果需要,与常规补充材料或添加剂组合使用,如增溶剂、佐剂、稀释剂、等渗剂、悬浮剂、乳化剂、稳定剂和防腐剂。
此外,所述酶可通过与各种基底(bases)例如乳化基底(emulsifying base)或水溶性基底(water-soluble base)混合制成栓剂用于直肠施用。所述栓剂可包括在体温熔化而在室温固化的媒介物如可可豆油、碳蜡和聚乙二醇。
使用脂质体作为递送媒介物也是一种通常可能感兴趣的方法。脂质可以是已知的脂质体形成脂质的任何有用组合,包括阳离子或两性离子的脂质,例如磷脂酰胆碱。剩余的脂质通常将是中性或酸性脂质,例如胆固醇、磷脂酰丝氨酸、磷脂酰甘油等。对于制备脂质体,可以使用Kato等(1991)J.Biol.Chem.266:3361所述的方法。
可以提供用于口服或直肠施用的单位剂型如浆、酏剂、粉剂和悬浮剂,其中每剂量单位,例如,一茶匙、一大汤匙、胶囊、片剂或栓剂,包含预先定量的酶。相似地,用于注射的单位剂型可将酶包含在作为无菌水、生理盐水或其它可药用载体的溶液的组合物中。
术语“单位剂型”用于本文指适合作为人和动物受试者单元剂量(unitarydosage)的物理上的离散单位(physically discrete unit),每单位含有预先定量的酶,所计算的量足以产生期望效果。
在具体实施方案中,本发明的药物组合物用于肠内施用,优选口服施用。
在进一步具体的实施方案中,口服组合物是(i)包含酶晶体的液体组合物;(ii)(高度)纯化酶的沉淀的液体悬浮液;(iii)包含固体或溶解的酶的凝胶;(iv)固定化酶或吸附于颗粒上的酶等的液体悬浮剂;或(v)以含酶粉剂、小丸、颗粒剂或微球形式存在的固体组合物,如果需要,以片剂、胶囊等形式存在的固体组合物,可任选地将所述固体组合物包覆,例如用酸稳定的包覆物。
在组合物的另一个具体的实施方案中,对酶进行区分(compartmentalize),即彼此分离,例如通过分离包覆的方法。
在组合物的还进一步具体的实施方案中,将蛋白酶与组合物的其它酶组分分隔,所述其它酶组分如脂肪酶和/或淀粉酶。
酶的剂量变化很大,其依赖于所施用的特定的酶、施用频率、施用方式、症状的严重性和受试者对副作用的易感性等。一些特定的酶可能比其它的酶更有效。
本发明的酶的固体口服制备物的实例包含:(i)本发明的蛋白酶,其包含与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的氨基酸序列;(ii)脂肪酶,其与具有SEQ ID NO:15的氨基酸1-269的脂肪酶有至少70%同一性;和(iii)淀粉酶,其与选自下组的淀粉酶具有至少70%同一性:a)具有SEQ IDNO:16的氨基酸1-481的淀粉酶,b)具有SEQ ID NO:17的氨基酸1-481的淀粉酶,和c)具有SEQ ID NO:18的氨基酸1-483的淀粉酶;其中优选地,(i)、(ii)和(iii)的酶的预期每日临床剂量如下(全部以mg酶蛋白每kg体重(bw)表示):对于(i)的蛋白酶:0.005-500、0.01-250、0.05-100或0.1-50mg/kg bw;对于(ii)的脂肪酶:0.01-1000、0.05-500、0.1-250或0.5-100mg/kg bw;对于(iii)的淀粉酶:0.001-250、0.005-100、0.01-50或0.05-10mg/kg bw。
本发明的酶的固体口服制备物的优选实例包含:(i)包含,优选具有,SEQID NO:2的氨基酸1-274的蛋白酶;(ii)包含SEQ ID NO:15的氨基酸2-269的脂肪酶,和/或(iii)包含SEQ ID NO:16的氨基酸1-481的淀粉酶。
(i)、(ii)和(iii)的酶的预期每日临床剂量的实例如下(全部以mg酶蛋白每kg体重(bw)表示):对于(i)的蛋白酶:0.05-100、0.1-50或0.5-25mg/kg bw;对于(ii)的脂肪酶:0.1-250、0.5-100或1-50mg/kg bw;对于(iii)的淀粉酶:0.01-50、0.05-10或0.1-5mg/kg bw。
为了口服施用时更好的稳定性,可对酰胺(肽)键以及氨基和羧基末端进行修饰。例如,可将羧基末端酰胺化。
本发明的药物组合物的具体实施方案,其适合于治疗消化性病症、PEI、胰腺炎、囊性纤维化、I型糖尿病和/或II型糖尿病,可通过将本发明的酶并入小丸中来制备。所述小丸通常可包含10-90%(重量/重量,相对于所得小丸的干重)生理上可以接受的有机聚合物,10-90%(重量/重量,相对于所得小丸的干重)的纤维素或纤维素衍生物,和80-20%(重量/重量,相对于所得小丸的干重)的酶,每种情况下,使有机聚合物、纤维素或纤维素衍生物和酶的总量满足100%。
生理上可以接受的有机聚合物可选自下组:聚乙二醇1500、聚乙二醇2000、聚乙二醇3000、聚乙二醇4000、聚乙二醇6000、聚乙二醇8000、聚乙二醇10000、聚乙二醇20000、羟丙基甲基纤维素、聚氧化乙烯(polyoxyethylen)、聚氧化乙烯-聚氧化丙烯共聚物(copolymers ofpolyoxyethylene-polyoxypropylen)和所述有机聚合物的混合物。聚乙二醇4000优选作为生理上可以接受的有机聚合物。
纤维素或纤维素衍生物可以例如选自:纤维素、乙酸纤维素、纤维素脂肪酸酯、硝酸纤维素、纤维素醚、羧甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、甲基纤维素、甲基乙基纤维素和甲基羟丙基纤维素。纤维素,特别是微晶纤维素优选作为纤维素或纤维素衍生物。
所得小丸可以用合适的肠溶衣包覆,用其它非功能性包覆物包覆或不进行这种包覆地直接使用。此外,可将所得小丸填充入胶囊如硬明胶胶囊或不含明胶的胶囊,所述胶囊的大小适合治疗上文详细描述的病症或疾病。在本发明的实施方案中,产生自不同酶类型,特别是产生自脂肪酶、蛋白酶和/或淀粉酶的小丸,可以填充入所述胶囊。当用不同酶类型填充胶囊时,通过向胶囊添加指定量的脂肪酶、蛋白酶和/淀粉酶中的任一种,可使单一酶类型(即脂肪酶、蛋白酶或淀粉酶)的定量适合于某种适应症组或某种患者亚组的特定需要,即可产生其中脂肪酶∶蛋白酶∶淀粉酶的特定比例不同的胶囊。
本发明的脂肪酶的优选药物组合物在WO 2005/092370中描述,特别是包含本文提到的优选赋形剂的制剂。在特别优选的实施方案中,药物组合物包含单、二和三酰基甘油酯和聚乙二醇(PEG)C6-C22脂肪族羧酸的单和二酯的聚乙二醇甘油酯(macrogolglyceride)混合物,并且也可能包含小部分的甘油和游离聚乙二醇。
包含于聚乙二醇甘油酯混合物中的聚乙二醇(PEG)优选为平均每分子有6个到最多40个环氧乙烷单元的PEG,或优选为分子量在200-2000的PEG。
本发明的另一个方面提供本发明的酶的药物组合物,其包含由表面活性剂、共表面活性剂(co-surfactant)和亲脂相组成的体系,所述体系具有大于或等于10的HLB(亲水-亲脂平衡,Hydrophilic-Lipophilic Balance)和高于或等于30℃的熔点。在优选实施方案中,所述体系具有10-16的HLB,优选12-15,和30-600℃的熔点,优选在40-500℃。具体而言,通过HLB值和熔点表征的体系是单、二和三酰基甘油酯与聚乙二醇(PEG)和脂肪族羧酸的单和双酯的混合物,所述脂肪族羧酸具有8-20个碳原子,优选8-18个,而聚乙二醇优选每分子具有大约6至大约32个环氧乙烷单元,并且所述体系任选地包含游离甘油和/或游离聚乙二醇。这种体系的HLB值优选用PEG的链长调控。这种体系的熔点通过脂肪酸的链长、PEG的链长和脂肪酸链的饱和度调控,并且因此受到制备聚乙二醇甘油酯混合物的起始油(starting oil)的调控。
“C8-C18脂肪族羧酸”指混合物,其中将辛酸(C8)、癸酸(C10)、月桂酸(C12)、肉豆蔻酸(C14)、棕榈酸(C16)和硬脂酸(C18)以重要而可变的比例包含在内,如果这些酸是饱和的,则还包括相应的不饱和C8-C18羧酸。这些脂肪酸的比例可以根据起始油而变化。
这样的单、二和三酰基甘油酯和聚乙二醇(PEG)与脂肪族羧酸的单和二酯的混合物,其中所述脂肪族羧酸带有8-18个碳原子,所述混合物可以例如用聚乙二醇和起始油的反应获得,其中聚乙二醇的分子量在200-1500,并且所述起始油由带有脂肪酸的甘油三酸酯混合物组成,所述脂肪酸选自包含以下脂肪酸的组:辛酸、癸酸、月桂酸、肉豆蔻酸、棕榈酸、硬脂酸、油酸和亚麻酸,单独存在或者作为混合物。任选地,这种反应的产物也可包含小比例的甘油和游离聚乙二醇。
50/13是混合物,包含单、二和三酰基甘油酯和聚乙二醇的单和二酯,分别具有40%-50%的棕榈酸(C16)和48%-58%的硬脂酸(C18),组成结合脂肪酸(bound fatty acid)的主要部分。在每种情况下辛酸(C8)和癸酸(C10)的比例少于3%,并且在每种情况下月桂酸(C12)和肉豆蔻酸(C14)的比例少于5%。
44/14是混合物,包含单、二和三酰基甘油酯和聚乙二醇的单和二酯,各比例为:棕榈酸(C16)4-25%,硬脂酸(C18)5-35%,辛酸(C8)少于15%,癸酸(C10)少于12%,月桂酸(C12)30-50%和肉豆蔻酸(C14)5-25%。44/14能够例如通过使用棕榈仁油和聚乙二醇1500的醇解/酯化反应制备。
本发明的优选实施方案提供本发明的酶的药物组合物,其包含的体系含有单、二和三酰基甘油酯与C8-C18脂肪族羧酸的聚乙二醇单和二酯的混合物,并还可能含有小比例的甘油和游离聚乙二醇,所述体系具有在40℃-55℃的熔点和在12-15的HLB值。更优选地,所述体系具有在44℃-50℃的熔点和在13-14的HLB值。或者,所述体系具有大约44℃的熔点和14的HLB值,或所述体系具有大约50℃的熔点和13的HLB值。
处理方法
本发明的蛋白酶,任选地与脂肪酶和/或淀粉酶(本发明的酶)组合,在对动物中各种疾病或病症的治疗处理和/或预防处理中是有用的。术语“动物”包括所有动物,特别是人类。动物的实例是非反刍动物和反刍动物,如绵羊、山羊和牛,例如肉牛(cattle beef)和奶牛。在具体实施方案中,动物是非反刍动物。非反刍动物包括单胃动物,例如马、猪(包括但不限于,小猪、正在生长的猪(growing pigs)和母猪(sow));家禽,如火鸡、鸭和小鸡(chickens)(包括但不限于雏鸡(broiler chick)、蛋鸡(layer));牛犊(young calves);宠物如猫和狗;和鱼(包括但不限于鲑鱼(salmon)、鳟鱼(trout)、罗非鱼(tilapia)、鲶鱼(catfish)和鲤鱼(carp));和甲壳类动物(包括但不限于河虾(shrimp)和对虾(prawn))。在具体实施方案中,动物是哺乳动物,更具体为人类。
例如,所述酶对于消化性病症如消化不良或胃弱(dyspepsia)等的治疗有用,所述消化性病症经常由消化酶的产生不足和/或向胃肠道的分泌不足引起,所述消化酶通常分泌自胃和胰腺。
此外,所述酶对PEI的治疗特别有用。PEI能够使用测试(JOP.J Pancreas(Online)2002;3(5):116-125)验证,并且它可能由以下疾病和症状导致:如胰腺癌、胰腺和/或胃的外科手术,例如胰腺的全部或部分切除术、胃切除术、后胃肠分流术(post gastrointestinal bypass surgery)(例如Billroth II式胃肠造口吻合术);慢性胰腺炎;施-戴综合征(Shwachman Diamond Syndrome);胰腺或总胆管的管梗阻(例如来自肿瘤);和/或囊性纤维化(遗传性疾病,其中厚粘液阻塞胰腺管)。所述酶也可以对急性胰腺炎的治疗有用。
所述酶对消化性病症的作用效果可以如EP 0600868中概括描述的测定;其中实施例2描述用于测定在胃条件下的脂肪酶稳定性测试的体外消化测试,而实施例3描述用于测定在存在胆汁盐时脂肪酶活性的体外消化测试。可以针对蛋白酶和淀粉酶建立相应的测试。WO 02/060474也公开了合适的测试,例如(1)用于测定猪的测试饲料中脂质消化的体外测试,和(2)用胰腺机能不全的猪进行的体内试验,测定其中脂肪、蛋白和淀粉的消化性。
在具体实施方案中,使用实施例3中用于蛋白酶效能的体内筛选测试测定本发明的蛋白酶的效能。
作为另一个实例,酶对I型和/或II型糖尿病(Diabetes mellitus)的治疗有用,特别是在糖尿病治疗中对经常伴随这种病症的消化性病症的辅助治疗有用,以逐渐减少晚期并发症为目的。
可以用WO 00/54799所述的一个或多个方法来确定酶对糖尿病的效果,例如通过控制糖基化血红蛋白的水平,血糖水平,低血糖发作(hypoglycaemicattack),脂溶性维生素如维生素A、D和E的状态,胰岛素的必需每日剂量,体重指标和高血糖期。
在具体实施方案中,本发明的蛋白酶不用作清创剂,和/或不用在伤口康复中。
本文描述和提出权利要求的发明不限于本文公开的特定实施方案范围,因为这些实施方案旨在说明本发明的几个方面。任何相当的实施方案应包含于本发明的范围内。事实上,除了本文所示和所述之外对本发明的各种修饰,根据前面的描述,对本领域的技术人员是显而易见的。这些修饰也应包含于所附权利要求的范围内。在发生冲突的情况下,按照包括定义在内的本发明内容为准。
本文引用的各种文献,所述文献的公开通过引用完全并入本文。
实施例
实施例1:纯化的地衣芽孢杆菌蛋白酶的制备
如下制备SEQ ID NO:1的氨基酸1-274的地衣芽孢杆菌蛋白酶的纯制备物:
材料和方法:
TY培养液:胰蛋白胨20g/l,酵母提取物5g/l,FeCl2·4H2O 7mg/l,MnCl2·4H2O 1mg/l,MgSO4·7H2O 15mg/l,pH 7.3。
PS-1培养液:蔗糖100g,大豆粉(Soybean meal)40g,Na2HPO4·12H2O(Merck 6579)10g,CaCO3 5g,Pluronic PE 6100(BASF)0.1ml,加自来水(tapwater)至1000ml。
发酵:
通过缺失编码另一个蛋白酶的基因(SEQ ID NO:3)得到源自地衣芽孢杆菌ATCC 14580的菌株,将所述菌株在TY琼脂培养基(用2%琼脂固化的TY培养液)上37℃过夜增殖,接种到包含100ml PS-1培养液的摇瓶中。将摇瓶以225rpm的摇动速度于37℃温育90小时。
纯化:
絮凝发酵液,将细胞通过离心从含酶的液体中分离。对上清的SDS聚丙烯酰胺凝胶电泳显示,有相对分子量大约为31kDa的强条带,其对应于期望的蛋白酶。在pH 7和9,在1%脱脂乳琼脂平板上出现大的澄清区(clearingzone),也确认上清中存在强蛋白酶活性。作为下一步,将离心得到的液体进行精细过滤(polish filter)以除去残余的悬浮固体,然后使用适当的膜通过超滤进行浓缩,即膜的截留值(cut-off value)在蛋白酶的大小以下。最后将浓缩物过滤除菌(germ-filter)。
用100mM H3BO3,10mM琥珀酸/NaOH,2mM CaCl2,pH 7.0将100ml过滤除菌的液体浓缩物稀释10倍。所得蛋白酶溶液的pH为7.0。将其中120ml施加于100ml杆菌肽-琼脂糖柱(UpFront Chromatography,目录号600-0100),所述柱用100mM H3BO3,10mM琥珀酸/NaOH,2mM CaCl2,pH 7.0平衡。在用平衡缓冲液彻底清洗柱后,将柱用100mM H3BO3,10mM琥珀酸/NaOH,2mM CaCl2,1M NaCl,pH 7.0,25%(体积/体积)异丙醇分步洗脱(step-elute)。将杆菌肽-硅石步骤重复7次(共8次)。合并所有洗出液(420ml),用脱矿质水将洗出液稀释至15L。将稀释的蛋白酶的pH用20%CH3COOH调至pH 6.0,并施加于400ml SP-sepharose FF柱,该柱用50mM H3BO3,5mM琥珀酸/NaOH,1mM CaCl2,pH 6.0平衡。将柱用平衡缓冲液彻底清洗,用超过3倍柱容积的线性NaCl梯度(0-0.5M)洗脱柱。通过在1.4L G25 sephadex柱上的缓冲液交换,将洗脱的蛋白酶峰(200ml)转移至20mM HEPES/NaOH,100mM NaCl,1mM CaCl2,pH 7.0(HEPES是4-(2-羟乙基)-1-(哌嗪乙磺酸))。将缓冲液交换后的蛋白酶(340ml)在0.22μ过滤单元(如Corning,目录号431097)上过滤。
实施例2:酶试验
蛋白酶Suc-AAPF-pNA试验
试验缓冲液:100mM琥珀酸、100mM HEPES(Sigma H-3375)、100mMCHES(Sigma C-2885)、100mM CABS(Sigma C-5580)、1mM CaCl2、150mMKCl、0.01%X-100,用HCl或NaOH调至pH 9.0。
试验温度:25℃。
将300μl稀释的蛋白酶样品与1.5ml试验缓冲液混合,通过加入1.5mlpNA底物(50mg溶于1.0ml DMSO中,并用0.01%X-100进一步稀释45×)开始活性反应,在混合后,用分光光度计监控A405的增加作为对蛋白酶活性的测量。在活性测量之前稀释蛋白酶样品,以确保所有活性测量结果都在试验的剂量-应答曲线的线性部分中。
蛋白酶FIP试验
也可以使用FIP试验(Fédéation Internationale Pharmaceutique)测定蛋白酶活性,1FIP-单位=1Ph.Eur.-单位(欧洲药典)。该试验和其它FIP试验一起,在Fédération Internationale Pharmaceutique,Scientific Section:InternationalCommission for the standardisation of pharmaceutical enzymes.a)“Pharmaceutical Enzymes,”Editors:R.Ruyssen和A.Lauwers,E.Story Scientia,Ghent,Belgium(1978),b)European Pharmacopoeia中描述。也可参见Deemesteret alin Lauwers A,S charpé S(eds):Pharmaceutical Enzymes,New York,MarcelDekker,1997,p.343-385。该试验可以用来确定胰酶制剂(pancreatin)中的蛋白酶活性。为了确定微生物蛋白酶的FIP活性,可以省略通过添加肠激酶的激活步骤。
原理:在pH 7.5和35℃的温度用蛋白酶水解底物酪蛋白。通过加入三氯乙酸使反应停止,将不降解的酪蛋白过滤去除。通过在275nm处的分光光度法测量确定溶液中残余的肽的量。
活性的定义:将蛋白酶的活性根据未由三氯乙酸的5.0%(重量/体积,即5.0g/100ml)溶液沉淀的肽的量来确定,参考FIP活性已知的胰腺参照粉末(蛋白酶参照标准)。
材料和方法:
酪蛋白溶液:
将1.25g酪蛋白(干物质),例如Calbiochem号218680,悬浮于水中,直至得到实际上澄清的溶液。将pH调至8.0,用水稀释溶液至100ml的终体积。在此处和下文中,水指去离子水。
硼酸盐缓冲液pH 7.5:
将2.5g氯化钠、2.85g四硼酸二钠和10.5g硼酸溶于900ml水中,将pH调至pH 7.5+/-0.1,并用水稀释至1000ml。
滤纸:
折制的滤器具有125mm直径,例如Schleicher & Schuell号15741/2。滤纸测试:通过滤器过滤5ml 5.0%三氯乙酸。滤液在275nm处的吸光度应该小于0.04,使用未过滤的三氯乙酸溶液作为空白。
蛋白酶参照标准:
蛋白酶(胰腺)可从International Commission on Pharmaceutical Enzymes,Centre for Standards,Harelbekestraat 72,B-9000 Ghent,Belgium以商业方法获得。标准品具有以FIP/Ph.Eur.-单位/g表示的标记活性(A)。准确称重相当于大约130蛋白酶-FIP/Ph.Eur.-单位的量。加入一抹刀尖(a spatula tip of)的海沙,用几滴冰冷的0.02 M氯化钙(pH 6.0-6.2)润湿,全部用平端的玻璃棒碾碎。用大约90ml相同的冰冷氯化钙溶液稀释,并在冰浴中搅拌悬浮液15至30分钟。将pH调至6.1,用相同的氯化钙溶液将体积调至100ml。用pH 7.5的硼酸盐缓冲液将5.0ml的这种悬浮液稀释至100ml。对于活性测试,将1.0、2.0和3.0ml的这种溶液用作参照(下文中称作S1、S2和S3,S表示标准)。
测试悬浮液:
如上所述制备蛋白酶参照标准的方法制备样品悬浮液,使用的样品量相当于大约260 FIP/Ph.Eur.-单位。将pH调至6.1,加水至100ml。将5.0ml这种溶液与5ml氯化钙溶液混合。将5ml这样的稀释液进一步用硼酸盐缓冲液稀释至100ml。将2.0ml这种溶液用于试验(下文中样品称作Un,未知活性的样品,数目用n表示)。
试验步骤(活性测试):
针对三种参照悬浮液(S1、S2、S3)和样品悬浮液(Un)进行试验,全部进行三次重复测定。每种样品一个空白是足够的(分别称作S1b、S2b、S3b和Unb)。制备不加样品/标准品的盲样品(blind)(B),作为分光光度计的补偿液体。如下将硼酸盐缓冲液加入试管中:盲样品(B)3.0ml;样品(Un)1.0ml;标准品(S1、S2和S3)分别为2.0、1.0和0ml。向S1、S2和S3中分别加入1.0、2.0和3.0ml蛋白酶参照标准品。向样品(Un)试管加入2.0ml测试悬浮液。向所有盲样品(S1b、S2b、S3b、Unb和B)中加入5 ml三氯乙酸,然后立即混合。所有试管用玻璃塞封口,与底物溶液一起置于恒温(35+/-0.5℃)水浴中。当温度达到平衡时,在时间零点,向试管S1、S2、S3和Un中加入2.0ml酪蛋白溶液,然后立即混合。恰好30分钟后,向S1、S2、S3和Un的每个试管中加入5.0ml三氯乙酸,然后立即混合。从水浴中取出试管,于室温放置20分钟,使蛋白质完全沉淀。每个试管中的内容物用相同的滤器过滤两次,使用来自试管B的滤液作为补偿液体测量275nm处滤液的吸收(absorption)。相对于标准品(S1、S2、S3)的已知标记活性(A)计算以FIP单位表示的样品(Un)的活性。吸收值减去相应的盲样品值(例如S1的吸光度减去S1b的吸光度)应该在0.15-0.60的区间内。
蛋白质AU试验
变性的血红蛋白(0.65%(重量/重量)于含脲的6.7mM KH2PO4/NaOH缓冲液中,pH 7.50)在25℃用蛋白酶降解10分钟,用三氯乙酸(TCA)将不降解的血红蛋白沉淀,并过滤去除。用Folin & Ciocalteu的苯酚试剂(将1体积Folin-Ciocalteu Phenol Reagent Merck 9001.0500加入2体积脱矿质水)确定滤液中TCA可溶的血红蛋白降解产物,所述苯酚试剂与几种氨基酸一起得到蓝色(在750nm测定)。活性单位(AU)参照标准品测定和定义。变性的血红蛋白底物可以如下制备:将1154g脲(Harnstoff,Merck 8487)溶于1000ml脱矿质水中,加入240.3g NaOH,然后缓慢地加入63.45g血红蛋白(Merck 4300),接着加入315.6g KH2PO4,并且加脱矿质水至3260g。将pH调至7.63。更多细节和合适的Alcalase标准品可向Novozymes A/S,Krogshoejvej 36,DK-2880Bagsvaerd,Denmark(试验号:EB-SM-0349.01)请求获得。
脂肪酶pNP试验
底物:对硝基苯基(pNP)戊酸
试验pH:7.7
试验温度:40℃
反应时间:25分钟
带有黄色的消化产物在405nm有特征吸收。用分光光度法确定它的量。一个脂肪酶单位是在给定试验条件下,每分钟释放1微摩尔可滴定的丁酸的酶量。更详细的试验描述AF95/6-GB可向Novozymes A/S,Krogshoejvej 36,DK-2880 Bagsvaerd,Denmark请求获得。
脂肪酶LU试验
在这个试验中,0.16M三丁酸甘油酯(tributyrin)(甘油三丁酸酯,Merck1.01958.000)在pH 7.00和30℃(+/-1℃)的脂肪酶催化降解,通过用0.025M脱气的(de-gassed)、不含CO2的氢氧化钠(Sodium hydroxide titrisol,Merck 9956)对释放的丁酸进行恒-pH滴定(pH-stat titration)来跟踪。将滴定剂的消耗作为时间的函数记录。
将底物用0.6%w/v阿拉伯树胶乳化剂乳化(20.0g阿拉伯树胶、89.5gNaCl、2.05g KH2PO4、加水至1.5l,放置直至全部溶解,加入2700ml甘油,调节pH至4.5。将90ml三丁酸甘油酯与300ml阿拉伯树胶乳化剂和1410ml脱矿质水(demineralised water)混合,并且使用例如Silverson乳化剂L4RT于7000rpm均质化3分钟,然后调节至pH 4.75)。脂肪酶样品首先在0.1M甘氨酸缓冲液(glycin buffr)pH 10.8中稀释,然后在脱矿质水中稀释,使活性水平为1.5-4.0LU/ml。将15ml乳化的底物溶液倒入滴定容器。加入1.0ml样品溶液,并且在滴定过程中将pH保持在7.0。测定为维持恒定的pH每分钟加入的滴定剂的量。活性计算基于滴定曲线线性范围的平均斜率。可以使用已知活性的标准品作为校验水平(level check)。
1LU(脂肪酶单位)是在上述给定试验条件下,每分钟释放1微摩尔可滴定的丁酸的酶量。1kLU(千脂肪酶单位)=1000LU。
更详细试验说明EB-SM-0095.02可向Novozymes A/S,Krogshoejvej 36,DK-2880 Bagsvaerd,Denmark请求获得。
脂肪酶恒定pH试验
试验基于在0.65mM胆汁盐存在下从橄榄油乳剂中由脂肪酶催化释放脂肪酸。将底物用作为乳化剂的阿拉伯树胶乳化(将175g橄榄油用630ml阿拉伯树胶溶液(4000ml水中的474.6g阿拉伯树胶、64g氯化钙)在搅拌器中乳化15分钟;冷却至室温后,使用4M NaOH将pH调节至pH 6.8-7.0)。
为了测定,将19ml乳剂和10ml胆汁盐溶液(将492mg胆汁盐溶于水中,并补充至500ml)在反应容器中混合并加热至36.9℃至37.5℃。通过加入1.0ml酶溶液开始反应。释放的酸通过加入0.1M氢氧化钠自动于pH 7.0滴定,共进行5分钟。从第一分钟和第五分钟之间滴定曲线的斜率计算活性。为了校准,在三种不同活性水平测定标准品。
淀粉酶
底物:Phadebas片剂(Pharmacia Diagnostics;交联、不溶、蓝色的淀粉聚合物,将其与牛血清白蛋白和缓冲物质混合,并制成片剂)。
试验温度:37℃
试验pH:4.3(或7.0,如果需要)
反应时间:20分钟
在悬浮于水中后,将淀粉用α-淀粉酶水解,得到可溶的蓝色片段。所得蓝色溶液于620nm测得的吸光度是α-淀粉酶活性的函数。一个真菌α-淀粉酶单位(1FAU)是在标准试验条件每小时分解5.26g淀粉(Merck,Amylumsolubile Erg.B.6,批号9947275)的酶量。更详细的试验说明APTSMYQI-3207可向Novozymes A/S,Krogshoejvej 36,DK-2880 Bagsvaerd,Denmark请求获得。
实施例3:地衣芽孢杆菌蛋白酶的体内筛选测试
在雌性迷你猪(Ellegaard)中测试实施例1的纯化的地衣芽孢杆菌蛋白酶,以胰酶制剂作为基准(benchmark)。通过结扎胰管诱导迷你猪的胰腺外分泌机能不全(PEI),并且配以回盲折返插管(ileo-caecal re-entrantcannula),上述全部在氟烷麻醉下进行,体重为大约25kg,如Tabeling et al.,J.1999,Studies on nutrient digestibilities(pre-caecal and total)in pancreaticduct-ligated pigs and the effcts of enzyme substitution,J.Anim.Physiol.A.Anim.Nutr.82:251-263(下文中称为“Tabeling 1999”)和Gregory et al.,J.1999.Growth and digestion in pancreatic duct ligated pigs,Effect of enzymesupplementation in“Biology of the Pancreas in Growing Animals”(SGPierzynowski & R.Zabielski eds),Elsevier Science BV,Amsterdam,pp 381-393(下文中称为“Gregory et al 1999”)中所述。在研究开始之前,允许用至少4周的时间从外科手术中恢复。在研究开始前,通过粪便胰凝乳蛋白酶测试(可从Immundiagnostik AG,Wiesenstrasse 4,D-64625 Bensheim,Germany以商业方法获得,目录号为K 6990)确定每头猪的PEI状态。
在研究过程中,将猪圈养在改良的代谢笼(modified metabolism cage)中,采用12∶12小时的明-暗循环,而且允许自由饮水,并每日喂食两餐。为了评估蛋白酶效能,将喂食猪的250g测试餐与1升水和0.625g Cr2O3(三氧化二铬标记)混合,并在喂食前即刻混合入不同量的蛋白酶(0、1000、2500、6000 FIPU蛋白酶/餐(蛋白酶FIP单位,参见实施例2))。测试餐包含21.4%蛋白质、51.9%淀粉和2.6%脂肪,并具有下述组合物(g/100g干物质):鱼粉3.5、家禽肉粉10.2、小麦粉29.5、带壳/脱壳稻(shelled rice)14、马铃薯淀粉11、玉米淀粉14、酪蛋白5.9、纤维素粉4.3、维生素、矿物质和痕量元素7.6(按照猪的营养需要,参见例如,WO 01/58276的表A)。
在回肠中第一次出现食物标记(绿色食糜)后,收集回肠食糜并置于冰上,持续进行8小时,在分析前于-20℃储存。在单独的测定之间允许有至少一天的冲洗(washout)。
简而言之,将冷冻样品冷冻干燥,并分析干物质(DM)和粗蛋白。在103℃温育8小时后冻干,然后根据重量估计DM。根据氮(N)乘以因子6.25计算粗蛋白,即粗蛋白(g/kg)=N(g/kg)×6.25,如Animal Nutrition,4th edition,Chapter 13(Eds.P.McDonald,R.A.Edwards and J.F.D.Greenhalgh,LongmanScientific and Technical,1988,ISBN 0-582-40903-9)中所述。通过Kjeldahl方法(Naumann and Bassler,1993,Die chemische Untersuchung von Futtermitteln.3edition VDLUFA-Verlag,Darmstadt,Germany(VDLUFA=Verband DeutscherLandwirtschaftlicher Untersuchungs-und Forschungsanstalten))确定含氮量。
根据下述公式计算表观盲肠前(pre-caecal)蛋白质消化性:
其中Cr2O3和蛋白质用g/100g干物质表示。Cr2O3的量可以用本领域已知的方法确定,优选通过氧化成铬酸盐并测定其在365nm处的消光来确定。如Petry和Rapp在Zeitung für Tierphysiologie(1970),vol.27,p.181-189中所述。本研究的结果在表1中描述。
表1:酶补充对表观蛋白质消化性的影响
酶补充 | 0 | 1000FIP U | 2500FIP U | 6000FIP U |
无补充 | 14.7+/-2.1 | |||
胰酶制剂 | 31.7+/-12.4 | 59.4+/-4.9 | 70.7+/-0.9 | |
地衣芽孢杆菌蛋白酶 | 39.1+/-8.6 | 58.5+/-11.3 | 65.5+/-1.1 |
数值是平均值±SD。
从表1中的结果显而易见的是,根据本发明的SEQ ID NO:2的蛋白酶与已知胰酶制剂制备物表现出相同的活性。本发明的蛋白酶引起在蛋白质消化性上大的且依赖于剂量的改进,其在测试的最低剂量已显示出高效的改进。
实施例4:蛋白酶的体外测试
在体外测试各种蛋白酶在模拟消化条件下降解蛋白质的能力。
蛋白酶
测试下述本发明的枯草杆菌蛋白酶:SEQ ID NO:1的氨基酸1-274的地衣芽孢杆菌蛋白酶;SEQ ID NO:10的氨基酸1-275的解淀粉芽孢杆菌蛋白酶,和SEQ ID NO:11的氨基酸1-269的迟缓芽孢杆菌蛋白酶的变体99aE(在SEQID NO:11的氨基酸1-269中,在第99个氨基酸残基S(Ser)后插入一个E(Glu))。这些蛋白酶均与SEQ ID NO:1的氨基酸1-274具有50%以上的百分比同一性。
为了比较,也将一些本发明之外的枯草杆菌蛋白酶包括在内,即来自Bacillus halmapalus NCIB 12513的蛋白酶(在WO 88/01293和WO 98/012005(SEQ ID NO:42,芽孢杆菌属菌种JP170)中都有描述),和来自芽孢杆菌属菌种NCIMB 40339的蛋白酶(在WO 92/017577中作为芽孢杆菌属菌种TY145描述)。这些蛋白酶均与SEQ ID NO:1的氨基酸1-274具有50%以下的百分比同一性。此外,将WO 2005/115445中描述的非枯草杆菌蛋白酶拟诺卡氏菌属蛋白酶(其中的SEQ ID NO:1的氨基酸1-188)包括在内以作比较。该蛋白酶与SEQ ID NO:1的氨基酸1-274也具有50%以下的同一性。最后,将胰酶制剂包括在内作为阳性对照。
蛋白酶在酶蛋白基础上均以相等剂量施用,即72、36、18和9mg酶蛋白(EP)每餐(250g)。蛋白酶酶蛋白的量根据A280的值和氨基酸序列(氨基酸组成)来计算,使用S.C.Gill & P.H.von Hippel,Analytical Biochemistry 182,319-326,(1989)中列出的原理。
材料和方法
胆汁盐(即牛磺胆酸钠(sodium taurocholate)BRP,lot 2,来自Ph.Eur或FIP,也可由例如LGC promochem以商业方法获得,500g/mol)、胃蛋白酶(Merck,VL 317492 437(1.07192))、胰酶制剂(来自Solvay Pharmaceuticals)。蛋白酶餐:51.9%淀粉、21.3%蛋白质和2.6%脂肪/脂质。
体外模型
将蛋白酶饮食(protease diet)溶于0.1M HCl中至0.2g饮食/mL的浓度。将pH调至pH 3.0(模拟胃的条件)。在微孔板(MTP)的每孔中加入100μL饮食浆、20μL胃蛋白酶(在脱矿质水(Milli-Q)中的终浓度为70mg/L)和30μL蛋白酶(或在无酶对照中加入Milli-Q)。于37℃、700rpm温育1小时。在1小时温育结束时,测得pH为3.4。为了将pH提高至6.0(模拟肠的条件),每孔中加入25μL混合的pH 5/9缓冲液(0.8M MES、0.8M咪唑、0.8M醋酸钠,pH 5.0或pH 9.0;40%pH 5和60%pH 9缓冲液)。此外,加入25μL胆汁盐(终浓度为5mM),于37℃、700rpm温育2小时。在体外培育后,将MTP于2700rpm(1500g)、4℃离心10分钟,收集上清用于进一步研究。
确定游离氨基(OPA)
通过与OPA(O-酞二醛(O-phthaldialdehyde))的反应来测定游离氨基,从而分析体外消化的上清。OPA测定的步骤如下:将20μL稀释的体外上清转移至新的MTP,并加入200μL OPA试剂(将80mg OPA溶于2ml 96%乙醇中;3.81g十水合四硼酸二钠、1ml 10%SDS、88mg DTT和所述OPA-乙醇溶液,用Milli-Q水加至100mL)。测定340nm的吸光度。测定试验中包括一行丝氨酸标准品(0.5mg/mL-0.0078mg/mL)。
下面的表2以水解的mM氨基表示结果。结果为两次重复测定的平均值,也示出了标准偏差(s.d.)。只给出了每餐72mg酶蛋白的结果,因为在该测试中,用较低酶剂量的结果无法在酶之间进行适当地区别。
表2
测试的蛋白酶 | SEQ1 | SEQ10 | JP170 | TY145 | 拟诺卡氏菌属 | 胰酶制剂 |
水解的氨基(mM) | 7.4 | 4.9 | 0.81 | 0.38 | 9.1 | 2.5 |
S.d. | 0.6 | 2.4 | 0.11 | 0.37 | 1.7 | 1.6 |
对于SEQ1的%同一性 | 100 | 70 | 35 | 47 | 18 | - |
表2的结果显示本发明的蛋白酶(SEQ1、SEQ10)在此体外模型中性能非常好。对于不是本发明的一部分的蛋白酶JP170和TY145则不是这样。事实上,不考虑拟诺卡氏菌属蛋白酶,其是完全不同类型的蛋白酶并且不包括在本发明中,显示出与本发明的SEQ ID NO:1的百分比同一性和在此模型中的性能之间存在关联(%同一性越高,性能越好)。
在如上所述进行的单独实验中,我们测试了本发明的迟缓芽孢杆菌蛋白酶变体(SEQ11变体)的体外性能,其中也将拟诺卡氏菌属蛋白酶包含在内用于比较。剂量-应答结果显示于下面的表3中。
表3
首先,这些结果表明良好的剂量-应答关系。其次,需要注意的是本发明的蛋白酶(SEQ11变体)也表现非常好,特别是在剂量为72mg EP/餐时。SEQ11变体甚至表现得非常符合上述与SEQ ID NO:1的百分比同一性和性能之间的关联(相对于拟诺卡氏菌属蛋白酶,其也包括在这两个实验中)。
实施例5:药用蛋白酶组合物
(A)高强度小丸
按照如实施例1所述制备SEQ ID NO:1的氨基酸1-274的蛋白酶过滤除菌的液体浓缩物,并喷雾干燥。测得的喷雾干燥的蛋白酶粉中蛋白酶蛋白质含量为58.5%。将粉末状的1125g喷雾干燥的蛋白酶与微晶纤维素(450g)和聚乙二醇4000(MacrogolTM 4000;675g)在商业上可获得的混合器中进行干式预混合。加入异丙醇(460g;100%),所得湿物质继续于室温完全混合。然后将均质化的物质在商业上可获得的挤压机中挤压以形成圆柱型小丸,所述挤压机装有冲孔模(piercing die),所述冲孔模的孔直径为0.8mm。在挤压时小珠温度(bead temperature)不超过50℃。产生的挤压物用商业上可获得的制粒机(spheronizer),通过加入必要量的异丙醇100%(54.5g)滚圆成球形小丸。将小丸在大约40℃的产品温度在商业上可获得的真空干燥机(来自Voetsch)中干燥。产品温度不超过45℃。然后通过使用带有0.7和1.4mm筛的机械筛选机分离干燥的小丸。收集≥0.7mm并且≤1.4mm的筛选级分,并且以每份200mg小丸填入尺寸2的胶囊中。所得干燥小丸的酶蛋白浓度为大约29.3%(w/w)。
(B)较低强度小丸
与(A)中提供的实例近似,以2250g的批次大小如下制备具有较低蛋白酶含量的小丸作为药物:使用562.5g粉末形式的喷雾干燥的蛋白酶(测得的蛋白酶蛋白质含量为58.5%)、微晶纤维素(1125g)、聚乙二醇4000(562.5g)、用于润湿的异丙醇(700g)和用于滚圆的异丙醇(61.2g)。所得干燥小丸的蛋白酶浓度为大约14.6%(w/w)。
通过应用用于来自胰腺粉末的蛋白酶的FIP方法来测定由实例(A)和(B)所得小丸的蛋白水解活性,其中对所述方法进行修饰,即省略活化步骤。相对于起始的粉状蛋白酶材料,每种情况下小丸中的蛋白水解活性均不存在损失。
然后根据Pharm.Eur.2.9.1(Section“Disintegration of tablets and capsules”)测试由实例(A)和(B)所得小丸的崩散性(测试溶液:水-500mL,37℃)。
来自实例(A)的小丸在3分钟内完成崩散。来自实例(B)的小丸在11分钟内完成崩散。
实施例6:蛋白酶和淀粉酶的药物组合物
如下制备包含淀粉酶和蛋白酶的高强度小丸:
如DK 2005 00931所述制备淀粉酶的液体浓缩物(过滤除菌的超滤液),所述淀粉酶具有SEQ ID NO:16的氨基酸1-486。将所述液体浓缩物喷雾干燥。喷雾干燥的淀粉酶粉末中测得的淀粉酶蛋白含量为37%。将粉末形式的喷雾干燥的淀粉酶(398.5g)连同实施例5中制备的喷雾干燥的蛋白酶粉末(746.5g;测得的蛋白酶蛋白含量为58.5%)、微晶纤维素(458g)和聚乙二醇4000(MacrogolTM 4000;687g)在商业上可获得的搅拌器中进行干式预混合。加入异丙醇100%(460g),将所得湿物质继续在室温彻底混合。然后将均质化的物质在商业上可获得的挤压机中挤压形成圆柱型小丸,所述挤压机装有冲孔模,所述冲孔模的孔直径为0.8mm。挤压时小珠温度不超过50℃。产生的挤压物用商业上可获得的制粒机(spheronizer)通过加入必要量的异丙醇100%(58g)滚圆成球形小丸。使用大约40℃的供给温度在商业上可获得的真空干燥机(来自Voetsch)中干燥小丸。产品温度不超过45℃。然后使用具有0.7和1.4mm筛的机械筛选机分离干燥的小丸。收集≥0.7mm和≤1.4mm的筛级分,并且可以每份200 mg填充到尺寸2的胶囊中。所得干燥小丸的蛋白酶浓度为大约19.1%(w/w),并且所得干燥小丸的淀粉酶浓度为大约6.4%(w/w)。
根据上述方法测试所得小丸的蛋白水解和淀粉分解活性。在每种情况下,分别相对于起始的粉状蛋白酶或淀粉酶材料,在蛋白水解或淀粉分解活性中均不存在损失。
实施例7:在蛋白酶存在下脂肪酶的体内稳定性和效能
如下测试在存在本发明蛋白酶(所述蛋白酶具有SEQ ID NO:1的氨基酸1-274)的条件下,SEQ ID NO:15的疏棉状腐质霉脂肪酶变体的稳定性和效能:
在体内试验中测试纯化的脂肪酶,如要求丹麦申请号2005 00929的优先权的PCT申请的实施例2中所述,但剂量根据胰腺FIP试验中估计的脂肪酶单位而定,所述FIP试验也在此参考文献中有描述。也如该参考专利申请中所述来估计消化性值(脂肪吸收系数;CFA)。
将脂肪酶单独测试,并且以各种剂量组合与蛋白酶组合进行测试。通过使用胰腺FIP试验确定蛋白酶活性(参见实施例1)。
结果显示于下表4中,给出的是平均CFA(%)值,并示出了标准偏差(sd)。
表4
处理 | 脂肪酶剂量(胰腺FIP单位每餐) | 蛋白酶剂量(胰腺FIP单位每餐) | CFA(%) | sd |
未处理的PEI(对照) | 0 | 0 | 21.7 | 4.5 |
单独的脂肪酶 | 107200 | 0 | 59.2 | 4.7 |
脂肪酶+蛋白酶 | 107200 | 1200 | 55.6 | 6.7 |
脂肪酶+蛋白酶 | 107200 | 2400 | 58.7 | 5.1 |
单独的脂肪酶 | 780892 | 0 | 75.6 | 4.7 |
脂肪酶+蛋白酶 | 780892 | 9000 | 81.4 | 4.0 |
脂肪酶+蛋白酶 | 780892 | 18000 | 76.0 | 3.2 |
对于测试的两种脂肪酶剂量中的每一种,不加蛋白酶和加入两种不同剂量的蛋白酶的结果之间不存在显著差异。因此能够得出结论,蛋白酶对体内的脂肪酶无反作用。
序列表
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索尔维医药有限责任公司(Solvay Pharmaceuticals GmbH)
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Gly Ile Ser Ile Tyr Ser Leu Gly Met His Pro Ala Gln Ala Ala Pro
-75 -70 -65
tcg cct cat act cct gtt tca agc gat cct tca tac aaa gcg gaa aca 144
Ser Pro His Thr Pro Val Ser Ser Asp Pro Ser Tyr Lys Ala Glu Thr
-60 -55 -50
tcg gtt act tat gac cca cac att aag agc gat caa tac ggc ttg tat 192
Ser Val Thr Tyr Asp Pro His Ile Lys Ser Asp Gln Tyr Gly Leu Tyr
-45 -40 -35
tca aaa gcg ttt aca ggc acc ggc aaa gtg aat gaa aca aag gaa aaa 240
Ser Lys Ala Phe Thr Gly Thr Gly Lys Val Asn Glu Thr Lys Glu Lys
-30 -25 -20 -15
gcg gaa aaa aag tca ccc gcc aaa gct cct tac agc att aaa tcg gtg 288
Ala Glu Lys Lys Ser Pro Ala Lys Ala Pro Tyr Ser Ile Lys Ser Val
-10 -5 -1 1
att ggt tct gat gat cgg aca agg gtc acc aac aca acc gca tat ccg 336
Ile Gly Ser Asp Asp Arg Thr Arg Val Thr Asn Thr Thr Ala Tyr Pro
5 10 15
tac aga gcg atc gtt cat att tca agc agc atc ggt tca tgc acc gga 384
Tyr Arg Ala Ile Val His Ile Ser Ser Ser Ile Gly Ser Cys Thr Gly
20 25 30
tgg atg atc ggt ccg aaa acc gtc gca aca gcc gga cac tgc atc tat 432
Trp Met Ile Gly Pro Lys Thr Val Ala Thr Ala Gly His Cys Ile Tyr
35 40 45 50
gac aca tca agc ggt tca ttt gcc ggt aca gcc act gtt tcg ccg gga 480
Asp Thr Ser Ser Gly Ser Phe Ala Gly Thr Ala Thr Val Ser Pro Gly
55 60 65
cgg aac ggg aca agc tat cct tac ggc tca gtt aaa tcg acg cgc tac 528
Arg Asn Gly Thr Ser Tyr Pro Tyr Gly Ser Val Lys Ser Thr Arg Tyr
70 75 80
ttt att ccg tca gga tgg aga agc gga aac acc aat tac gat tac gga 576
Phe Ile Pro Ser Gly Trp Arg Ser Gly Asn Thr Asn Tyr Asp Tyr Gly
85 90 95
gca atc gaa cta agc gaa ccg atc ggc aat act gtc gga tac ttc gga 624
Ala Ile Glu Leu Ser Glu Pro Ile Gly Asn Thr Val Gly Tyr Phe Gly
100 105 110
tac tcg tac act act tca tca ctt gtt ggg aca act gtt acc atc agc 672
Tyr Ser Tyr Thr Thr Ser Ser Leu Val Gly Thr Thr Val Thr Ile Ser
115 120 125 130
ggc tac cca ggc gat aaa aca gca ggc aca caa tgg cag cat tca gga 720
Gly Tyr Pro Gly Asp Lys Thr Ala Gly Thr Gln Trp Gln His Ser Gly
135 140 145
ccg att gcc atc tcc gaa acg tat aaa ttg cag tac gca atg gac acg 768
Pro Ile Ala Ile Ser Glu Thr Tyr Lys Leu Gln Tyr Ala Met Asp Thr
150 155 160
tac gga gga caa agc ggt tca ccg gta ttc gaa caa agc agc tcc aga 816
Tyr Gly Gly Gln Ser Gly Ser Pro Val Phe Glu Gln Ser Ser Ser Arg
165 170 175
acg aac tgt agc ggt ccg tgc tcg ctt gcc gta cac aca aat gga gta 864
Thr Asn Cys Ser Gly Pro Cys Ser Leu Ala Val His Thr Asn Gly Val
180 185 190
tac ggc ggc tcc tcg tac aac aga ggc acc cgg att aca aaa gag gtg 912
Tyr Gly Gly Ser Ser Tyr Asn Arg Gly Thr Arg Ile Thr Lys Glu Val
195 200 205 210
ttc gac aat ttg acc aac tgg aaa aac agc gca caa 948
Phe Asp Asn Leu Thr Asn Trp Lys Asn Ser Ala Gln
215 220
<210>4
<211>316
<212>PRT
<213>地衣芽孢杆菌(Bacillus licheniformis)
<400>4
Leu Val Ser Lys Lys Ser Val Lys Arg Gly Leu Ile Thr Gly Leu Ile
-90 -85 -80
Gly Ile Ser Ile Tyr Ser Leu Gly Met His Pro Ala Gln Ala Ala Pro
-75 -70 -65
Ser Pro His Thr Pro Val Ser Ser Asp Pro Ser Tyr Lys Ala Glu Thr
-60 -55 -50
Ser Val Thr Tyr Asp Pro His Ile Lys Ser Asp Gln Tyr Gly Leu Tyr
-45 -40 -35
Ser Lys Ala Phe Thr Gly Thr Gly Lys Val Asn Glu Thr Lys Glu Lys
-30 -25 -20 -15
Ala Glu Lys Lys Ser Pro Ala Lys Ala Pro Tyr Ser Ile Lys Ser Val
-10 -5 -1 1
Ile Gly Ser Asp Asp Arg Thr Arg Val Thr Asn Thr Thr Ala Tyr Pro
5 10 15
Tyr Arg Ala Ile Val His Ile Ser Ser Ser Ile Gly Ser Cys Thr Gly
20 25 30
Trp Met Ile Gly Pro Lys Thr Val Ala Thr Ala Gly His Cys Ile Tyr
35 40 45 50
Asp Thr Ser Ser Gly Ser Phe Ala Gly Thr Ala Thr Val Ser Pro Gly
55 60 65
Arg Asn Gly Thr Ser Tyr Pro Tyr Gly Ser Val Lys Ser Thr Arg Tyr
70 75 80
Phe Ile Pro Ser Gly Trp Arg Ser Gly Asn Thr Asn Tyr Asp Tyr Gly
85 90 95
Ala Ile Glu Leu Ser Glu Pro Ile Gly Asn Thr Val Gly Tyr Phe Gly
100 105 110
Tyr Ser Tyr Thr Thr Ser Ser Leu Val Gly Thr Thr Val Thr Ile Ser
115 120 125 130
Gly Tyr Pro Gly Asp Lys Thr Ala Gly Thr Gln Trp Gln His Ser Gly
135 140 145
Pro Ile Ala Ile Ser Glu Thr Tyr Lys Leu Gln Tyr Ala Met Asp Thr
150 155 160
Tyr Gly Gly Gln Ser Gly Ser Pro Val Phe Glu Gln Ser Ser Ser Arg
165 170 175
Thr Asn Cys Ser Gly Pro Cys Ser Leu Ala Val His Thr Asn Gly Val
180 185 190
Tyr Gly Gly Ser Ser Tyr Asn Arg Gly Thr Arg Ile Thr Lys Glu Val
195 200 205 210
Phe Asp Asn Leu Thr Asn Trp Lys Asn Ser Ala Gln
215 220
<210>5
<211>379
<212>PRT
<213>地衣芽孢杆菌(Bacillus licheniformis)
<220>
<221>信号
<222>(1)..(29)
<220>
<221>前肽
<222>(30)..(105)
<220>
<221>成熟肽
<222>(106)..(379)
<400>5
Met Met Arg Lys Lys Ser Phe Trp Leu Gly Met Leu Thr Ala Phe Met
-105 -100 -95 -90
Leu Val Phe Thr Met Ala Phe Ser Asp Ser Ala Ser Ala Ala Gln Pro
-85 -80 -75
Ala Lys Asn Val Glu Lys Asp Tyr Ile Val Gly Phe Lys Ser Gly Val
-70 -65 -60
Lys Thr Ala Ser Val Lys Lys Asp Ile Ile Lys Glu Ser Gly Gly Lys
-55 -50 -45
Val Asp Lys Gln Phe Arg Ile Ile Asn Ala Ala Lys Ala Lys Leu Asp
-40 -35 -30
Lys Glu Ala Leu Lys Glu Val Lys Asn Asp Pro Asp Val Ala Tyr Val
-25 -20 -15 -10
Glu Glu Asp His Val Ala His Ala Leu Ala Gln Thr Val Pro Tyr Gly
-5 -1 1 5
Ile Pro Leu Ile Lys Ala Asp Lys Val Gln Ala Gln Gly Phe Lys Gly
10 15 20
Ala Asn Val Lys Val Ala Val Leu Asp Thr Gly Ile Gln Ala Ser His
25 30 35
Pro Asp Leu Asn Val Val Gly Gly Ala Ser Phe Val Ala Gly Glu Ala
40 45 50 55
Tyr Asn Thr Asp Gly Asn Gly His Gly Thr His Val Ala Gly Thr Val
60 65 70
Ala Ala Leu Asp Asn Thr Thr Gly Val Leu Gly Val Ala Pro Ser Val
75 80 85
Ser Leu Tyr Ala Val Lys Val Leu Asn Ser Ser Gly Ser Gly Thr Tyr
90 95 100
Ser Gly Ile Val Ser Gly Ile Glu Trp Ala Thr Thr Asn Gly Met Asp
105 110 115
Val Ile Asn Met Ser Leu Gly Gly Pro Ser Gly Ser Thr Ala Met Lys
120 125 130 135
Gln Ala Val Asp Asn Ala Tyr Ala Arg Gly Val Val Val Val Ala Ala
140 145 150
Ala Gly Asn Ser Gly Ser Ser Gly Asn Thr Asn Thr Ile Gly Tyr Pro
155 160 165
Ala Lys Tyr Asp Ser Val Ile Ala Val Gly Ala Val Asp Ser Asn Ser
170 175 180
Asn Arg Ala Ser Phe Ser Ser Val Gly Ala Glu Leu Glu Val Met Ala
185 190 195
Pro Gly Ala Gly Val Tyr Ser Thr Tyr Pro Thr Ser Thr Tyr Ala Thr
200 205 210 215
Leu Asn Gly Thr Ser Met Ala Ser Pro His Val Ala Gly Ala Ala Ala
220 225 230
Leu Ile Leu Ser Lys His Pro Asn Leu Ser Ala Ser Gln Val Arg Asn
235 240 245
Arg Leu Ser Ser Thr Ala Thr Tyr Leu Gly Ser Ser Phe Tyr Tyr Gly
250 255 260
Lys Gly Leu Ile Asn Val Glu Ala Ala Ala Gln
265 270
<210>6
<211>381
<212>PRT
<213>枯草芽孢杆菌纳豆变种(Bacillus subtilis var.natto)
<220>
<221>信号
<222>(1)..(23)
<220>
<221>前肽
<222>(24)..(106)
<220>
<221>成熟肽
<222>(107)..(381)
<400>6
Met Arg Ser Lys Lys Leu Trp Ile Ser Leu Leu Phe Ala Leu Thr Leu
-105 -100 -95
Ile Phe Thr Met Ala Phe Ser Asn Met Ser Ala Gln Ala Ala Gly Lys
-90 -85 -80 -75
Ser Ser Thr Glu Lys Lys Tyr Ile Val Gly Phe Lys Gln Thr Met Ser
-70 -65 -60
Ala Met Ser Ser Ala Lys Lys Lys Asp Val Ile Ser Glu Lys Gly Gly
-55 -50 -45
Lys Val Gln Lys Gln Phe Lys Tyr Val Asn Ala Ala Ala Ala Thr Leu
-40 -35 -30
Asp Glu Lys Ala Val Lys Glu Leu Lys Lys Asp Pro Ser Val Ala Tyr
-25 -20 -15
Val Glu Glu Asp His Ile Ala His Glu Tyr Ala Gln Ser Val Pro Tyr
-10 -5 -1 1 5
Gly Ile Ser Gln Ile Lys Ala Pro Ala Leu His Ser Gln Gly Tyr Thr
10 15 20
Gly Ser Asn Val Lys Val Ala Val Ile Asp Ser Gly Ile Asp Ser Ser
25 30 35
His Pro Asp Leu Asn Val Arg Gly Gly Ala Ser Phe Val Pro Ser Glu
40 45 50
Thr Asn Pro Tyr Gln Asp Gly Ser Ser His Gly Thr His Val Ala Gly
55 60 65 70
Thr Ile Ala Ala Leu Asn Asn Ser Ile Gly Val Leu Gly Val Ala Pro
75 80 85
Ser Ala Ser Leu Tyr Ala Val Lys Val Leu Asp Ser Thr Gly Ser Gly
90 95 100
Gln Tyr Ser Trp Ile Ile Asn Gly Ile Glu Trp Ala Ile Ser Asn Asn
105 110 115
Met Asp Val Ile Asn Met Ser Leu Gly Gly Pro Thr Gly Ser Thr Ala
120 125 130
Leu Lys Thr Val Val Asp Lys Ala Val Ser Ser Gly Ile Val Val Ala
135 140 145 150
Ala Ala Ala Gly Asn Glu Gly Ser Ser Gly Ser Thr Ser Thr Val Gly
155 160 165
Tyr Pro Ala Lys Tyr Pro Ser Thr Ile Ala Val Gly Ala Val Asn Ser
170 175 180
Ser Asn Gln Arg Ala Ser Phe Ser Ser Val Gly Ser Glu Leu Asp Val
185 190 195
Met Ala Pro Gly Val Ser Ile Gln Ser Thr Leu Pro Gly Gly Thr Tyr
200 205 210
Gly Ala Tyr Asn Gly Thr Ser Met Ala Thr Pro His Val Ala Gly Ala
215 220 225 230
Ala Ala Leu Ile Leu Ser Lys His Pro Thr Trp Thr Asn Ala Gln Val
235 240 245
Arg Asp Arg Leu Glu Ser Thr Ala Thr Tyr Leu Gly Asn Ser Phe Tyr
250 255 260
Tyr Gly Lys Gly Leu Ile Asn Val Gln Ala Ala Ala Gln
265 270 275
<210>7
<211>275
<212>PRT
<213>短小芽孢杆菌(Bacillus pumilus)(肠膜种(mesentericus))
<220>
<221>成熟肽
<222>(1)..(275)
<400>7
Ala Gln Ser Val Pro Tyr Gly Ile Ser Gln Ile Lys Ala Pro Ala Leu
1 5 10 15
His Ser Gln Gly Tyr Thr Gly Ser Asn Val Lys Val Ala Val Ile Asp
20 25 30
Ser Gly Ile Asp Ser Ser His Pro Asp Leu Asn Val Arg Gly Gly Ala
35 40 45
Ser Phe Val Pro Ser Glu Thr Asn Pro Tyr Gln Asp Gly Ser Ser His
50 55 60
Gly Thr His Val Ala Gly Thr Ile Ala Ala Leu Asn Asn Ser Ile Gly
65 70 75 80
Val Leu Gly Val Ala Pro Ser Ser Ala Leu Tyr Ala Val Lys Val Leu
85 90 95
Asp Ser Thr Gly Ser Gly Gln Tyr Ser Trp Ile Ile Asn Gly Ile Glu
100 105 110
Trp Ala Ile Ser Asn Asn Met Asp Val Ile Asn Met Ser Leu Gly Gly
115 120 125
Pro Thr Gly Ser Thr Ala Leu Lys Thr Val Val Asp Lys Ala Val Ser
130 135 140
Ser Gly Ile Val Val Ala Ala Ala Ala Gly Asn Glu Gly Ser Ser Gly
145 150 155 160
Ser Thr Ser Thr Val Gly Tyr Pro Ala Lys Tyr Pro Ser Thr Ile Ala
165 170 175
Val Gly Ala Val Asn Ser Ala Asn Gln Arg Ala Ser Phe Ser Ser Ala
180 185 190
Gly Ser Glu Leu Asp Val Met Ala Pro Gly Val Ser Ile Gln Ser Thr
195 200 205
Leu Pro Gly Gly Thr Tyr Gly Ala Tyr Asn Gly Thr Ser Met Ala Thr
210 215 220
Pro His Val Ala Gly Ala Ala Ala Leu Ile Leu Ser Lys His Pro Thr
225 230 235 240
Trp Thr Asn Ala Gln Val Arg Asp Arg Leu Glu Ser Thr Ala Thr Tyr
245 250 255
Leu Gly Ser Ser Phe Tyr Tyr Gly Lys Gly Leu Ile Asn Val Gln Ala
260 265 270
Ala Ala Gln
275
<210>8
<211>381
<212>PRT
<213>枯草芽孢杆菌(Bacillus subtilis)
<220>
<221>信号
<222>(1)..(23)
<220>
<221>前肽
<222>(24)..(106)
<220>
<221>成熟肽
<222>(107)..(381)
<400>8
Met Arg Ser Lys Lys Leu Trp Ile Ser Leu Leu Phe Ala Leu Thr Leu
-105 -100 -95
Ile Phe Thr Met Ala Phe Ser Asn Met Ser Val Gln Ala Ala Gly Lys
-90 -85 -80 -75
Ser Ser Thr Glu Lys Lys Tyr Ile Val Gly Phe Lys Gln Thr Met Ser
-70 -65 -60
Ala Met Ser Ser Ala Lys Lys Lys Asp Val Ile Ser Glu Lys Gly Gly
-55 -50 -45
Lys Val Gln Lys Gln Phe Lys Tyr Val Asn Ala Ala Ala Ala Thr Leu
-40 -35 -30
Asp Glu Lys Ala Val Lys Glu Leu Lys Lys Asp Pro Ser Val Ala Tyr
-25 -20 -15
Val Glu Glu Asp His Ile Ala His Glu Tyr Ala Gln Ser Val Pro Tyr
-10 -5 -1 1 5
Gly Ile Ser Gln Ile Lys Ala Pro Ala Leu His Ser Gln Gly Tyr Thr
10 15 20
Gly Ser Asn Val Lys Val Ala Val Ile Asp Ser Gly Ile Asp Ser Ser
25 30 35
His Pro Asp Leu Asn Val Arg Gly Gly Ala Ser Phe Val Pro Ser Glu
40 45 50
Thr Asn Pro Tyr Gln Asp Gly Ser Ser His Gly Thr His Val Ala Gly
55 60 65 70
Thr Ile Ala Ala Leu Asn Asn Ser Ile Gly Val Leu Gly Val Ser Pro
75 80 85
Ser Ala Ser Leu Tyr Ala Val Lys Val Leu Asp Ser Thr Gly Ser Gly
90 95 100
Gln Tyr Ser Trp Ile Ile Asn Gly Ile Glu Trp Ala Ile Ser Asn Asn
105 110 115
Met Asp Val Ile Asn Met Ser Leu Gly Gly Pro Thr Gly Ser Thr Ala
120 125 130
Leu Lys Thr Val Val Asp Lys Ala Val Ser Ser Gly Ile Val Val Ala
135 140 145 150
Ala Ala Ala Gly Asn Glu Gly Ser Ser Gly Ser Thr Ser Thr Val Gly
155 160 165
Tyr Pro Ala Lys Tyr Pro Ser Thr Ile Ala Val Gly Ala Val Asn Ser
170 175 180
Ser Asn Gln Arg Ala Ser Phe Ser Ser Ala Gly Ser Glu Leu Asp Val
185 190 195
Met Ala Pro Gly Val Ser Ile Gln Ser Thr Leu Pro Gly Gly Thr Tyr
200 205 210
Gly Ala Tyr Asn Gly Thr Ser Met Ala Thr Pro His Val Ala Gly Ala
215 220 225 230
Ala Ala Leu Ile Leu Ser Lys His Pro Thr Trp Thr Asn Ala Gln Val
235 240 245
Arg Asp Arg Leu Glu Ser Thr Ala Thr Tyr Leu Gly Asn Ser Phe Tyr
250 255 260
Tyr Gly Lys Gly Leu Ile Asn Val Gln Ala Ala Ala Gln
265 270 275
<210>9
<211>381
<212>PRT
<213>嗜热脂肪芽孢杆菌(Bacillus stearothermophilus)
<220>
<221>信号
<222>(1)..(29)
<220>
<221>前肽
<222>(30)..(106)
<220>
<221>成熟肽
<222>(107)..(381)
<400>9
Met Arg Ser Lys Lys Leu Trp Ile Ser Leu Leu Phe Ala Leu Thr Leu
-105 -100 -95
Ile Phe Thr Met Ala Phe Ser Asn Met Ser Val Gln Ala Ala Gly Lys
-90 -85 -80 -75
Ser Ser Thr Glu Lys Lys Tyr Ile Val Gly Phe Lys Gln Thr Met Ser
-70 -65 -60
Ala Met Ser Ser Ala Lys Lys Lys Asp Val Ile Ser Glu Lys Gly Gly
-55 -50 -45
Lys Val Gln Lys Gln Phe Lys Tyr Val Asn Ala Ala Ala Ala Thr Leu
-40 -35 -30
Asp Glu Lys Ala Val Lys Glu Leu Lys Lys Asp Pro Ser Val Ala Tyr
-25 -20 -15
Val Glu Glu Asp His Ile Ala His Glu Tyr Ala Gln Ser Val Pro Tyr
-10 -5 -1 1 5
Gly Ile Ser Gln Ile Lys Ala Pro Ala Leu His Ser Gln Gly Tyr Thr
10 15 20
Gly Ser Asn Val Lys Val Ala Val Ile Asp Ser Gly Ile Asp Ser Ser
25 30 35
His Pro Asp Leu Asn Val Arg Gly Gly Ala Ser Phe Val Pro Ser Glu
40 45 50
Thr Asn Pro Tyr Gln Asp Gly Ser Ser His Gly Thr His Val Ala Gly
55 60 65 70
Thr Ile Ala Ala Leu Asn Asn Ser Ile Gly Val Leu Gly Val Ser Pro
75 80 85
Ser Ala Ser Leu Tyr Ala Val Lys Val Leu Asp Ser Thr Gly Ser Gly
90 95 100
Gln Tyr Ser Trp Ile Ile Asn Gly Ile Glu Trp Ala Ile Ser Asn Asn
105 110 115
Met Asp Val Ile Asn Met Ser Leu Gly Gly Pro Ser Gly Ser Thr Ala
120 125 130
Leu Lys Thr Val Val Asp Lys Ala Val Ser Ser Gly Ile Val Val Ala
135 140 145 150
Ala Ala Ala Gly Asn Glu Gly Ser Ser Gly Ser Ser Ser Thr Val Gly
155 160 165
Tyr Pro Ala Lys Tyr Pro Ser Thr Ile Ala Val Gly Ala Val Asn Ser
170 175 180
Ser Asn Gln Arg Ala Ser Phe Ser Ser Ala Gly Ser Glu Leu Asp Val
185 190 195
Met Ala Pro Gly Val Ser Ile Gln Ser Thr Leu Pro Gly Gly Thr Tyr
200 205 210
Gly Ala Tyr Asn Gly Thr Ser Met Ala Thr Pro His Val Ala Gly Ala
215 220 225 230
Ala Ala Leu Ile Leu Ser Lys His Pro Thr Trp Thr Asn Ala Gln Val
235 240 245
Arg Asp Arg Leu Glu Ser Thr Ala Thr Tyr Leu Gly Asn Ser Phe Tyr
250 255 260
Tyr Gly Lys Gly Leu Ile Asn Val Gln Ala Ala Ala Gln
265 270 275
<210>10
<211>382
<212>PRT
<213>解淀粉芽孢杆菌(Bacillus amyloliquefaciens)
<220>
<221>信号
<222>(1)..(32)
<220>
<221>前肽
<222>(33)..(107)
<220>
<221>成熟肽
<222>(108)..(382)
<400>10
Met Arg Gly Lys Lys Val Trp Ile Ser Leu Leu Phe Ala Leu Ala Leu
-105 -100 -95
Ile Phe Thr Met Ala Phe Gly Ser Thr Ser Ser Ala Gln Ala Ala Gly
-90 -85 -80
Lys Ser Asn Gly Glu Lys Lys Tyr Ile Val Gly Phe Lys Gln Thr Met
-75 -70 -65 -60
Ser Thr Met Ser Ala Ala Lys Lys Lys Asp Val Ile Ser Glu Lys Gly
-55 -50 -45
Gly Lys Val Gln Lys Gln Phe Lys Tyr Val Asp Ala Ala Ser Ala Thr
-40 -35 -30
Leu Asn Glu Lys Ala Val Lys Glu Leu Lys Lys Asp Pro Ser Val Ala
-25 -20 -15
Tyr Val Glu Glu Asp His Val Ala His Ala Tyr Ala Gln Ser Val Pro
-10 -5 -1 1 5
Tyr Gly Val Ser Gln Ile Lys Ala Pro Ala Leu His Ser Gln Gly Tyr
10 15 20
Thr Gly Ser Asn Val Lys Val Ala Val Ile Asp Ser Gly Ile Asp Ser
25 30 35
Ser His Pro Asp Leu Lys Val Ala Gly Gly Ala Ser Met Val Pro Ser
40 45 50
Glu Thr Asn Pro Phe Gln Asp Asn Asn Ser His Gly Thr His Val Ala
55 60 65
Gly Thr Val Ala Ala Leu Asn Asn Ser Ile Gly Val Leu Gly Val Ala
70 75 80 85
Pro Ser Ala Ser Leu Tyr Ala Val Lys Val Leu Gly Ala Asp Gly Ser
90 95 100
Gly Gln Tyr Ser Trp Ile Ile Asn Gly Ile Glu Trp Ala Ile Ala Asn
105 110 115
Asn Met Asp Val Ile Asn Met Ser Leu Gly Gly Pro Ser Gly Ser Ala
120 125 130
Ala Leu Lys Ala Ala Val Asp Lys Ala Val Ala Ser Gly Val Val Val
135 140 145
Val Ala Ala Ala Gly Asn Glu Gly Thr Ser Gly Ser Ser Ser Thr Val
150 155 160 165
Gly Tyr Pro Gly Lys Tyr Pro Ser Val Ile Ala Val Gly Ala Val Asp
170 175 180
Ser Ser Asn Gln Arg Ala Ser Phe Ser Ser Val Gly Pro Glu Leu Asp
185 190 195
Val Met Ala Pro Gly Val Ser Ile Gln Ser Thr Leu Pro Gly Asn Lys
200 205 210
Tyr Gly Ala Tyr Asn Gly Thr Ser Met Ala Ser Pro His Val Ala Gly
215 220 225
Ala Ala Ala Leu Ile Leu Ser Lys His Pro Asn Trp Thr Asn Thr Gln
230 235 240 245
Val Arg Ser Ser Leu Glu Asn Thr Thr Thr Lys Leu Gly Asp Ser Phe
250 255 260
Tyr Tyr Gly Lys Gly Leu Ile Asn Val Gln Ala Ala Ala Gln
265 270 275
<210>11
<211>269
<212>PRT
<213>迟缓芽孢杆菌(Bacillus lentus)
<220>
<221>成熟肽
<222>(1)..(269)
<400>11
Ala Gln Ser Val Pro Trp Gly Ile Ser Arg Val Gln Ala Pro Ala Ala
l 5 10 15
His Asn Arg Gly Leu Thr Gly Ser Gly Val Lys Val Ala Val Leu Asp
20 25 30
Thr Gly Ile Ser Thr His Pro Asp Leu Asn Ile Arg Gly Gly Ala Ser
35 40 45
Phe Val Pro Gly Glu Pro Ser Thr Gln Asp Gly Asn Gly His Gly Thr
50 55 60
His Val Ala Gly Thr Ile Ala Ala Leu Asn Asn Ser Ile Gly Val Leu
65 70 75 80
Gly Val Ala Pro Ser Ala Glu Leu Tyr Ala Val Lys Val Leu Gly Ala
85 90 95
Ser Gly Ser Gly Ser Val Ser Ser Ile Ala Gln Gly Leu Glu Trp Ala
100 105 110
Gly Asn Asn Gly Met His Val Ala Asn Leu Ser Leu Gly Ser Pro Ser
115 120 125
Pro Ser Ala Thr Leu Glu Gln Ala Val Asn Ser Ala Thr Ser Arg Gly
130 135 140
Val Leu Val Val Ala Ala Ser Gly Asn Ser Gly Ala Gly Ser Ile Ser
145 150 155 160
Tyr Pro Ala Arg Tyr Ala Asn Ala Met Ala Val Gly Ala Thr Asp Gln
165 170 175
Asn Asn Asn Arg Ala Ser Phe Ser Gln Tyr Gly Ala Gly Leu Asp Ile
180 185 190
Val Ala Pro Gly Val Asn Val Gln Ser Thr Tyr Pro Gly Ser Thr Tyr
195 200 205
Ala Ser Leu Asn Gly Thr Ser Met Ala Thr Pro His Val Ala Gly Ala
210 215 220
Ala Ala Leu Val Lys Gln Lys Asn Pro Ser Trp Ser Asn Val Gln Ile
225 230 235 240
Arg Asn His Leu Lys Asn Thr Ala Thr Ser Leu Gly Ser Thr Asn Leu
245 250 255
Tyr Gly Ser Gly Leu Val Asn Ala Glu Ala Ala Thr Arg
260 265
<210>12
<211>380
<212>PRT
<213>克劳氏芽孢杆菌(Bacillus clausii)
<220>
<221>信号
<222>(1)..(27)
<220>
<221>前肽
<222>(28)..(111)
<220>
<221>成熟肽
<222>(112)..(380)
<400>12
Met Lys Lys Pro Leu Gly Lys Ile Val Ala Ser Thr Ala Leu Leu
-110 -105 -100
Ile Ser Val Ala Phe Ser Ser Ser Ile Ala Ser Ala Ala Glu Glu Ala
-95 -90 -85
Lys Glu Lys Tyr Leu Ile Gly Phe Asn Glu Gln Glu Ala Val Ser Glu
-80 -75 -70 -65
Phe Val Glu Gln Val Glu Ala Asn Asp Glu Val Ala Ile Leu Ser Glu
-60 -55 -50
Glu Glu Glu Val Glu Ile Glu Leu Leu His Glu Phe Glu Thr Ile Pro
-45 -40 -35
Val Leu Ser Val Glu Leu Ser Pro Glu Asp Val Asp Ala Leu Glu Leu
-30 -25 -20
Asp Pro Ala Ile Ser Tyr Ile Glu Glu Asp Ala Glu Val Thr Thr Met
-15 -10 -5 -1
Ala Gln Ser Val Pro Trp Gly Ile Ser Arg Val Gln Ala Pro Ala Ala
1 5 10 15
His Asn Arg Gly Leu Thr Gly Ser Gly Val Lys Val Ala Val Leu Asp
20 25 30
Thr Gly Ile Ser Thr His Pro Asp Leu Asn Ile Arg Gly Gly Ala Ser
35 40 45
Phe Val Pro Gly Glu Pro Ser Thr Gln Asp Gly Asn Gly His Gly Thr
50 55 60
His Val Ala Gly Thr Ile Ala Ala Leu Asn Asn Ser Ile Gly Val Leu
65 70 75 80
Gly Val Ala Pro Ser Ala Glu Leu Tyr Ala Val Lys Val Leu Gly Ala
85 90 95
Ser Gly Ser Gly Ser Val Ser Ser Ile Ala Gln Gly Leu Glu Trp Ala
100 105 110
Gly Asn Asn Gly Met His Val Ala Asn Leu Ser Leu Gly Ser Pro Ser
115 120 125
Pro Ser Ala Thr Leu Glu Gln Ala Val Asn Ser Ala Thr Ser Arg Gly
130 135 140
Val Leu Val Val Ala Ala Ser Gly Asn Ser Gly Ala Gly Ser Ile Ser
145 150 155 160
Tyr Pro Ala Arg Tyr Ala Asn Ala Met Ala Val Gly Ala Thr Asp Gln
165 170 175
Asn Asn Asn Arg Ala Ser Phe Ser Gln Tyr Gly Ala Gly Leu Asp Ile
180 185 190
Val Ala Pro Gly Val Asn Val Gln Ser Thr Tyr Pro Gly Ser Thr Tyr
195 200 205
Ala Ser Leu Asn Gly Thr Ser Met Ala Thr Pro His Val Ala Gly Ala
210 215 220
Ala Ala Leu Val Lys Gln Lys Asn Pro Ser Trp Ser Asn Val Gln Ile
225 230 235 240
Arg Asn His Leu Lys Asn Thr Ala Thr Ser Leu Gly Ser Thr Asn Leu
245 250 255
Tyr Gly Ser Gly Leu Val Asn Ala Glu Ala Ala Thr Arg
260 265
<210>13
<211>378
<212>PRT
<213>芽孢杆菌属菌种(Bacillus sp.)
<220>
<221>信号
<222>(1)..(27)
<220>
<221>前肽
<222>(28)..(110)
<220>
<221>成熟肽
<222>(111)..(378)
<400>13
Met Asn Lys Lys Met Gly Lys Ile Val Ala Gly Thr Ala Leu Ile
-110 -105 -100
Ile Ser Val Ala Phe Ser Ser Ser Ile Ala Gln Ala Ala Glu Glu Ala
-95 -90 -85 -80
Lys Glu Lys Tyr Leu Ile Gly Phe Lys Glu Gln Glu Val Met Ser Gln
-75 -70 -65
Phe Val Asp Gln Ile Asp Gly Asp Glu Tyr Ser Ile Ser Ser Gln Ala
-60 -55 -50
Glu Asp Val Glu Ile Asp Leu Leu His Glu Phe Asp Phe Ile Pro Val
-45 -40 -35
Leu Ser Val Glu Leu Asp Pro Glu Asp Val Asp Ala Leu Glu Leu Asp
-30 -25 -20
Pro Ala Ile Ala Tyr Ile Glu Glu Asp Ala Glu Val Thr Thr Met Gln
-15 -10 -5 -1 1
Thr Val Pro Trp Gly Ile Asn Arg Val Gln Ala Pro Ile Ala Gln Ser
5 10 15
Arg Gly Phe Thr Gly Thr Gly Val Arg Val Ala Val Leu Asp Thr Gly
20 25 30
Ile Ser Asn His Ala Asp Leu Arg Ile Arg Gly Gly Ala Ser Phe Val
35 40 45
Pro Gly Glu Pro Asn Ile Ser Asp Gly Asn Gly His Gly Thr Gln Val
50 55 60 65
Ala Gly Thr Ile Ala Ala Leu Asn Asn Ser Ile Gly Val Leu Gly Val
70 75 80
Ala Pro Asn Val Asp Leu Tyr Gly Val Lys Val Leu Gly Ala Ser Gly
85 90 95
Ser Gly Ser Ile Ser Gly Ile Ala Gln Gly Leu Gln Trp Ala Ala Asn
100 105 110
Asn Gly Met His Ile Ala Asn Met Ser Leu Gly Ser Ser Ala Gly Ser
115 120 125
Ala Thr Met Glu Gln Ala Val Asn Gln Ala Thr Ala Ser Gly Val Leu
130 135 140 145
Val Val Ala Ala Ser Gly Asn Ser Gly Ala Gly Asn Val Gly Phe Pro
150 155 160
Ala Arg Tyr Ala Asn Ala Met Ala Val Gly Ala Thr Asp Gln Asn Asn
165 170 175
Asn Arg Ala Thr Phe Ser Gln Tyr Gly Ala Gly Leu Asp Ile Val Ala
180 185 190
Pro Gly Val Gly Val Gln Ser Thr Val Pro Gly Asn Gly Tyr Ala Ser
195 200 205
Phe Asn Gly Thr Ser Met Ala Thr Pro His Val Ala Gly Val Ala Ala
210 215 220 225
Leu Val Lys Gln Lys Asn Pro Ser Trp Ser Asn Val Gln Ile Arg Asn
230 235 240
His Leu Lys Asn Thr Ala Thr Asn Leu Gly Asn Thr Thr Gln Phe Gly
245 250 255
Ser Gly Leu Val Asn Ala Glu Ala Ala Thr Arg
260 265
<210>14
<211>269
<212>PRT
<213>细毛嗜热霉(Thermomyces lanuginosus)
<220>
<221>成熟肽
<222>(1)..()
<400>14
Glu Val Ser Gln Asp Leu Phe Asn Gln Phe Asn Leu Phe Ala Gln Tyr
1 5 10 15
Ser Ala Ala Ala Tyr Cys Gly Lys Asn Asn Asp Ala Pro Ala Gly Thr
20 25 30
Asn Ile Thr Cys Thr Gly Asn Ala Cys Pro Glu Val Glu Lys Ala Asp
35 40 45
Ala Thr Phe Leu Tyr Ser Phe Glu Asp Ser Gly Val Gly Asp Val Thr
50 55 60
Gly Phe Leu Ala Leu Asp Asn Thr Asn Lys Leu Ile Val Leu Ser Phe
65 70 75 80
Arg Gly Ser Arg Ser Ile Glu Asn Trp Ile Gly Asn Leu Asn Phe Asp
85 90 95
Leu Lys Glu Ile Asn Asp Ile Cys Ser Gly Cys Arg Gly His Asp Gly
100 105 110
Phe Thr Ser Ser Trp Arg Ser Val Ala Asp Thr Leu Arg Gln Lys Val
115 120 125
Glu Asp Ala Val Arg Glu His Pro Asp Tyr Arg Val Val Phe Thr Gly
130 135 140
His Ser Leu Gly Gly Ala Leu Ala Thr Val Ala Gly Ala Asp Leu Arg
145 150 155 160
Gly Asn Gly Tyr Asp Ile Asp Val Phe Ser Tyr Gly Ala Pro Arg Val
165 170 175
Gly Asn Arg Ala Phe Ala Glu Phe Leu Thr Val Gln Thr Gly Gly Thr
180 185 190
Leu Tyr Arg Ile Thr His Thr Asn Asp Ile Val Pro Arg Leu Pro Pro
195 200 205
Arg Glu Phe Gly Tyr Ser His Ser Ser Pro Glu Tyr Trp Ile Lys Ser
210 215 220
Gly Thr Leu Val Pro Val Thr Arg Asn Asp Ile Val Lys Ile Glu Gly
225 230 235 240
Ile Asp Ala Thr Gly Gly Asn Asn Gln Pro Asn Ile Pro Asp Ile Pro
245 250 255
Ala Hi s Leu Trp Tyr Phe Gly Leu Ile Gly Thr Cys Leu
260 265
<210>15
<211>274
<212>PRT
<213>疏棉状腐质霉(Humicola lanuginose)
<220>
<221>变体
<222>(1)..(269)
<220>
<221>成熟肽
<222>(6)..(269)
<400>15
Ser Pro Ile Arg Arg Glu Val Ser Gln Asp Leu Phe Asn Gln Phe Asn
-5 -1 1 5 10
Leu Phe Ala Gln Tyr Ser Ala Ala Ala Tyr Cys Gly Lys Asn Asn Asp
15 20 25
Ala Pro Ala Gly Thr Asn Ile Thr Cys Thr Gly Asn Ala Cys Pro Glu
30 35 40
Val Glu Lys Ala Asp Ala Thr Phe Leu Tyr Ser Phe Glu Asp Ser Gly
45 50 55
Val Gly Asp Val Thr Gly Phe Leu Ala Leu Asp Asn Thr Asn Lys Leu
60 65 70 75
Ile Val Leu Ser Phe Arg Gly Ser Arg Ser Ile Glu Asn Trp Ile Gly
80 85 90
Asn Leu Asn Phe Asp Leu Lys Glu Ile Asn Asp Ile Cys Ser Gly Cys
95 100 105
Arg Gly His Asp Gly Phe Thr Ser Ser Trp Arg Ser Val Ala Asp Thr
110 115 120
Leu Arg Gln Lys Val Glu Asp Ala Val Arg Glu His Pro Asp Tyr Arg
125 130 135
Val Val Phe Thr Gly His Ser Leu Gly Gly Ala Leu Ala Thr Val Ala
140 145 150 155
Gly Ala Asp Leu Arg Gly Asn Gly Tyr Asp Ile Asp Val Phe Ser Tyr
160 165 170
Gly Ala Pro Arg Val Gly Asn Arg Ala Phe Ala Glu Phe Leu Thr Val
175 180 185
Gln Thr Gly Gly Thr Leu Tyr Arg Ile Thr His Thr Asn Asp Ile Val
190 195 200
Pro Arg Leu Pro Pro Arg Glu Phe Gly Tyr Ser His Ser Ser Pro Glu
205 210 215
Tyr Trp Ile Lys Ser Gly Thr Leu Val Pro Val Arg Arg Arg Asp Ile
220 225 230 235
Val Lys Ile Glu Gly Ile Asp Ala Thr Gly Gly Asn Asn Gln Pro Asn
240 245 250
Ile Pro Asp Ile Pro Ala His Leu Trp Tyr Phe Gly Leu Ile Gly Thr
255 260 265
Cys Leu
<210>16
<211>513
<212>PRT
<213>嗜热脂肪芽孢杆菌(Bacillus stearothermophilus)
<220>
<221>变体
<222>(1)..(513)
<400>16
Ala Ala Pro Phe Asn Gly Thr Met Met Gln Tyr Phe Glu Trp Tyr Leu
1 5 10 15
Pro Asp Asp Gly Thr Leu Trp Thr Lys Val Ala Asn Glu Ala Asn Asn
20 25 30
Leu Ser Ser Leu Gly Ile Thr Ala Leu Trp Leu Pro Pro Ala Tyr Lys
35 40 45
Gly Thr Ser Arg Ser Asp Val Gly Tyr Gly Val Tyr Asp Leu Tyr Asp
50 55 60
Leu Gly Glu Phe Asn Gln Lys Gly Thr Val Arg Thr Lys Tyr Gly Thr
65 70 75 80
Lys Ala Gln Tyr Leu Gln Ala Ile Gln Ala Ala His Ala Ala Gly Met
85 90 95
Gln Val Tyr Ala Asp Val Val Phe Asp His Lys Gly Gly Ala Asp Gly
100 105 110
Thr Glu Trp Val Asp Ala Val Glu Val Asn Pro Ser Asp Arg Asn Gln
115 120 125
Glu Ile Ser Gly Thr Tyr Gln Ile Gln Ala Trp Thr Lys Phe Asp Phe
130 135 140
Pro Gly Arg Gly Asn Thr Tyr Ser Ser Phe Lys Trp Arg Trp Tyr His
145 150 155 160
Phe Asp Gly Val Asp Trp Asp Glu Ser Arg Lys Leu Ser Arg Ile Tyr
165 170 175
Lys Phe Arg Gly Lys Ala Trp Asp Trp Glu Val Asp Thr Glu Phe Gly
180 185 190
Asn Tyr Asp Tyr Leu Met Tyr Ala Asp Leu Asp Met Asp His Pro Glu
195 200 205
Val Val Thr Glu Leu Lys Asn Trp Gly Lys Trp Tyr Val Asn Thr Thr
210 215 220
Asn Ile Asp Gly Phe Arg Leu Asp Ala Val Lys His Ile Lys Phe Ser
225 230 235 240
Phe Phe Pro Asp Trp Leu Ser Tyr Val Arg Ser Gln Thr Gly Lys Pro
245 250 255
Leu Phe Thr Val Gly Glu Tyr Trp Ser Tyr Asp Ile Asn Lys Leu His
260 265 270
Asn Tyr Ile Thr Lys Thr Asp Gly Thr Met Ser Leu Phe Asp Ala Pro
275 280 285
Leu His Asn Lys Phe Tyr Thr Ala Ser Lys Ser Gly Gly Ala Phe Asp
290 295 300
Met Arg Thr Leu Met Thr Asn Thr Leu Met Lys Asp Gln Pro Thr Leu
305 310 315 320
Ala Val Thr Phe Val Asp Asn His Asp Thr Glu Pro Gly Gln Ala Leu
325 330 335
Gln Ser Trp Val Asp Pro Trp Phe Lys Pro Leu Ala Tyr Ala Phe Ile
340 345 350
Leu Thr Arg Gln Glu Gly Tyr Pro Cys Val Phe Tyr Gly Asp Tyr Tyr
355 360 365
Gly Ile Pro Gln Tyr Asn Ile Pro Ser Leu Lys Ser Lys Ile Asp Pro
370 375 380
Leu Leu Ile Ala Arg Arg Asp Tyr Ala Tyr Gly Thr Gln His Asp Tyr
385 390 395 400
Leu Asp His Ser Asp Ile Ile Gly Trp Thr Arg Glu Gly Gly Thr Glu
405 410 415
Lys Pro Gly Ser Gly Leu Ala Ala Leu Ile Thr Asp Gly Pro Gly Gly
420 425 430
Ser Lys Trp Met Tyr Val Gly Lys Gln His Ala Gly Lys Val Phe Tyr
435 440 445
Asp Leu Thr Gly Asn Arg Ser Asp Thr Val Thr Ile Asn Ser Asp Gly
450 455 460
Trp Gly Glu Phe Lys Val Asn Gly Gly Ser Val Ser Val Trp Val Pro
465 470 475 480
Arg Lys Thr Thr Val Ser Thr Ile Ala Arg Pro Ile Thr Thr Arg Pro
485 490 495
Trp Thr Gly Glu Phe Val Arg Trp Thr Glu Pro Arg Leu Val Ala Trp
500 505 510
Pro
<210>17
<211>481
<212>PRT
<213>地衣芽孢杆菌(Bacillus licheniformis)
<220>
<221>变体
<222>(1)..(481)
<400>17
Val Asn Gly Thr Leu Met Gln Tyr Phe Glu Trp Tyr Thr Pro Asn Asp
1 5 10 15
Gly Gln His Trp Lys Arg Leu Gln Asn Asp Ala Glu His Leu Ser Asp
20 25 30
Ile Gly Ile Thr Ala Val Trp Ile Pro Pro Ala Tyr Lys Gly Thr Ser
35 40 45
Gln Ala Asp Val Gly Tyr Gly Ala Tyr Asp Leu Tyr Asp Leu Gly Glu
50 55 60
Phe His Gln Lys Gly Thr Val Arg Thr Lys Tyr Gly Thr Lys Gly Glu
65 70 75 80
Leu Gln Ser Ala Ile Lys Ser Leu His Ser Arg Asp Ile Asn Val Tyr
85 90 95
Gly Asp Val Val Ile Asn His Lys Gly Gly Ala Asp Ala Thr Glu Asp
100 105 110
Val Thr Ala Val Glu Val Asp Pro Ala Asp Arg Asn Arg Val Ile Ser
115 120 125
Gly Glu His Leu Ile Lys Ala Trp Thr His Phe His Phe Pro Gly Arg
130 135 140
Gly Ser Thr Tyr Ser Asp Phe Lys Trp Tyr Trp Tyr His Phe Asp Gly
145 150 155 160
Thr Asp Trp Asp Glu Ser Arg Lys Leu Asn Arg Ile Tyr Lys Phe Gln
165 170 175
Gly Lys Thr Trp Asp Trp Glu Val Ser Asn Glu Phe Gly Asn Tyr Asp
180 185 190
Tyr Leu Met Tyr Ala Asp Ile Asp Tyr Asp His Pro Asp Val Val Ala
195 200 205
Glu Ile Lys Arg Trp Gly Thr Trp Tyr Ala Asn Glu Leu Gln Leu Asp
210 215 220
Gly Phe Arg Leu Asp Ala Val Lys His Ile Lys Phe Ser Phe Leu Arg
225 230 235 240
Asp Trp Val Asn His Val Arg Glu Lys Thr Gly Lys Glu Met Phe Thr
245 250 255
Val Ala Glu Tyr Trp Ser Asn Asp Leu Gly Ala Leu Glu Asn Tyr Leu
260 265 270
Asn Lys Thr Asn Phe Asn His Ser Val Phe Asp Val Pro Leu His Tyr
275 280 285
Gln Phe His Ala Ala Ser Thr Gln Gly Gly Gly Tyr Asp Met Arg Lys
290 295 300
Leu Leu Asn Gly Thr Val Val Ser Lys His Pro Leu Lys Ser Val Thr
305 310 315 320
Phe Val Asp Asn His Asp Thr Gln Pro Gly Gln Ser Leu Glu Ser Thr
325 330 335
Val Gln Thr Trp Phe Lys Pro Leu Ala Tyr Ala Phe Ile Leu Thr Arg
340 345 350
Glu Ser Gly Tyr Pro Gln Val Phe Tyr Gly Asp Met Tyr Gly Thr Lys
355 360 365
Gly Asp Ser Gln Arg Glu Ile Pro Ala Leu Lys His Lys Ile Glu Pro
370 375 380
Ile Leu Lys Ala Arg Lys Gln Tyr Ala Tyr Gly Ala Gln His Asp Tyr
385 390 395 400
Phe Asp His His Asp Ile Val Gly Trp Thr Arg Glu Gly Asp Ser Ser
405 410 415
Val Ala Asn Ser Gly Leu Ala Ala Leu Ile Thr Asp Gly Pro Gly Gly
420 425 430
Ala Lys Arg Met Tyr Val Gly Arg Gln Asn Ala Gly Glu Thr Trp His
435 440 445
Asp Ile Thr Gly Asn Arg Ser Glu Pro Val Val Ile Asn Ser Glu Gly
450 455 460
Trp Gly Glu Phe His Val Asn Gly Gly Ser Val Ser Ile Tyr Val Gln
465 470 475 480
Arg
<210>18
<211>483
<212>PRT
<213>芽孢杆菌属菌种(Bacillus sp.)
<220>
<221>变体
<222>(1)..(483)
<400>18
His His Asn Gly Thr Asn Gly Thr Met Met Gln Tyr Phe Glu Trp Tyr
1 5 10 15
Leu Pro Asn Asp Gly Asn His Trp Asn Arg Leu Arg Ser Asp Ala Ser
20 25 30
Asn Leu Lys Asp Lys Gly Ile Ser Ala Val Trp Ile Pro Pro Ala Trp
35 40 45
Lys Gly Ala Ser Gln Asn Asp Val Gly Tyr Gly Ala Tyr Asp Leu Tyr
50 55 60
Asp Leu Gly Glu Phe Asn Gln Lys Gly Thr Ile Arg Thr Lys Tyr Gly
65 70 75 80
Thr Arg Asn Gln Leu Gln Ala Ala Val Asn Ala Leu Lys Ser Asn Gly
85 90 95
Ile Gln Val Tyr Gly Asp Val Val Met Asn His Lys Gly Gly Ala Asp
100 105 110
Ala Thr Glu Met Val Lys Ala Val Glu Val Asn Pro Asn Asn Arg Asn
115 120 125
Gln Glu Val Ser Gly Glu Tyr Thr Ile Glu Ala Trp Thr Lys Phe Asp
130 135 140
Phe Pro Gly Arg Gly Asn Thr His Ser Asn Phe Lys Trp Arg Trp Tyr
145 150 155 160
His Phe Asp Gly Val Asp Trp Asp Gln Ser Arg Lys Leu Asn Asn Arg
165 170 175
Ile Tyr Lys Phe Arg Gly Lys Gly Trp Asp Trp Glu Val Asp Thr Glu
180 185 190
Phe Gly Asn Tyr Asp Tyr Leu Met Tyr Ala Asp Ile Asp Met Asp His
195 200 205
Pro Glu Val Val Asn Glu Leu Arg Asn Trp Gly Val Trp Tyr Thr Asn
210 215 220
Thr Leu Gly Leu Asp Gly Phe Arg Ile Asp Ala Val Lys His Ile Lys
225 230 235 240
Tyr Ser Phe Thr Arg Asp Trp Ile Asn His Val Arg Ser Ala Thr Gly
245 250 255
Lys Asn Met Phe Ala Val Ala Glu Phe Trp Lys Asn Asp Leu Gly Ala
260 265 270
Ile Glu Asn Tyr Leu Asn Lys Thr Asn Trp Asn His Ser Val Phe Asp
275 280 285
Val Pro Leu His Tyr Asn Leu Tyr Asn Ala Ser Lys Ser Gly Gly Asn
290 295 300
Tyr Asp Met Arg Gln Ile Phe Asn Gly Thr Val Val Gln Lys His Pro
305 310 315 320
Met His Ala Val Thr Phe Val Asp Asn His Asp Ser Gln Pro Glu Glu
325 330 335
Ala Leu Glu Ser Phe Val Glu Glu Trp Phe Lys Pro Leu Ala Tyr Ala
340 345 350
Leu Thr Leu Thr Arg Glu Gln Gly Tyr Pro Ser Val Phe Tyr Gly Asp
355 360 365
Tyr Tyr Gly Ile Pro Thr His Gly Val Pro Ala Met Lys Ser Lys Ile
370 375 380
Asp Pro Ile Leu Glu Ala Arg Gln Lys Tyr Ala Tyr Gly Arg Gln Asn
385 390 395 400
Asp Tyr Leu Asp His His Asn Ile Ile Gly Trp Thr Arg Glu Gly Asn
405 410 415
Thr Ala His Pro Asn Ser Gly Leu Ala Thr Ile Met Ser Asp Gly Ala
420 425 430
Gly Gly Asn Lys Trp Met Phe Val Gly Arg Asn Lys Ala Gly Gln Val
435 440 445
Trp Thr Asp Ile Thr Gly Asn Lys Ala Gly Thr Val Thr Ile Asn Ala
450 455 460
Asp Gly Trp Gly Asn Phe Ser Val Asn Gly Gly Ser Val Ser Ile Trp
465 470 475 480
Val Asn Lys
Claims (19)
1.与SEQ ID NO:2的氨基酸1-274具有至少50%同一性的蛋白酶,所述蛋白酶用作药物。
2.根据权利要求1的蛋白酶,其中
a)所述蛋白酶包含选自下组的氨基酸序列:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ IDNO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268;和/或
b)所述蛋白酶是选自下组的氨基酸序列的变体:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ IDNO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ NO:13的氨基酸1-268,其中所述变体与相应的氨基酸序列的差异不多于25个氨基酸,并且其中:
(i)和相应的氨基酸序列比较,所述变体包含一个或多个氨基酸的取代、缺失和/或插入中至少一种;和/或
(ii)和相应的氨基酸序列比较,所述变体包含至少一个小缺失;和/或
(iii)和相应的氨基酸序列比较,所述变体包含至少一个小的N-或C-末端延伸;和/或
c)所述蛋白酶是具有选自下组的氨基酸的蛋白酶的等位变体:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ IDNO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268;和/或
d)所述蛋白酶是具有选自下组的氨基酸的蛋白酶的片段:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQ ID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268。
3.根据权利要求2的蛋白酶,其中所述蛋白酶具有选自下组的氨基酸序列:SEQ ID NO:2的氨基酸1-274、SEQ ID NO:5的氨基酸1-274、SEQ ID NO:6的氨基酸1-275、SEQ ID NO:7的氨基酸1-275、SEQ ID NO:8的氨基酸1-275、SEQ ID NO:9的氨基酸1-275、SEQ ID NO:10的氨基酸1-275、SEQID NO:11的氨基酸1-269、SEQ ID NO:12的氨基酸1-269和SEQ ID NO:13的氨基酸1-268。
4.权利要求1-3任一项的蛋白酶,与脂肪酶或淀粉酶组合,用作药物。
5.权利要求1-3任一项的蛋白酶,与脂肪酶和淀粉酶组合,用作药物。
6.根据权利要求4或5的与脂肪酶和/或淀粉酶组合的蛋白酶,其中
(i)所述脂肪酶与具有SEQ ID NO:15的氨基酸1-269的脂肪酶有至少70%的同一性;并且
(ii)所述淀粉酶与选自下组的淀粉酶有至少70%的同一性:
a)具有SEQ ID NO:16的氨基酸1-481的淀粉酶,
b)具有SEQ ID NO:17的氨基酸1-481的淀粉酶,和
c)具有SEQ ID NO:18的氨基酸1-483的淀粉酶。
7.根据权利要求4或5的与脂肪酶和/或淀粉酶组合的蛋白酶,其中
(i)所述蛋白酶具有SEQ ID NO:2的氨基酸1-274;
(ii)所述脂肪酶包含SEQ ID NO:15的氨基酸2-269;并且
(iii)所述淀粉酶是选自下组的淀粉酶:
a)包含SEQ ID NO:16的氨基酸1-481的淀粉酶,
b)具有SEQ ID NO:17的氨基酸1-481的淀粉酶,和
c)具有SEQ ID NO:18的氨基酸1-483的淀粉酶。
8.权利要求1-3任一项所定义的蛋白酶用于制备药物的用途,所述药物用于治疗消化性病症、胰腺外分泌机能不全、胰腺炎、囊性纤维化、I型糖尿病和/或II型糖尿病。
9.权利要求8的用途,还包含脂肪酶或淀粉酶的用途。
10.权利要求8的用途,还包含脂肪酶和淀粉酶的用途。
11.权利要求9或10的用途,其中所述脂肪酶和/或淀粉酶如权利要求6或7所定义。
12.药物组合物,其包含权利要求1-3任一项定义的蛋白酶,连同至少一种可药用的辅助材料。
13.权利要求12的组合物,其还包含脂肪酶或淀粉酶。
14.权利要求12的组合物,其还包含脂肪酶和淀粉酶。
15.权利要求13或14的组合物,其中所述脂肪酶和/或淀粉酶如权利要求6或7所定义。
16.用于治疗消化性病症、胰腺外分泌机能不全、胰腺炎、囊性纤维化、I型糖尿病和/或II型糖尿病的方法,所述方法通过施用治疗上有效量的权利要求1-3任一项所定义的蛋白酶进行。
17.权利要求16的方法,其还包括施用治疗上有效量的脂肪酶或淀粉酶。
18.权利要求16的方法,其还包括施用治疗上有效量的脂肪酶和淀粉酶。
19.权利要求17或18的方法,其中所述脂肪酶和/或淀粉酶如权利要求6或7所定义。
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103013960A (zh) * | 2012-12-21 | 2013-04-03 | 青岛蔚蓝生物集团有限公司 | 一种碱性蛋白酶及其重组表达工程菌 |
CN109182287A (zh) * | 2018-08-16 | 2019-01-11 | 湖北省宏源药业科技股份有限公司 | 一种具有催化活性转氨酶的提取方法 |
CN110846299A (zh) * | 2019-11-22 | 2020-02-28 | 江南大学 | 一种前导肽突变体及其在角蛋白酶生产中的应用 |
-
2006
- 2006-06-16 CN CNA200680022643XA patent/CN101203238A/zh active Pending
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103013960A (zh) * | 2012-12-21 | 2013-04-03 | 青岛蔚蓝生物集团有限公司 | 一种碱性蛋白酶及其重组表达工程菌 |
CN109182287A (zh) * | 2018-08-16 | 2019-01-11 | 湖北省宏源药业科技股份有限公司 | 一种具有催化活性转氨酶的提取方法 |
CN110846299A (zh) * | 2019-11-22 | 2020-02-28 | 江南大学 | 一种前导肽突变体及其在角蛋白酶生产中的应用 |
CN110846299B (zh) * | 2019-11-22 | 2021-09-24 | 江南大学 | 一种前导肽突变体及其在角蛋白酶生产中的应用 |
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