CN1791612A - 具有肝素结合活性的新的抗微生物肽 - Google Patents
具有肝素结合活性的新的抗微生物肽 Download PDFInfo
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- CN1791612A CN1791612A CNA2004800137282A CN200480013728A CN1791612A CN 1791612 A CN1791612 A CN 1791612A CN A2004800137282 A CNA2004800137282 A CN A2004800137282A CN 200480013728 A CN200480013728 A CN 200480013728A CN 1791612 A CN1791612 A CN 1791612A
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Abstract
本发明涉及具有肝素结合活性的抗微生物肽,其来源于基本无抗微生物活性的内源哺乳动物蛋白质并且具有10到36个氨基酸残基,所述蛋白质选自层粘连蛋白同种型、补体因子C3、富含组氨酸的糖蛋白和激肽原,其中抗微生物肽包含至少4个选自K、R和H的氨基酸残基。本发明也涉及包含所述抗微生物肽的药物组合物和抗微生物肽和/或抗微生物/药物组合物的用途。
Description
技术领域
本发明涉及具有肝素结合活性的抗微生物肽,其来源于基本无抗微生物活性的内源哺乳动物蛋白质并且具有10到36个氨基酸残基,其中所述蛋白质选自层粘连蛋白同种型(laminin isoforms)、补体因子C3(complement factor C3)、富含组氨酸的糖蛋白和激肽原,其中抗微生物肽包含至少4个选自K、R和H的氨基酸残基。本发明也涉及包含所述抗微生物肽的药物组合物和抗微生物肽和/或抗微生物/药物组合物的用途。
背景技术
哺乳动物诸如人类的免疫系统成功地战胜了几种感染。然而,在一些情况下,细菌、真菌或病毒并不总是能被清除,而这可以引起局部或全身性急性感染。在围产期、烧伤或重病特护室和在无免疫应答个体中,这是需要重要关注的问题。在其它情况下,上皮表面连续的细菌存留可以引起或加重慢性病。人类中,可以例举的是慢性皮肤溃疡、特应性皮炎和其它类型的湿疹、痤疮或泌尿生殖器感染。
可以用各种药物治疗有症状的感染。也可以通过例如疫苗与一些疾病斗争。然而,疫苗不总是最好的治疗选择,并且对于一些微生物没有可用的疫苗。当无法获得保护时,就要寻求疾病的治疗。通常,通过使用杀死微生物的抗生素进行治疗。然而,在过去的许多年期间,几种微生物已经开始抵抗抗生素了。最可能地,抗性问题在不久的将来将会增加。此外,几种个体已经对抗生素产生变应反应,因此减少了有效地使用一些抗生素的可能性。
各种生物体的上皮表面连续地暴露于细菌。最近几年期间,已经认识到基于抗细菌肽的天然免疫系统在易感染的生物学边界处的最初细菌清除中起重要作用(Lehrer,R.I.,和Ganz,T.(1999)Curr OpinImmunol 11:23-27,Boman,H.G.(2000)Immunol.Rev.173,5-16)。抗微生物肽通过渗透细菌膜杀死细菌,因此特异性分子微生物靶的缺少最小化了抗性发展。
本领域已知几种与这里所述肽不相关的抗微生物肽和蛋白质。
US 6,503,881公开了是indolicidin类似物的用做抗微生物肽的阳离子肽。该阳离子肽来源于不同物种,包括动物和植物。
US 5,912,230公开了抗真菌和抗细菌的基于组氨酸的肽。该肽是基于天然人类histatin的氨基酸序列的确定部分,以及公开了真菌和细菌感染治疗的方法。
US 5,717,064公开了甲基化富含赖氨酸的裂解肽。该裂解肽抗胰蛋白酶消化,并且是非天然的。该裂解肽适于体内给药。
US 5,646,014公开了抗微生物肽。该肽是从来源于蚕血淋巴的抗微生物部分分离的。该肽显示了抗几种微生物株系诸如大肠杆菌(Escherichia coli),金黄色葡萄球菌(Staphylococcus aureus)和蜡状芽孢杆菌(Bacillus cereus)的优良的抗微生物活性。
McCabe等,J.Biol.Chem.277卷:27477-27488,2002描述了37kDa抗微生物的趋化蛋白质-azurocidin,其含有肝素结合共有基序XBBXBX和XBBBXXBX。
WO2004016653公开了基于azurocidin 20-44序列的肽。该肽含有通过二硫键连接的环结构。
US 6495516和相关的专利公开了基于杀细菌55kDa蛋白质—杀菌/渗透性增加蛋白质(BPI)的肽。该肽发挥了抗微生物作用及具有肝素和LPS中和能力。
WO 01/81578公开了编码G偶联蛋白质-受体相关多肽的大量序列,它们可以用于大量疾病。
WO 00/27415公开了适于抑制血管生成的肽。该肽是高分子量激肽原5的类似物。BLASTp检索显示在不同物种中保守的或具有相似性的序列诸如激肽原,没有说明这种保守性区域的功能或者它们作为小肽是否究竟具有功能。
目前,已知700多种不同的抗微生物肽序列(www.bbcm.univ.trieste.it/~tossi/search.htm),包括杀菌肽、防卫素爪蟾抗菌肽和cathelicidins。
尽管今天有巨大数量的抗微生物肽可用,但是还存在对新改进的抗微生物肽的日益增加的需要。抗微生物肽可以用于抗击抗或耐受抗生素和/或其它抗微生物剂的微生物。此外,需要新的抗微生物肽,当将其引入到哺乳动物诸如人类中时,它是非变应原性的。细菌在进化期间已经遇到过内源产生的抗微生物肽,而未出现显著的抗性诱导。
发明内容
根据第一方面,本发明涉及具有肝素结合活性的抗微生物肽,其来源于基本无抗微生物活性的内源哺乳动物蛋白质并且具有10到36个氨基酸残基,所述蛋白质选自层粘连蛋白同种型、补体因子C3、富含组氨酸的糖蛋白和激肽原,其中该抗微生物肽包含至少4个选自K、R和H的氨基酸残基。
通过提供这种抗微生物肽,由于该肽来源于内源蛋白质和/或肽的事实,可以减少对此抗微生物肽产生变应性反应的风险。与较长的肽和蛋白质比较,通过使用短肽,可以增加肽的稳定性和减少生产花费,因此本发明在经济上是有利的。如本申请优先权日后公开的Andersson等,Eur J Biochem,2004,271:1219-1226所述,本发明来源于下面的发现:具有来源于非抗微生物的内源蛋白质的肝素结合基序的肽显示了抗微生物活性。一般地,文献已详细地记载了各种蛋白质中肝素结合和肝素结合基序存在的结构前提条件。这组分子包括各种层粘连蛋白同种型、纤连蛋白、凝固因子(coagulation factor)、生长因子、趋化因子、富含组氨酸的糖蛋白、激肽原和许多其它分子(参见,Andersson等,(2004)Eur J Biochem 271;271:1219-26和其中引用的参考文献),它们中没有一种是天然抗微生物的。
本发明的抗微生物肽和相应的抗微生物/药物组合物提供了利于有效地预防、减少或消除微生物的肽和组合物。因此可以增加抗击抵抗或耐受抗生素的微生物的可能性。而且,可以治疗对商购抗微生物剂具变应性的哺乳动物。通过提供来源于内源蛋白质的抗微生物/药物组合物,可以减少甚至排除哺乳动物出现针对这些特定肽的变态反应的可能性。这使得本发明抗微生物/药物组合物可以用于几种应用,其中抗微生物/药物组合物做为药物或者做为添加剂接触哺乳动物以防止感染。
此外,短肽的使用改进了生物利用率。而且,对革兰氏阴性和革兰氏阳性细菌或真菌具有特异性或优先作用的结构不同的肝素结合性抗微生物肽的应用能够实现对各种微生物的特异性靶向,由此使得抗性的发生和生态学问题得以最小化。通过补加哺乳动物中已经存在的肽,进一步减少了由新抗生素造成另外生态学压力的风险。最后,这些制剂也可以增强内源抗微生物肽的作用。
根据第二方面,本发明涉及抗微生物/药物组合物,其包含上述的一种或多种抗微生物肽和药物学可接受的缓冲液、稀释剂、载体、助剂或赋形剂。
根据第三方面,本发明涉及此后所述抗微生物肽和/或抗微生物/药物组合物的用途。
本发明的抗微生物肽增加了抗微生物剂的列表,这有助于针对各种应用进行选择以预防、减少或消除微生物,包括但不限于侵袭或感染哺乳动物诸如人类的微生物。
附图说明
图1A-C是证明肽对粪肠球菌(Enterococcus faecalis)的抗菌作用的图。
图2A和B是说明利用一组高活性肽进行的径向扩散测定的培养皿。
图3A-C是描述富含组氨酸的肽的抗细菌作用的图和表格。
图4A-H是电子显微镜照片,显示了对受到抗微生物肽处理的铜绿假单胞菌(Pseudomonas aeruginosa)的分析。
图5A-C是表示来源于补体C3,富含组氨酸的糖蛋白和激肽原的肽的肝素结合活性的照片。
图6是说明在镍-琼脂糖凝胶上纯化含组氨酸的抗微生物片段的照片。
发明详述
定义
在本申请和发明的范围中,应用了下列定义:
术语“核苷酸序列”意指具有两个或两个以上核苷酸的序列。核苷酸可以是基因组DNA、cDNA、RNA来源的、半合成或合成来源的或其混合物。该术语包含单链和双链形式的DNA或RNA。
术语“抗微生物肽”意指这样一种肽,该肽包含约10到约36个氨基酸残基,具有抗微生物和肝素结合活性,并且来源于天然没有抗微生物作用的内源哺乳动物。“抗微生物肽”防止、抑制、减少或破坏微生物。通过例如,实施例2,4或5中的方法可以测定抗微生物活性。
术语“肝素结合亲和性”意指直接或间接地结合肝素的肽。例如,通过实施例7中的方法可以测定肝素结合活性。显示了对肝素具有亲和性的本发明抗微生物肽也结合硫酸皮肤素。因此,肝素结合性抗微生物肽也与内源糖胺聚糖硫酸皮肤素相互作用。
术语“两亲性的”意指沿着α-螺旋结构、β-链、线型、环型或其它二级构象的相对面分布亲水性和疏水性氨基酸残基,其引起分子的一个面主要是带电荷的,另一面主要是亲水性的。可以通过各种基于web的算法,例如在http://us.expasy.org/cgi-bin/protscale.pl上发现的算法,对氨基酸残基序列进行作图来评估肽的两亲性程度。可以通过螺旋轮图(helical wheel diagram)观察疏水性残基的分布。可以在www.expasy.com.发现二级结构预测算法,诸如GORIV。
术语“阳离子”意指在pH约4到约12范围内具有净正电荷的分子。
术语“微生物”意指任何活的微生物。微生物的例子是细菌、真菌、病毒、寄生虫和酵母。
术语“抗微生物剂”意指任何防止、抑制或破坏微生物的药剂。在The Sanford Guide to Antimicrobial Therapy(32版,Antimicrobial Therapy,Inc,US)中可以发现抗微生物剂的例子。
在本发明范围中,基于IUPAC命名法(氨基酸和肽的IUPAC命名法和符号(残基名称,原子名称等),Eur J Biochem.,138,9-37(1984)以及Eur J Biochem.,152,1(1985)中的修正),如Protein DataBank(PNB)(www.pdb.org)所定义,使用氨基酸名称和原子名称。术语“氨基酸”意指选自丙氨酸(Ala或A)、半胱氨酸(Cys或C)、天冬氨酸(Asp或D)、谷氨酸(Glu或E)、苯丙氨酸(Phe或F)、甘氨酸(Gly或G)、组氨酸(His或H)、异亮氨酸(Ile或I)、赖氨酸(Lys或K)、亮氨酸(Leu或L)、甲硫氨酸(Met或M)、天冬酰胺(Asn或N)、脯氨酸(Pro或P)、谷氨酰胺(Gln或Q)、精氨酸(Arg或R)、丝氨酸(Ser或S)、苏氨酸(Thr或T)、缬氨酸(Val或V)、色氨酸(Trp或W)和酪氨酸(Tyr或Y)或其衍生物的氨基酸。
详述
抗微生物肽
本发明涉及具有肝素结合活性的抗微生物肽,其来源于基本无抗微生物活性的内源哺乳动物蛋白质并且具有10到36个氨基酸残基,其中该抗微生物肽包含至少4个选自K、R和H的氨基酸残基。这些氨基酸残基中的两个残基可以邻接。如Margalit等,1993 J Biol Chem268,19228-31所报道,B氨基酸残基之间约20的距离构成了肝素结合的前提条件,而与肽构象无关。与较长的肽或蛋白质比较,使用短肽增加了生物利用率(例如通过增加皮肤渗透能力)及减少生产和纯化花费。本发明抗微生物肽是对今天可商购获得的抗微生物肽的补充,并且增加了抗击耐受和/或抗现有抗微生物剂的微生物的可能性。通过从内源非抗微生物蛋白质衍生新的抗微生物肽可以鉴定对肽所基于的哺乳动物而言不是变应原性的新肽。
而且,利用日益增加的肽作用及对各种盐和离子环境的依赖性的知识能够设计出增强和控制肽作用的特定组合物。经剪裁而作用于真菌的肽将更有利于靶向特定疾病诸如粘膜上的酵母感染,而不显著地影响这些位点的细菌生态学。抗微生物肽作用于细菌细胞膜的事实表明它们可以与抗生素协同作用。因此,抗生素和肽的联合可以具有治疗优势。最后,也需要低成本的非变应原性抗微生物剂,以便用在需要防止微生物生长的不同种类产品中。
此外,对革兰氏阴性和革兰氏阳性细菌或真菌具有特异性或优先作用的结构不同的肝素结合性短抗微生物肽的应用,也使得能够实现对各种微生物的特异性靶向,由此最小化抗性问题和生态学问题。通过补加生物体中已经存在的肽,进一步减少了由新抗生素造成另外生态学压力的风险。引入能增加肽作用的制剂可以使外源提供的肽限于局部并得以加强,这可以进一步最小化治疗区域外肽副作用的风险,诸如抗性诱导的风险。最后,这些制剂也可以增强内源抗微生物肽的作用。如果抗微生物肽被开发用于抗击人类中微生物,那么内源抗微生物肽来源于人类内源蛋白质。同样的原则适用于其它动物,诸如马、牛、猪或家禽。抗微生物肽可以基于血浆、血液、结缔组织和组成细胞中存在的肽和/或蛋白质的结构,并且可以从肝素结合蛋白质;层粘连蛋白同种型,von Willebrand因子,玻连蛋白、蛋白质C抑制剂、纤连蛋白、凝固因子、生长因子、趋化因子、富含组氨酸的糖蛋白、激肽原或补体因子C3中进行选择。
本发明的抗微生物肽对肝素具有约10nM到约20μM的结合亲和性(Kd)。
肽可以具有10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35或36个氨基酸残基大小。肽的长度和序列取决于抗微生物肽的来源和要抗击的微生物、以及是否肽要用于防止、抑制、减少或破坏微生物和微生物存在于何种环境中、给药后抗微生物肽将遇到何种环境。
根据第一实施方式,本发明涉及基于激肽原蛋白质或富含组氨酸的糖蛋白的抗微生物肽,其中至少20%的氨基酸残基是H。抗微生物肽可以包含超过30,40或甚至50%的H,R和/或K氨基酸残基。在具体例子中,1、2、3、4、5或6个氨基酸残基是H。例如,抗微生物肽可以选自SEQ ID NO:1、2、3和4。这些肽分别来源于非抗微生物的蛋白质激肽原和富含组氨酸的糖蛋白的肝素结合结构域,并且富含H残基。
根据另一个实施方式,本发明涉及基于补体因子蛋白质的抗微生物肽。例如,抗微生物肽可以选自SEQ ID NO:5、6和7。SEQ ID NO:5、6和7肽来源于补体因子C3分子中明确的螺旋片段。如Hugli和同事(Chazin等,(1988)Biochemistry 27,9139-48,Hugli,Currenttopics in Microbiology and Immunology,1989,153,181-208)所证明的,由片段19-28(用SEQ ID NO:5表示)和47-70(用SEQ IDNO:6和7表示)限定C3来源的C3a分子的螺旋区域。全蛋白质C3不发挥抗微生物作用。最近已经公开了来源于C3的肽片段的肝素结合和抗微生物能力(Andersson等,Eur J Biochem,2004,271;271:1219-1226)。
根据第三实施方式,本发明涉及来源于层粘连蛋白的抗微生物肽。例如,抗微生物肽可以选自SEQ ID NO:8、9、10、11、12、13、14、15和16。层粘连蛋白α链LG结构域由已经被鉴定为肝素和其它细胞表面受体的结合位点的5个(1-5)LG模块组成(Timpl.,等,MatrixBiol,2000,19,309-317)。这些模块蛋白质是在发育过程诸如伤口愈合期间被合成的,并且已经描述在这些事件期间出现LG模块的蛋白酶解加工。最近描述了以前未公开的LG模块的肝素结合表位的抗微生物功能(Andersson等,Eur J Biochem,2004,271;271:1219-1226)。
尽管肽来源于内源蛋白质,但是可以以半合成或合成肽形式及在微生物中产生它们。
可以用一个或多个氨基酸残基,诸如1-100个氨基酸残基,5-50个氨基酸残基或6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29和30个氨基酸残基延伸抗微生物肽。这种添加的氨基酸可以复制来源于非抗微生物蛋白质的邻接抗微生物肽序列的序列。所添加的数量取决于将要对抗哪种微生物,肽的稳定性、毒性,待要治疗的哺乳动物或肽应该在哪种产品中和抗微生物肽基于哪种肽结构。待要添加给肽的氨基酸残基数也取决于生产的选择,例如表达载体和表达宿主,及制备抗微生物/药物组合物的选择。可以在抗微生物肽的N-或C-末端部分延伸或者在两个末端部分同时延伸,只要该延伸不破坏肽的抗微生物作用即可。抗微生物肽也可以是融合蛋白,其中抗微生物肽与另一肽融合。
此外,抗微生物肽可以可操作地连接其它已知的抗微生物肽或其它物质,诸如其它肽、蛋白质、寡糖、多糖、其它有机化合物或无机物质。例如抗微生物肽可以与在抗微生物肽抑制、防止或破坏微生物生命前防止抗微生物肽在哺乳动物中降解的物质偶联。
因此,可以通过在抗微生物肽C-末端部分酰胺化或酯化和在N-末端部分酰化、乙酰化、PEG化、烷基化等,修饰抗微生物肽。
做为可替代的方案,可以通过1到6个氨基酸的置换修饰来源于非抗微生物全蛋白质的功能性抗微生物片段的肽。
被抗微生物肽抑制、防止或破坏的微生物的例子是细菌,包括革兰氏阳性和革兰氏阴性细菌,诸如粪肠球菌(Enterococcusfaecalis)、大肠杆菌(Eschericia coli)、铜绿假单胞菌(Pseudomonas aeruginosa)、奇异变形菌(Proteus mirabilis)、肺炎链球菌(Streptococcus pneumoniae)、酿脓链球菌(Streptococcus pyogenes)、金黄色葡萄球菌(Staphylococcusaureu),病毒、寄生虫、真菌和酵母诸如白色念珠菌(Candidaalbicans)和近平滑念珠菌(Candida parapsilosis)。
抗微生物肽可以从天然来源,诸如从人类细胞,c-DNA,基因组克隆获得、或者化学合成,或者通过重组DNA技术从细胞来源以表达产物形式获得。
可以用标准化学方法,包括通过自动程序合成的方法合成抗微生物肽。一般地,根据标准固相Fmoc保护策略,用HATU(N-[二甲基氨基-1H-1,2,3-三唑并[4,5-B]吡啶-1-基亚甲基]-N-甲基甲铵六氟代磷酸盐N-氧化物)做为偶联剂或者用其它偶联剂诸如HOAt-1-羟基-7-氮杂苯并三唑合成肽类似物。用也可脱保护侧链官能团的含有适合清除剂的三氟乙酸从固相树脂切割肽。利用制备型反相层析进一步纯化粗肽。可以使用其它的纯化方法诸如分配层析、凝胶过滤、凝胶电泳或离子交换层析。可以利用本领域已知的其它合成技术诸如tBoc保护策略,或者不同偶联试剂等以产生等同的肽。
做为可替代的方案,可以通过重组产生合成肽(参见例如美国专利号5,593,866)。各种宿主系统均适于肽类似物的产生,所述宿主系统包括细菌诸如大肠杆菌(E.coli),酵母诸如酿酒酵母(Saccharomyces cerevisiae)或毕赤酵母(pichia),昆虫诸如Sf9和哺乳动物细胞诸如CHO或COS-7。现有许多表达载体可以用于每种宿主,并且只要载体和宿主能产生抗微生物肽,本发明不限于它们中任何一种。可以在例如,Sambrook等((Molecular Cloning.:ALaboratory Manual,Cold Spring Harbor Laboratory Press,ColdSpring Harbor,N.Y.,1987)和Ausubel等.(Current Protocols inMolecular Biology,Greene Publishing Co.,1995)中发现用于在大肠杆菌(E.coli)中克隆和表达的载体和方法。
最后,可以从血浆、血液、各种组织等纯化肽。肽可以是内源的,或者是酶促或化学消化纯化蛋白质后产生的。例如,可以用胰蛋白酶消化肝素结合蛋白质,并且更大规模地进一步分离所得到的抗细菌肽。
编码抗微生物肽的DNA序列被引入到适于宿主的适合表达载体中。在优选的实施方式中,将基因克隆到载体中以产生融合蛋白质。为了有利于肽序列的分离,使用易于化学切割(例如CNBr)或酶促切割(例如V8蛋白酶、胰蛋白酶)的氨基酸连接肽和融合配偶体。为了在大肠杆菌(E.coli)中表达,优选地,融合配偶体是引导表达为包涵体形式的正常的细胞内蛋白质。在这种情况下,切割释放终产物后,不需要肽的复性。在本发明中,包含融合配偶体和肽基因的DNA盒可以被插入到表达载体中。优选地,表达载体是含有诱导型或组成型启动子以利于插入的DNA序列在宿主中有效转录的质粒。
可以通过常规的转化技术诸如通过钙介导的技术、电穿孔或本领域普通技术人员熟知的其它方法将表达载体引入到宿主中。
编码抗微生物肽的序列可以来源于天然来源诸如哺乳动物细胞、现有cDNA或基因组克隆,或者可以合成。可以使用的一种方法是利用扩增引物,通过PCR扩增抗微生物肽,所述引物来源于抗微生物DNA模板的5’和3’末端,并且通常掺入了相对于载体克隆位点选定的限制位点。如果必要,可以将翻译起始和终止密码子引入到引物序列中。只要考虑待要处理的最终哺乳动物来选择密码子,编码抗微生物肽的序列可以经密码子优化而便于在特定宿主中表达。例如,如果在细菌中表达抗微生物肽,那么针对细菌进行密码子优化。
表达载体应该含有启动子序列以利于引入的抗微生物肽的表达。如果必要,也可以包含调节序列,诸如一个或多个增强子、核糖体结合位点、转录终止信号序列、分泌信号序列、复制起点、选择性标记等。调节序列可操作地互相连接在一起以允许转录和随后的翻译。如果要在细菌中表达抗微生物肽,调节序列是被设计的在细菌中使用的调节序列,并且这是本领域普通技术人员所熟知的。适合的启动子诸如组成型和诱导型启动子是可广泛获得的,并且包括来源于T5、T7、T3、SP6噬菌体和trp、lpp和lac操纵子的启动子。
如果含有抗微生物肽的载体将要在细菌中表达,复制起点的例子是产生高拷贝数的复制起点或产生低拷贝数的复制起点,例如fl-ori和col E1 ori。
优选地,质粒包含至少一种在宿主中起作用的选择性标记,该选择性标记允许鉴定和/或选择性生长转化细胞。用于细菌宿主的适合的选择性标记基因包括氨苄青霉素抗性基因、氯霉素抗性基因、四环素抗性基因、卡那霉素抗性基因和本领域已知的其它选择性标记基因。
用于在细菌中表达的质粒的例子包括pET表达载体pET3a、pET11a、pET12a-c和pET 15b(获自Novagen,Madison,Wis.)。低拷贝数的载体(例如pPD100)可以用于有效地超量产生对大肠杆菌(E.coli)宿主有害的肽(Dersch等,FEMS Microbiol.Lett.123:19,1994)。
适合宿主的例子是细菌、酵母、昆虫和哺乳动物细胞。然而,常常使用的是细菌诸如大肠杆菌(E.coli)。
用常规分离技术诸如亲和、大小排阻或离子交换层析、HPLC等分离表达的抗微生物肽。在A Biologist’s Guide to Principles andTechniques of Practical Biochemistry(Wilson和Golding编辑,Edward Arnold,London,或Current Protocols in Molecular Biology(John Wiley & Sons,Inc)中可以发现不同的纯化技术。
抗微生物组合物/药物组合物
此外,本发明涉及抗微生物组合物/药物组合物,其包含上述抗微生物肽和药物学可接受的缓冲液、稀释剂、载体、助剂或赋形剂。组合物中可以包含另外的化合物。这些另外的化合物包括,例如螯合剂诸如EDTA、EGTA或谷胱甘肽。可以用本领域已知的方法制备具有足够的贮藏稳定性并且适于向人类和动物给药的抗微生物/药物组合物。例如,通过冷冻干燥、喷雾干燥或喷雾冷却,可以冻干药物组合物。
“药物学可接受”意指不干扰活性组分,即抗微生物肽的生物学活性有效性的非毒性物质。这种药物学可接受的缓冲液、载体或赋形剂是本领域所熟知的(参见Remington′s Pharmaceutical Sciences,第18版,A.R Gennaro编辑,Mack Publishing Company(1990)和handbook of Pharmaceutical Excipients,第3版,A.Kibbe编辑,Pharmaceutical Press(2000))。
术语“缓冲液”意指含有酸碱混合物的水溶液,其目的是稳定pH。缓冲液的例子是Trizma、Bicine、Tricine、MOPS、MOPSO、MOBS、Tris、Hepes、HEPBS、MES、磷酸盐、碳酸盐、醋酸盐、柠檬酸盐、羟乙酸盐、乳酸盐、硼酸盐、ACES、ADA、酒石酸盐、AMP、AMPD、AMPSO、BES、CABS、二甲砷酸盐、CHES、DIPSO、EPPS、乙醇胺、甘氨酸、HEPPSO、咪唑、咪唑乳酸、PIPES、SSC、SSPE、POPSO、TAPS、TABS、TAPSO、TES和tricine。
术语“稀释剂”意指水或非水溶液,目的是稀释药物制剂中的肽。稀释剂可以是盐水、水、聚乙二醇、丙二醇、乙醇或油(诸如红花油、玉米油、花生油、棉籽油或芝麻油)中的一种或多种。
术语“助剂”意指添加到制剂中以增加肽的生物学作用的任何化合物。助剂可以是一种或多种具有不同阴离子的锌、铜或银盐,例如但不限于氟化物、氯化物、溴化物、碘化物、硫氰酸盐、亚硫酸盐、氢氧化物、磷酸盐、碳酸盐、乳酸盐、羟乙酸盐、柠檬酸盐、硼酸盐、酒石酸盐和具有不同酰基组成的醋酸盐。
赋形剂可以是一种或多种碳水化合物、聚合物、脂质和矿物质。碳水化合物的例子包括乳糖、蔗糖、甘露糖醇和环糊精,它们被添加到组合物中以便例如利于冻干。
聚合物的例子是淀粉、纤维素醚、纤维素羧甲基纤维素、藻酸盐、角叉菜胶、透明质酸、聚丙烯酸、聚磺酸酯、聚乙二醇/聚环氧乙烷、不同程度水解的聚乙烯醇/聚乙酸乙烯酯和聚乙烯吡咯烷酮(所有这些聚合物的不同分子量的分子),向组合物中添加它们例如用于粘度控制,用于实现生物吸附,或者用于保护脂质免受化学和蛋白酶解降解。脂质的例子是有不同的酰基链长度和饱和度的脂肪酸、磷脂、单、二和三甘油酯、神经酰胺、鞘脂和糖脂,卵的卵磷酯、大豆卵磷脂、氢化的卵的卵磷脂和大豆卵磷脂,它们以与聚合物相似的原因被添加到组合物中。矿物质的例子是滑石、氧化镁、氧化锌和氧化钛,将它们添加到组合物中以获得利益诸如减少液体积累或有利的着色特性。
载体的特征取决于给药途径。一种给药途径是局部给药。例如,对于局部给药,优选的载体是包含活性肽的乳化膏,但是可以使用其它常用的载体诸如一些基于矿脂/矿物和基于植物的软膏,及聚合物凝胶、液晶体相和微乳。
抗微生物/药物组合物可以包含一种或多种肽,诸如在抗微生物/药物组合物中包含1、2、3或4种不同肽。通过使用不同肽的联合,可以增加抗微生物作用及减少待抗击的微生物出现针对该微生物剂的抗性和/或耐受性的可能性。
基于富含组氨酸的蛋白质和/或激肽原的肽,特别是短肽具有有限的抗微生物活性。然而,如果这些肽处于包含盐和/或pH从约5.0到约7.0的组合物中,该肽就变得有活性,即通过添加盐和/或选定特定pH范围获得增强的作用。
盐形式的肽可以是与无机酸或有机酸的酸加成物,所述无机酸是诸如盐酸、硫酸、硝酸、氢溴酸、磷酸、高氯酸、硫氰酸、硼酸等,所述有机酸是诸如甲酸、乙酸、卤代乙酸、丙酸、乙醇酸、柠檬酸、酒石酸、琥珀酸、葡糖酸、乳酸、丙二酸、延胡索酸、邻氨基苯甲酸、苯甲酸、肉桂酸、对-甲苯磺酸、萘磺酸、对氨基苯磺酸等。可以添加无机盐诸如一价钠、钾或二价锌、镁、铜、钙等,及相应的阴离子,以改进抗微生物组合物的生物学活性。可以在确定和控制pH(例如,pH5.5-6.0)的确定溶液,诸如凝胶中使用基于激肽原和富含组氨酸的糖蛋白的抗微生物的富H肽,以增加所添加的抗微生物肽的作用。例如,在有或无离子环境下具有约5.0到约7.0,诸如约5.5到约6.0的确定pH的凝胶、软膏或绷带将增强、控制抗微生物肽的功能和使之局部化。
本发明的抗微生物/药物组合物也可以是脂质体形式,其中除了其它药物学可接受的载体外,肽还与两亲性试剂诸如脂质混合,该两亲性试剂以聚集形式作为微团、不溶单层和液晶存在。用于脂质体制剂的适合脂质非限制性地包括甘油单酯、甘油二酯、硫脑苷脂、溶血卵磷脂、磷脂、皂苷、胆酸等。例如,可以在US 4,235,871中发现这种脂质体制剂的制备。
本发明的抗微生物/药物学组合物也可以是生物可降解的微球体形式。在微球体生产中已经广泛使用脂族聚酯诸如聚(乳酸)(PLA)、聚(乙醇酸)(PGA)、PLA和PGA的共聚物(PLGA)或者聚(己内酯)(PLC)和聚(酐)做为生物可降解的聚合物。在US 5,851,451和EP0213303中可以发现这种微球体的制备。
做为可替代的方案,抗微生物肽可以溶解在盐水、水、聚乙二醇、丙二醇、乙醇或油(诸如红花油、玉米油、花生油、棉籽油或芝麻油)、黄蓍胶和/或各种缓冲液中。药物学组合物也可以包含离子和确定的pH以增强抗微生物肽的作用。
也可以对抗微生物/药物组合物进行常规药物学操作诸如灭菌,和/或所述组合物可以含有例如,如这里以外其它地方所公开的常规助剂诸如防腐剂、稳定剂、湿润剂、乳化剂、缓冲液和填充剂等。
可以局部或系统地给药本发明的抗微生物/药物组合物。给药途径包括局部、眼睛、鼻子、肺、口腔、非肠道(静脉内、皮下和肌内)、口服、肠胃外、阴道和直肠给药。也可以从植入物给药。例如,适合的抗微生物制剂形式是颗粒、粉末、片剂、包衣片剂(微)胶囊、栓剂、糖浆剂、乳剂、微乳剂(定义为由水、油和表面活性剂组成的光学各向同性的热动力学稳定系统),液晶相(定义为特征在于长程有序但是短程无序的系统(例子包括水或油连续的层状、六角形和立方相)),或者它们分散的对应物、凝胶、软膏、分散体、悬浮液、乳膏、气溶胶、滴剂或安瓿形式的可注射溶液,还有活性化合物持久释放的制剂,其中在这些制剂中常规地使用上述赋形剂、稀释剂、助剂或载体。在绷带或石膏等中也可以提供本发明药物组合物。
以药物学有效剂量向患者给药药物组合物。用“药物学有效剂量”意指相对于给药的病症而言足以产生期望效果的剂量。确切的剂量取决于化合物活性、给药方式、疾病的性质和严重性、患者年龄和体重,可能需要不同剂量。可以通过以单个剂量单位或几个较小剂量单位形式一次给药,并可以通过以特定间隔分剂量地多次给药进行剂量的施用。
本发明的药物组合物可以被单独给药,或者联合其它治疗剂诸如抗生素或防腐剂(antiseptic agent)诸如抗细菌剂、杀真菌剂、抗病毒剂和抗寄生虫剂给药。例子是青霉素类、头孢菌素类、碳头孢烯类、头霉素类、碳青霉烯类、单菌霉素类、氨基糖苷类、糖肽、喹诺酮类、四环素类、大环内酯类和氟喹诺酮类。防腐剂包括碘、银、铜、clorhexidine、聚己缩胍和其它双胍、脱乙酰壳多糖、乙酸和过氧化氢。这些药剂可以并入为相同药物组合物的部分,或者可以被单独给药。
本发明涉及人类和其它哺乳动物诸如马、狗、猫、牛、猪、骆驼等。因此该方法可应用于人类治疗和兽医应用。可以通过已成熟建立的感染标志诸如发热、puls、生物体培养等鉴定适于这种治疗的目标。可以用抗微生物肽治疗的感染包括由或因微生物引起的感染。微生物的例子包括细菌(例如,革兰氏阳性,革兰氏阴性)、真菌(例如酵母和霉菌)、寄生虫(例如,原生动物、线虫、绦虫和吸虫)、病毒和朊病毒。熟知这些类别中具体的生物体(参见,例如Davis等,Microbiology,第3次增补版本,Harper & Row,1980)。感染包括但不限于慢性皮肤溃疡、感染的急性伤口和烧伤伤口、感染的皮肤湿疹、脓疱病、特应性皮炎、痤疮、外耳炎、阴道感染、皮脂溢性皮炎、口腔感染和牙周炎、念珠菌性擦烂、结膜炎和其它眼睛感染和肺炎。
因此,抗微生物/药物组合物可以用于外科手术后、皮肤损伤后及烧伤伤口的预防性治疗。药物组合物也可以被包含在旨在用以贮存和处理与人体接触的外部物质诸如隐形眼镜、矫形移植物和导管的溶液中。
此外,抗微生物/药物组合物可以用于特应性皮炎、脓疱病、慢性皮肤溃疡、感染的急性伤口和烧伤伤口、痤疮、外耳炎、真菌感染、肺炎、皮脂溢性皮炎、念珠菌性擦烂、念珠菌性阴道炎、口咽念珠菌病、眼睛感染(细菌性结膜炎)和鼻子感染(包括携带MRSA)的治疗。
在洗液,诸如镜片消毒剂和贮存溶液中也可以使用抗微生物/药物组合物,或者抗微生物/药物组合物可以用于预防与尿导管使用或中央静脉导管使用有关的细菌感染。
此外,抗微生物组合物可以用于预防膏剂(plasters)、粘合剂、缝线中的手术后感染或者可以被掺入到伤口敷料中。
也可以在聚合物、织物等中使用抗微生物肽以产生抗细菌表面或者化妆品和个人护理品(肥皂、洗发剂、牙膏、抗痤疮剂、防晒霜、卫生棉条、尿布)中可以补加抗微生物/药物组合物。鉴定抗微生物人类肽和/或蛋白质的方法
本发明也涉及鉴定一种或多种新的抗微生物肽的方法,这使得可以提供给哺乳动物诸如人类一组新的抗微生物肽,该组抗微生物肽具有低变应原性并可以有效低抗侵袭该哺乳动物的微生物。通过这种方法,将可以获得新改进的抗微生物肽,从而提供大量抗微生物剂,由此减少或甚至消除目前普遍遇到的针对市场上商购的抗生素出现的抗性和/或耐受性问题。
该方法包括下面的步骤:提供内源肽和/或蛋白质,提供肝素,混合内源肽和/或蛋白质与肝素以产生肽和/或蛋白质肝素复合物,检测肽和/或蛋白质肝素复合物,并且鉴定抗微生物人类内源肽和/或蛋白质。此外,可以使用镍如镍琼脂糖代替肝素。肝素可以存在于溶液中,或者与基质连接。在后一种情况下,这适于分离目的(h.p.l.c或f.p.l.c)或Biocore分析。对于分离目的,可以使用肝素琼脂糖凝胶或相似的介质。因为抗微生物肽也与其它糖胺聚糖相互作用,所以可以将这些分子,诸如硫酸皮肤素或硫酸乙酰肝素用于新抗微生物肽的纯化。肝素硫酸乙酰肝素和硫酸皮肤素含有散布和空间确定的磺基或羧基基团。原则上,任何与这些糖胺聚糖具有相似相互作用能力的其它聚合化合物都可以用于抗微生物肽的特异性结合。此外,可以单独在镍-琼脂糖凝胶或相似介质上或进一步与肝素层析联合,纯化富含H的肽。
下面的实施例意欲示例本发明,但不是以任何方法、形式或方式明确或隐含地限制本发明。
实施例
微生物
在实验中使用原始获自慢性静脉溃疡的粪肠球菌(Enterococcusfaecalis)2374、大肠杆菌(Escherichia coli)37.4、铜绿假单胞菌(Pseudomonas aeruginosa)27.4,和获自特应性湿疹患者的白色念珠菌(Candida aibicans)BM 4435。
实施例1
抗微生物肽
由Innovagen AB,Ideon,SE-22370,Lund,Sweden合成序列表和下面表1中所示的抗微生物肽。通过质谱分析(MALDI.TOF Voyager)证实这些肽的纯度和分子量
表1
来源 | 肽 | 代码 |
C3a | LRKCCEDGMR ENPMRFSCQR RTRFIS | LRK26 |
C3a | LGEACKKVFL DCCNYITELR RQHARAS | LGE27 |
C3a | CNYITELRRQHARASHLGLAR | CNY21 |
层粘连蛋白-α1 | SRNLSEIKLLISQARK | SRN16 |
层粘连蛋白-α1 | SRNLSEIKLL ISQARKQAAS IKVAVSADR | SRN29 |
层粘连蛋白-α1 | KDFLSIELFR GRVKV | KDF15 |
层粘连蛋白-α1 | SAVRKKLSVE LSIRT | SAV15 |
层粘连蛋白-α5 | LGTRLRAQSR QRSRPGRWHK VSVRW | LGT25 |
层粘连蛋白-α5 | PPPPLTSASK AIQVFLLGGS RKRVL | PPP25 |
层粘连蛋白-α5 | RLRAQSRQRS RPGRWHKVSV RW | RLR22 |
层粘连蛋白-α1 | PGRWHKVSVR W | PGR11 |
层粘连蛋白-β1 | RIQNLLKITNLRIKFVKL | RIQ18 |
纤连蛋白 | QPPRARITGY IIKYEKPG | QPP18 |
Von Willebrand因子 | YIGLKDRKRP SELRRIASQV KYA | YIG23 |
玻连蛋白 | AKKQRFRHRN RKGYR | AKK15 |
蛋白质C抑制剂 | SEKTLRKWLK MFKKRQLELY | SEK20 |
富含组氨酸的糖蛋白 | GHHPHGHHPH GHHPHGHHPH | GHH20 |
激肽原 | KHNLGHGHKH ERDQGHGHQR | KHN20 |
激肽原 | GGHVLDHKHGHGHGKHKNKG | GGH20 |
激肽原 | HKHGHGHGKH KNKGKKNGKH | HKH20 |
合成的序列 | AKKARAAKKA RAAKKARAAK KARA | AKK24 |
合成的序列 | AKKARAAKKA RAAKKARA | AKK18 |
合成的序列 | AKKARAAKKA RA | AKK12 |
合成的序列 | ARKKAAKAAR KKAAKAARKK AAKA | ARK24 |
合成的序列 | ARKKAAKAAR KKAAKA | ARK16 |
合成的K->H序列 | AHHAHAAHHA HAAHHAHAAH HAHA | AHH24∶1 |
合成的K->H序列 | AHHHAAHAAH HHAAHAAHHH AAHA | AHH24∶2 |
实施例2
图1描述了富含精氨酸和赖氨酸的肽(序列表)对粪肠球菌(Enterococcus faecalis)的杀细菌作用。在Todd-Hewitt(TH)培养基中培养细菌达到对数中期。用含有5mM葡萄糖的10mM Tris,pH7.4洗涤和稀释细菌。在37℃与合成肽一起温育细菌(50μl;2×106cfu/ml)2小时,其中合成肽为0.03到60μM浓度。为了定量杀细菌活性,在TH琼脂平板上涂系列稀释度的温育混合物,接着在37℃温育过夜,并且测定菌落形成单位的数量。
2×106菌落形成单位(CFU)×ml-1的粪肠球菌(E.faecalis)(分离株2374)与0.03到60μM浓度的肽在50μl中温育。(A)来源于层粘连蛋白的合成的肽。示出了来源于α5链(PPP25:SEQ ID NO:13,LGT25:SEQ ID NO:12,RLR22:SEQ ID NO:14,PGR11:SEQ ID NO:15)和α1链(SRN16:SEQ ID NO:8,SRN29:SEQ ID NO:9,KDF15:SEQ IDNO:10,SAV15:SEQ ID NO:11)的LG结构域的肽的作用。一种肽(RIQ18:SEQ ID NO:16)来源于β1链。(B)三种肽来源于补体因子C3(LRK26:SEQ ID NO:5,LGE27:SEQ ID NO:6和CNY21:SEQ ID NO:7),AKK15来源于玻连蛋白,SEK20:SEQ ID NO:19来源于蛋白质C抑制剂,QPP18:SEQ ID NO:17来源于纤连蛋白和YIG23:SEQ ID NO:18来源于von Willebrand因子。(C)肝素结合共有序列(AKKARA)n(n=1-4)和(ARKKAAKA)n(n=1-3)的抗细菌作用。n=1肽不发挥抗微生物作用。不与肝素相互作用的肽:GHRPLDKKREEAPSLRPA、LVTSKGDKELRTGKEKVTS和KNNQKSEPLIGRKKT(Andersson等,Eur J Biochem,2004,271;271:1219-1226)是不抗微生物的。
实施例3
抗微生物肽的径向扩散测定法分析(表2)
基本如以前(Andersson等,Eur J Biochem,2004,271:1219-1226)所述进行径向扩散测定(RDA)。简而言之,在10ml全强度(3% w/v)胰胨豆胨培养液(TSB)(Becton-Dickinson,Cockeysville,MD)中培养细菌(大肠杆菌(E.coli))或真菌(白色念珠菌(C.albicans))达到对数中期。用10mM Tris,pH 7.4洗微生物1次。向5ml由0.03%(w/v)TSB、1%(w/v)低电渗型(Low-EEO)琼脂糖(Sigma,St Louise MO)和终浓度0.02%(v/v)Tween 20(Sigma)组成的下层琼脂糖凝胶添加4×106细菌cfu或1×105真菌cfu。向85mm培养皿中倾倒入该下层琼脂糖凝胶。琼脂糖固化后,打出4mm直径的孔,并且向每个孔添加6μl待测样品。在37℃温育平板3小时以允许肽扩散。然后用5ml熔化的覆盖层(dH2O中6% TSB和1% Low-EEO琼脂糖)覆盖下层凝胶。37℃温育18-24小时后,通过每个孔周围的清亮区观察肽的抗微生物活性。检测100μM浓度的合成肽以确定相对于已知肽LL-37的抗细菌作用。为了最小化实验之间的差异,在每个板上都包含LL-37标准(100μM)。以径向扩散单位(以毫米为单位的清亮区的直径-孔直径)×10)表示肽的活性。结果如下面表2所示。
表2
来源 | 代码 | 径向扩散单位 |
hCAP-18 | LL-37 | 50 |
C3a | LRK26 | 70 |
C3a | LGE27 | 40 |
C3a | CNY21 | 32 |
层粘连蛋白-α1 | SRN16 | 77 |
层粘连蛋白-α1 | SRN29 | 71 |
层粘连蛋白-α1 | KDF15 | 65 |
层粘连蛋白-α1 | SAV15 | 75 |
层粘连蛋白-α5 | LGT25 | 85 |
层粘连蛋白-α5 | PPP25 | 81 |
层粘连蛋白-α5 | RLR22 | 92 |
层粘连蛋白-α1 | PGR11 | 86 |
层粘连蛋白-β1 | RIQ18 | 93 |
纤连蛋白 | QPP18 | 59 |
Von Willebrand因子 | YIG23 | 80 |
玻连蛋白 | AKK15 | 101 |
蛋白质C抑制剂 | SEK20 | 92 |
合成序列 | AKK24 | 67 |
合成序列 | ARK24 | 74 |
实施例4
肽抗大肠杆菌(E.coli)和白色念珠菌(C.albicans)的径向扩散测定(图2)
图2表示利用一组抗微生物肽进行的径向扩散测定。如上所述进行该测定。在37℃温育粪肠球菌(E.faecalis)细菌(图A)和在28℃温育白色念珠菌(Candida albicans)(图B)18-24小时后,通过每个孔周围的清亮区观察肽的抗微生物活性。
实施例5
富含组氨酸的肽的抗细菌作用
图3描述了富含组氨酸的肽的杀细菌作用。在Todd-Hewitt(TH)培养基中将粪肠球菌(E.faecalis)细菌培养到对数中期。在含有5mM葡萄糖,有或无50μM ZnCl的10mM Tris,pH 7.4中或者在10mM MES缓冲液,5mM葡萄糖,pH 5.5中洗涤和稀释细菌。在37℃温育细菌(50μl;2×106cfu/ml)和合成肽2小时,合成肽的浓度为0.03到60μM(Tris缓冲液,有或无锌)或者为30和60μM(Tris和MES缓冲液)。为了定量杀细菌活性,在TH琼脂平板上涂系列稀释度的温育混合物,接着在37℃温育过夜,并且测定菌落形成单位的数量。(A)显示在有或无50μM ZnCl的情况下,来源于富含组氨酸的糖蛋白(GHH20:SEQ ID NO:4)和激肽原(KHN20:SEQ ID NO:3,GGH20:SEQID NO:2和HKH20:SEQ ID NO:1)的肝素结合结构域的肽的作用。(B):在含有5mM葡萄糖的10mM Tris,pH 7.4中或者在10mM MES缓冲液,5mM葡萄糖,pH 5.5中肽(30和60μM)的作用。数字表示%存活率,其中100%是对照(无肽)。(C):在固定肽/锌摩尔比(1∶100)的情况下,肽AHH24∶1和AHH24∶2对粪肠球菌(E.faecalis)的作用。没有锌的情况下肽不发挥抗微生物活性。
实施例6
肽作用的电子显微镜分析
图4显示经过抗微生物肽作用的铜绿假单胞菌(Pseudomonasaeruginosa)细菌的电子显微镜分析。(A):对照。(B-H)对用约50%所需杀细菌浓度的肽处理过的细菌的分析。也分析了200%的HKH20。(B)LL-37、(C)ARK24、(D)SEK20、(E)AKK24、(F)LGT25、(G)HKH20和(H)200%杀细菌浓度的HKH20。除了G和H(0.5μm)外,棒条表示1μm。肽处理的细菌的电子显微镜分析证明了与对照比较,处理过的细菌在形态学上有明显的差异。Cathelicidin LL-37沿着铜绿假单胞菌(P.aeruginosa)细菌细胞膜引起局部微扰及破坏,并且偶尔地在细胞外发现了细胞内物质,并且用这里所公开的内源抗微生物肽获得了相似的观察结果。
实施例7
内源抗微生物肽的肝素结合(图5)
检测肽的肝素结合活性。肽被施加在硝酸纤维素膜(Hybond,Amersham Biosciences)上。封闭膜(PBS,pH 7.4,0.25% Tween 20,3%牛血清白蛋白)1小时,并且在相同的缓冲液中与放射性标记的肝素温育1小时。在有或无50μM ZnCl的情况下检测富含组氨酸的肽的肝素结合。如前述进行肝素的放射性碘化(Andersson等,Eur JBiochem,2004,271;271:1219-1226)。添加未标记的多糖(2mg/ml)用于竞争性结合。洗膜(PBS,pH 7.4,0.25% Tween 20中3×10min)。使用Bas 2000放射成像系统(Fuji)观察放射性。
未标记的肝素(6mg/ml)抑制125I-肝素与C3来源的肽LRK26和LGE27和LL-37的结合(上部分)。
实施例8
在镍-琼脂糖凝胶上纯化含组氨酸的抗微生物片段(图6)
在大肠杆菌(E.coli)株系(BL21DE3)中表达人类激肽原的结构域D5,其含有肽表位KHN20、GGH20和HKH20。通过向指数生长的细菌添加1mM异丙基-硫代-β-D-半乳糖苷诱导蛋白质产生。3h温育后,通过离心收集细菌。在50mM磷酸盐、300mM NaCl,pH 8.0(缓冲液A)中重悬浮沉淀,并且通过重复冷冻-融化循环裂解细菌。然后,以29000g离心裂解物30分钟。上清液与加载有镍和用缓冲液A平衡的2ml NiNTA-琼脂糖混合。将琼脂糖加到柱子中,用含有0.1% TritonX-100的10ml缓冲液A、10ml缓冲液A、含有1M NaCl的5ml缓冲液A、5ml缓冲液A、10ml 20%乙醇、含有5mM咪唑的10ml缓冲液A和含有30mM咪唑的缓冲液A洗涤。在500mM咪唑中洗脱蛋白质(箭头)。在径向扩散测定中该结构域发挥了抵抗大肠杆菌(E.coli)的抗细菌作用。
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Claims (25)
1、具有肝素结合活性的抗微生物肽,其来源于基本无抗微生物活性的内源哺乳动物蛋白质并且具有10到36个氨基酸残基,所述蛋白质选自层粘连蛋白同种型、补体因子C3、富含组氨酸的糖蛋白和激肽原,其中抗微生物肽包含至少4个选自K、R和H的氨基酸残基。
2、如权利要求1所述的抗微生物肽,其中该抗微生物肽基于激肽原蛋白质或富含组氨酸的糖蛋白,并且其中至少30%的氨基酸残基是H。
3、如权利要求2所述的抗微生物肽,其中抗微生物肽的至少50%包含H,K和/或R氨基酸残基。
4、如权利要求2或3所述的抗微生物肽,其中该抗微生物肽选自SEQ ID NO:1、2、3和4。
5、如权利要求1所述的抗微生物肽,其中该抗微生物肽基于补体因子蛋白质。
6、如权利要求5所述的抗微生物肽,其中该抗微生物肽选自SEQID NO:5、6和7。
7、如权利要求1所述的抗微生物肽,其中该抗微生物肽基于层粘连蛋白蛋白质。
8、如权利要求7所述的抗微生物肽,其中该抗微生物肽选自SEQID NO:8、9、10、11、12、13、14、15和16。
9、如前述任一权利要求所述的抗微生物肽,其中该肽是内源的、合成的或半合成的。
10、如权利要求1-9中任一权利要求所述的抗微生物肽,其中该肽与一种或多种其它抗微生物肽或其它物质连接。
11、如权利要求1-10中任一权利要求所述的抗微生物肽,其中通过酰胺化、酯化、酰化、乙酰化、PEG化或烷基化修饰该肽。
12、抗微生物组合物/药物组合物,其包含
a)如权利要求1-11中任一权利要求所述的抗微生物肽和
b)药物学可接受的缓冲液、稀释剂、载体、助剂或赋形剂。
13、如权利要求12所述的抗微生物组合物/药物组合物,其包含盐。
14、如权利要求13所述的抗微生物组合物/药物组合物,其中该盐可以选自一价钠、钾或二价锌、镁、铜、钙。
15、如权利要求14所述的抗微生物组合物/药物组合物,其中该盐是二价锌。
16、如权利要求13-15中任一权利要求所述的抗微生物组合物/药物组合物,其中该组合物具有约5.0到约7.0的pH。
17、如权利要求12-16中任一权利要求所述的抗微生物组合物/药物组合物,其中该组合物包含1、2、3或4种不同多肽之间的混合物。
18、如权利要求12-17中任一权利要求所述的抗微生物组合物/药物组合物,其中该抗微生物组合物/药物组合物包含一种或多种抗生素和/或防腐剂。
19、如权利要求12-18中任一权利要求所述的抗微生物组合物/药物组合物,其中抗微生物组合物/药物组合物是颗粒、粉末、片剂、包衣片剂、胶囊、栓剂、糖浆剂、乳剂、凝胶、软膏、悬浮液、乳膏、气溶胶、滴剂形式或可注射形式。
20、如权利要求1-11中任一权利要求所述的抗微生物肽或者如权利要求12-19中任一权利要求所述的抗微生物组合物/药物组合物在预防、抑制、减少或破坏选自细菌、病毒、寄生虫、真菌和酵母的微生物中的用途。
21、如权利要求20所述的抗微生物肽或抗微生物组合物/药物组合物的用途,所述用途为在治疗或诊断中的用途。
22、如权利要求1-11中任一权利要求所述的抗微生物肽或者如权利要求12-19中任一权利要求所述的抗微生物组合物/药物组合物用于制备治疗抗微生物疾病的药物的用途,其中所述疾病由选自细菌、病毒、寄生虫、真菌和酵母的微生物引起。
23、如权利要求20-22中任一权利要求所述的抗微生物肽或抗微生物组合物/药物组合物的用途,用于治疗由微生物引起的疾病,所述微生物选自粪肠球菌(Enterococcus faecalis)、大肠杆菌(Eschericiacoli)、铜绿假单胞菌(Pseudomonas aeruginosa)、奇异变形菌(Proteusmirabilis)、肺炎链球菌(Streptococcus pneumoniae)、酿脓链球菌(Streptococcus pyogenes)、金黄色葡萄球菌(Staphylococcusaureus)。
24、如权利要求20-22中任一权利要求所述的抗微生物肽或抗微生物组合物/药物组合物的用途,用于治疗由微生物引起的疾病,所述微生物选自白色念珠菌(Candida albicans)和近平滑念珠菌(Candidaparapsilosis)。
25、治疗患有微生物感染的哺乳动物的方法,该方法包括向患者施用治疗有效量的权利要求12-19中任一权利要求所述的药物组合物。
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2013067750A1 (zh) * | 2011-11-09 | 2013-05-16 | 北京正旦国际科技有限责任公司 | 一种肝癌标志物多抗免疫质谱试剂盒 |
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SE0402807D0 (sv) * | 2004-11-17 | 2004-11-17 | Dermagen Ab | Novel antimicrobial peptides |
WO2007091958A1 (en) * | 2006-02-10 | 2007-08-16 | Dermagen Ab | Novel antimicrobial peptides and use thereof |
EP1987056B1 (en) * | 2006-02-10 | 2012-07-25 | Dermagen AB | Novel antimicrobial peptides and use thereof |
US8227406B2 (en) | 2006-05-16 | 2012-07-24 | Dermagen Ab | Antimicrobial peptides |
WO2008070116A2 (en) * | 2006-12-04 | 2008-06-12 | Concert, Llc | Topical compositions for treatment of skin conditions |
CA2690734A1 (en) * | 2007-06-14 | 2008-12-24 | Richard A. Clark | Polypeptides and methods of use |
GB0821721D0 (en) * | 2008-11-27 | 2008-12-31 | Hansa Medical Ab | Antimicrobial therapy |
WO2010080836A2 (en) | 2009-01-06 | 2010-07-15 | C3 Jian, Inc. | Antibacterial and antifungal peptides |
US8883153B2 (en) * | 2009-03-27 | 2014-11-11 | The Research for The State University of New York | Methods for preventing and treating angioedema |
FR2960877B1 (fr) * | 2010-06-04 | 2014-08-29 | Agronomique Inst Nat Rech | Fraction de proteines et peptides issus du blanc d'oeuf et proteine issue du blanc d'oeuf et leur utilisation comme agent anti-listeria |
JP6456819B2 (ja) * | 2012-05-14 | 2019-01-23 | メルク パテント ゲーエムベーハー | 電気泳動ディスプレイ用の粒子 |
WO2015138494A1 (en) | 2014-03-10 | 2015-09-17 | Georges Belfort | Anti-microbial peptides and method for designing novel anti-microbial peptides |
WO2017001731A1 (en) * | 2015-06-30 | 2017-01-05 | Oulun Yliopisto | New antimicrobial peptides, their variants and uses |
US11174288B2 (en) * | 2016-12-06 | 2021-11-16 | Northeastern University | Heparin-binding cationic peptide self-assembling peptide amphiphiles useful against drug-resistant bacteria |
JP2022538903A (ja) * | 2019-07-02 | 2022-09-06 | トラスティーズ オブ タフツ カレッジ | 細胞および組織への薬剤の送達のための新規ペプチド、組成物および方法 |
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US5912230A (en) * | 1991-11-01 | 1999-06-15 | Periodontix, Inc. | Anti-fungal and anti-bacterial histatin-based peptides |
US5593866A (en) | 1992-08-21 | 1997-01-14 | The University Of British Columbia | Cationic peptides and method for production |
WO1994020532A1 (en) * | 1993-03-12 | 1994-09-15 | Xoma Corporation | Biologically active peptides from functional domains of bactericidal/permeability-increasing protein and uses thereof |
US5733872A (en) | 1993-03-12 | 1998-03-31 | Xoma Corporation | Biologically active peptides from functional domains of bactericidal/permeability-increasing protein and uses thereof |
AU1086595A (en) | 1993-11-08 | 1995-05-29 | Demeter Biotechnologies, Ltd. | Methylated lysine-rich lytic peptides and method of making same by reductive alkylation |
JP3459314B2 (ja) | 1994-08-31 | 2003-10-20 | 社団法人農林水産技術情報協会 | 新規ペプチド、抗菌剤、新規ペプチド遺伝子、新規な組み換え体dna及び新規ペプチドの製造法 |
JPH08208692A (ja) * | 1994-09-28 | 1996-08-13 | Sumitomo Pharmaceut Co Ltd | 新規な細胞接着抑制ペプチド誘導体 |
CA2192782C (en) | 1995-12-15 | 2008-10-14 | Nobuyuki Takechi | Production of microspheres |
US6503881B2 (en) | 1996-08-21 | 2003-01-07 | Micrologix Biotech Inc. | Compositions and methods for treating infections using cationic peptides alone or in combination with antibiotics |
IL121134A0 (en) * | 1997-06-22 | 1997-11-20 | Yeda Res & Dev | Peptides and antiallergic compositions comprising them |
IL142822A0 (en) | 1998-11-10 | 2002-03-10 | Univ Temple | Inhibition of angiogenesis by high molecular weight kininogen and peptide analogs thereof |
WO2000027415A2 (en) | 1998-11-10 | 2000-05-18 | Temple University - Of The Commonwealth System Of Higher Education | Inhibition of angiogenesis by peptide analogs of high molecular weight kininogen domain 5 |
US20030083244A1 (en) | 2000-04-26 | 2003-05-01 | Vernet Corine A.M. | Novel proteins and nucleic acids encoding same |
WO2002032459A2 (en) * | 2000-10-17 | 2002-04-25 | Massachusetts Institute Of Technology | Method of increasing the efficacy of antibiotics by complexing with cyclodextrins |
GB2382775B (en) * | 2001-12-06 | 2005-05-25 | Johnson & Johnson Medical Ltd | Controlled release therapeutic wound dressings |
JP2006506969A (ja) * | 2002-07-12 | 2006-03-02 | バイエル・フアーマシユーチカルズ・コーポレーシヨン | 下垂体アデニル酸シクラーゼ活性化ペプチド(pacap)受容体(vpac2)アゴニストおよびそれらの薬理学的使用方法 |
US20060173162A1 (en) | 2002-08-15 | 2006-08-03 | Rene Djurup | Bactericidak anti-apoptotic, pro-inflammatory and anti-inflammatory peptides of heparin-binding protein (hbp) |
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2003
- 2003-05-19 SE SE0301431A patent/SE0301431D0/xx unknown
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2004
- 2004-05-19 ES ES04734024T patent/ES2395206T3/es not_active Expired - Lifetime
- 2004-05-19 CN CNB2004800137282A patent/CN100362017C/zh not_active Expired - Fee Related
- 2004-05-19 US US10/557,455 patent/US20070185019A1/en not_active Abandoned
- 2004-05-19 WO PCT/SE2004/000797 patent/WO2005061535A1/en active Application Filing
- 2004-05-19 KR KR1020057021961A patent/KR101160474B1/ko not_active IP Right Cessation
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013067750A1 (zh) * | 2011-11-09 | 2013-05-16 | 北京正旦国际科技有限责任公司 | 一种肝癌标志物多抗免疫质谱试剂盒 |
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AU2004303728A1 (en) | 2005-07-07 |
EP1625155A1 (en) | 2006-02-15 |
US8551954B2 (en) | 2013-10-08 |
KR101160474B1 (ko) | 2012-06-28 |
CA2523998C (en) | 2014-05-13 |
CN101161284B (zh) | 2011-10-05 |
CA2523998A1 (en) | 2005-07-07 |
PL1625155T3 (pl) | 2013-06-28 |
CN101161284A (zh) | 2008-04-16 |
US20090074864A1 (en) | 2009-03-19 |
JP2007531691A (ja) | 2007-11-08 |
SE0301431D0 (sv) | 2003-05-19 |
WO2005061535A1 (en) | 2005-07-07 |
US20070185019A1 (en) | 2007-08-09 |
CN100362017C (zh) | 2008-01-16 |
HK1119390A1 (en) | 2009-03-06 |
AU2004303728B2 (en) | 2011-03-31 |
ES2395206T3 (es) | 2013-02-11 |
EP1625155B1 (en) | 2012-08-29 |
JP4611979B2 (ja) | 2011-01-12 |
KR20060028676A (ko) | 2006-03-31 |
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