CN104245721A - 抗微生物肽 - Google Patents
抗微生物肽 Download PDFInfo
- Publication number
- CN104245721A CN104245721A CN201380012350.3A CN201380012350A CN104245721A CN 104245721 A CN104245721 A CN 104245721A CN 201380012350 A CN201380012350 A CN 201380012350A CN 104245721 A CN104245721 A CN 104245721A
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- peptide
- amino acid
- microorganism
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Abstract
本发明涉及新的抗微生物肽,其具有至少8个连续的氨基酸,其中所述肽具有下式的序列:Ter1-X1-B1-X2-B2-X3-Z1-Z2-X4-Ter2。此外,所述肽也可具有经修饰的末端。该肽有效用于治疗或预防由微生物,如细菌和真菌引起的炎性和感染性疾病。
Description
本发明涉及新的抗微生物肽及其在医药中的用途。
抗微生物肽,也简称为"AMP",是先天免疫系统的一部分,并且对于防止微生物感染的上皮防御至关重要。
在健康人中,皮肤和黏膜形成防止微生物感染的物理屏障。该物理屏障在健康皮肤中由角质层构成,在粘膜中由粘液层构成,其中脱屑和粘膜分泌导致表面不断更新,并且同时导致附着在表面上的微生物的连续消除。该物理屏障与此外存在于皮肤中的脂质相互协作,防止微生物渗透到活的表皮中。
但是,除该物理屏障而外,对于健康皮肤和粘膜的有效的感染防御而言还有其他的因素是必需的,尤其包括内生性抗微生物肽。例如,溶菌酶是一种存在于鼻腔分泌物中的抗微生物肽,并且其尤其可以杀死革兰氏阳性菌。此外,已知在肠粘膜中防御素为抗微生物肽,尤其是在肠上皮(Darmepitelien)暴露于非常大量的细菌的背景下它们的存在似乎是必要的。除了对于微生物而言难于透过的粘液层而外,在肠道的粘膜中发现帕内特细胞,其分泌人防御素-5并且此外还保护干细胞,这对于肠粘膜的持续再生是重要的。
此外已知的AMP是作为牛皮癣素(Psoriasin)已知的肽,以及RNase-7,其是有效的人类内生性广谱抗生素。
除了已知的内生性抗微生物肽而外,在现有技术中此外还已知大量抗生素,其中包括生物来源的物质和合成制备的物质,即,它们是 - 如在最初意义上的 - 天然形成的真菌或细菌的低分子量代谢产物或者化学合成药物。
尤其是在对天然和合成抗生素的抗性的发展使得治疗微生物感染性疾病日益困难的背景下,总是存在对新的以副作用少、易于制备和施用为特点的抗微生物活性物质的需求。
在此背景下,本发明的目的是提供新的抗微生物物质,其可以用于治疗微生物感染性疾病。
根据本发明,所述目的通过具有抗微生物活性和具有C-端和N-端的肽得以实现,并且所述肽由至少8个和最多12个连续的氨基酸构成,其中所述肽具有下式I的序列:
Ter1-X1-B1-X2-B2-X3-Z1-Z2-X4-Ter2,
(式I)
其中
Ter1是N-端氨基酸X1的游离N-端氨基基团,或者是经修饰的N-端氨基基团;
X1、X2和X3各自相同或不同,并且彼此独立地各自选自具有碱性侧链的氨基酸,优选选自下述之一:精氨酸、赖氨酸、6-羟基赖氨酸、高精氨酸、2,4-二氨基丁酸、[β]-高精氨酸、D-精氨酸、精氨醛、2-氨基-3-胍基丙酸、硝基精氨酸、N-甲基-精氨酸、[ε]-N-甲基赖氨酸、别羟基赖氨酸、2,3-二氨基丙酸、2,2'-二氨基庚二酸、鸟氨酸、对称性二甲基精氨酸、不对称性二甲基精氨酸,
B1和B2相同或不同,并且各自彼此独立地各自选自具有脂族侧链或碱性侧链的氨基酸,并且优选选自丙氨酸或甘氨酸,
Z1和Z2各自是半胱氨酸,或者是半胱氨酸和丙氨酸,和
Ter2是C-端氨基酸X4的游离C-端羧基基团,或者是经修饰的C-端羧基基团。
在此优选的是该肽由8个氨基酸构成,并且具有式I的序列。
Z1和Z2,如已提及的,在此各自是半胱氨酸,或者是半胱氨酸和丙氨酸,即当Z1是半胱氨酸时,Z2是丙氨酸,而当Z1是丙氨酸时,Z2是半胱氨酸。
在此,所述肽优选合成制备、重组制备、通过酶切制得和/或分离。因为根据本发明的肽是相对短的肽,所以根据本发明的肽优选是合成制备的;合成制备方法在现有技术中充分已知,并且尤其包括液相和固相化学合成方法。示例性可参阅综述文章/权威著作Kent, S., „Chemical
Synthesis of Peptides and Proteins", Annual Review of Biochemistry
57:957-989 (1988)。相关领域中,许多企业目前正从事商业制备合成肽。
除了式I的八个氨基酸而外,在本发明的肽中,在N-端和C-端还可具有另外的氨基酸,其没有损害或仅略微损害本发明的肽的效果和稳定性;本领域技术人员基于本发明的肽的结构清楚知晓,在C-端和N-端上还可附加何种氨基酸或氨基酸残基,以能够获得与由8个氨基酸构成的肽相同或者非常相似的抗微生物作用。
在发明人自己的实验中已证实,根据本发明的肽对一系列的细菌菌株和真菌菌株非常有效。
在此,将术语“肽”理解为是指各自经由肽键彼此连接的氨基酸的序列,其中所述氨基酸优选选自二十种天然存在的氨基酸,并且其中所述氨基酸可以以L-构型或D-构型存在。替代该肽和由其作用方式和结构出发也可制备肽模拟物,因此根据本发明其也包括在本发明中。肽模拟物在本文中定义为低分子量化学化合物,其主要结构元件是按本发明的肽仿造的。根据本发明的肽在此可以例如,分离、合成或重组存在,或以合适的形式提供。
在这里,将术语“抗微生物”理解为能够减少微生物的增殖能力或者感染性,或将其杀死或使其失活的性能。在此将“微生物”理解为小得用显微镜才能看见的生物体或单位,其大都不可为肉眼所见,并且其中在此尤其理解为细菌、病毒和真菌,它们在其他生物体,特别是人类或者其他哺乳动物中引发有害健康的过程(疾病)。
根据一个优选的实施方案,根据本发明的肽在此选自SEQ ID No.1-6或其衍生物中的一个,其中所述衍生物是通过至少一个氨基酸被所述氨基酸的衍生物取代而形成的。在此特别优选下述肽:具有序列RGKAKCCK
(SEQ ID No.1)的肽,具有序列RGKAKCAK (SEQ ID No.2)的肽和具有序列RGKAKACK (SEQ ID No.3)的肽,更确切地说以未修饰的形式,即具有未经修饰的端位或者以经修饰的形式,即具有至少一个经修饰的(C-或者N-)端或者以具有经修饰的N-端和经修饰的C-端的经修饰的形式(参见SEQ ID No. 4、5和6)。
在此将术语“氨基酸的衍生物”理解为衍生自各氨基酸的所有氨基酸残基,其例如通过官能团的结构变化由各自的氨基酸得到。
在此将术语“经修饰的N-端氨基基团”和“经修饰的C-端羧基基团”理解为改变的氨基基团或者羧基基团。N-端修饰的实例为乙酰化、甲酰化或者脒基化的N-端。C-端修饰的实例为酰胺化的C-端。
在此特别优选所述肽在各个情况下全部由D-氨基酸或L-氨基酸或者它们的混合物构成。在此,“D-氨基酸”或者“L-氨基酸-”意味着待使用的天然氨基酸、非天然氨基酸或氨基酸衍生物(如亚氨基酸)可以以L-或D-构型存在。
根据另一实施方式,优选在C-端和/或在N-端修饰所述肽,并且尤其通过乙酰化、酰胺化、甲酰化或脒基化来修饰。
本发明的肽的C-端和/或N-端的修饰具有使它们由此对肽酶和蛋白酶的降解更稳定的优点;由此,根据本发明的肽具有在例如血清中增加的半衰期。N-端和C-端的修饰也允许所述肽偶联到其他基团,例如其他氨基酸序列或者其他生物分子上。
在根据本发明的肽的另一实施方案中,所述肽被还原或以氧化态存在。
根据本发明,所述肽用于治疗和/或预防由微生物引发的炎性疾病或感染性疾病。
因此,根据本发明,所述应用在由细菌、病毒或者真菌引发的炎性疾病和/或感染性疾病中进行。
根据本发明的应用尤其在由选自下述的微生物引发的炎性疾病或感染性疾病中进行:双歧杆菌属种(Bifidobacterium sp.)、乳杆菌属种(Lactobacillus sp.)、大肠杆菌、链球菌属种(Streptococcus sp.)、葡萄球菌属种(Staphylococcus sp.)、拟杆菌属种(Bacteroides sp.)、假丝酵母菌属种(Candida sp.)、假单胞菌属种(Pseudomonas sp.)、丙酸杆菌属种(Propionibakterium sp.)、密螺旋体属种(Treponema sp.)、肠杆菌属种(Enterobacter sp.)、沙门氏菌属种(Salmonella sp.)、军团菌属种(Legionella sp.),其中不言而喻,此列举并未穷尽,所述肽也对未列出于此的细菌菌株和/或真菌菌株有效,特别是对通常属于奈瑟氏菌科、肠杆菌科的细菌有效。
特别优选在慢性炎症性肠疾病、口腔-咽腔的炎症性疾病,例如龋齿和牙龈炎症,肺病、泌尿生殖道疾病、胰腺疾病、女性生殖系统疾病、皮肤的疾病和/或损伤(皮肤病)中使用本发明的肽。
相应地,本发明也涉及含有至少一种根据本发明的肽以及任选的药学上可接受的载体和另外的在现有技术中常见的制剂物质和助剂的药物组合物,和涉及治疗罹患由微生物引起的炎症性感染性疾病的哺乳动物的方法,其中施用治疗有效量的本发明的肽或者本发明的药物组合物。在这里,“治疗有效”或者“治疗有效量”是指能够减少或完全防止细菌和/或真菌增殖和菌落形成或者能够实现可测量的治疗或预防成效的至少一种根据本发明的肽或者含至少一种根据本发明的肽的药物组合物的量。患者的确切有效量取决于其大小和健康状况、疾病的性质和程度以及所述至少一种肽或者所述药物组合物或者多个上述提及因素的组合。
本发明的制剂/药物可在体外或者体内使用。
本发明的药物组合物可以适应于所选择的给药途径,即肠胃外、口服、腹膜内、经皮等以多种形式向患者给药。肠胃外给药在此包括下述途径的给药:静脉内、肌肉内、间质内、动脉内、皮下、滑膜内、经上皮,包括经皮、通过吸入经肺、眼、舌下和颊,局部包括眼、真皮、眼、直肠和通过吹入法经鼻吸入。
所述给药可以以溶液、酊剂、膏剂、粉剂、悬浮剂、乳剂、以及其他固体或者液体制剂的形式和作为片剂、胶囊剂、喷雾给药。
可用本发明的肽或者含有本发明的肽的药物治疗的皮肤疾病包括例如痤疮、皮炎、烧伤和其他由微生物引起的皮肤疾病,或在存在微生物感染危险的皮肤损伤的情况中。
根据一个优选的实施方案,所述药物组合物通过或经由皮肤给药,这是非侵入性的患者友好的给药,并且与口服给药相比,具有不必注意消化系统中的介质的优点。通过皮肤的吸收,例如,在鼻、颊中,在舌下、在牙龈上或者在阴道内是可行的。可以用已知的技术来获得合适的剂型;它们可以被加工成滴鼻剂、鼻喷雾剂、填充物(Einlagen)、薄膜剂、贴剂、凝胶剂、栓剂、软膏剂或者片剂。优选地,用于经皮肤吸收的赋形剂包含一种或多种附着在皮肤上并由此延长该剂型与吸收表面的接触时间的组分,以由此提高通过吸收的摄取。因此,可将所述至少一种根据本发明的肽配制成例如有利于所述肽进入皮肤中的脂质体。
此外,根据本发明的肽可用于治疗口腔-咽腔的疾病,并且可以在这样的应用中以牙膏、漱口水、凝胶剂的形式存在,和/或例如存在于牙线上。
所述药物组合物,如前已述及的,除了所述至少一种根据本发明的肽而外还可包含两种或多种根据本发明的肽。此外,所述药物组合物除了所述至少一种根据本发明的肽而外还可包含一种或多种其它活性物质,例如现有技术中已知的抗生素(例如链霉素、青霉素、四环素)或者其他抗微生物活性化合物如杀真菌剂,例如咪康唑,或者用于治疗通常伴随感染出现的症状(例如发烧或皮疹)的其他物质。
此外,所述药物也可含有药学上可接受的载体、粘合剂、赋形剂或助剂。药物载体、赋形剂或者稀释剂的选择可以考虑预期的给药途径和标准化的制药实践进行。作为药学上可接受的载体可以使用溶剂、增容剂或其它液体粘合剂如分散助剂或者混悬助剂,表面活性剂、等渗剂、增稠剂或者乳化剂、防腐剂、包衣剂(包封剂)、固体粘合剂或者润滑剂,取决于对于各自的剂量而言何种是最适合的且同时与所述肽相容。该药物组合物也还可以包含缓冲剂、稀释剂和/或添加剂。合适的缓冲剂包括例如Tris-HCl、甘氨酸和磷酸盐,而合适的稀释剂包括例如NaCl-水溶液、乳糖或甘露醇。合适的添加剂包括例如清洁剂、溶剂、抗氧化剂和防腐剂和保护胶体,例如,同源白蛋白或者生物相容的水凝胶。关于这些附加内容物的综述可见于例如A. Kibbe:“Handbook of
Pharmaceutical Excipients", 第3版, 2000, American
Pharmaceutical Association and Pharmaceutical Press。
此外,根据本发明的药物组合物还可以具有药学上可接受的盐,例如无机酸的盐,如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐以及类似的;和有机酸的盐,如醋酸盐、丙酸盐、丙二酸盐、苯甲酸盐以及类似的。
一般而言,治疗有效日剂量为大概在0.01-50毫克/千克,优选0.1-20毫克/公斤待治疗的患者体重的范围。也如上面已经提到的,该药物可以以片剂或胶囊剂的形式提供,其可以单独地或者两种或者多种在同一时间给药。该药物还可以以缓释制剂的形式提供。
通常,医生将根据患者的年龄、体重和一般健康状况确定适合于某一患者的实际剂量。
根据应用,该药物可如下所述给药:通过吸入,以栓剂或者子宫托的形式,局部给药,作为溶液剂、洗剂、软膏剂、乳膏剂或者粉剂,使用皮肤贴剂,以任选含芳香性物质或着色剂的片剂或胶囊剂、酏剂,溶液剂或者混悬剂的形式口服。
除了用于治疗感染的治疗用途,所述至少一种根据本发明的肽还可以用于消毒剂或清洁剂中,其可用于表面或物体的消毒或清洁。另一应用领域是包装,在其中肽可粘合在包装材料上或者引入其中,或者作为易被微生物降解的其他材料的防腐剂。
除了在人用药品中的用途而外,根据本发明的肽也可以用于兽用药品。
本发明还涉及经分离的核酸分子,其序列编码根据本发明的肽,并尤其编码具有SEQ
ID No.1至6的肽,所述SEQ
ID No.1至6的肽代表根据本发明的抗微生物的,即抗细菌或抗真菌的肽,或者与控制其在宿主细胞中的表达的调节序列呈操作性连接的编码核酸。本发明的另一组成部分是转染或转化了上述核酸分子的宿主细胞。
另外的优点由以下的说明和附图体现。
应当理解的是,以上提及的和以下将要说明的特征不仅可在个给出的组合中使用,而且也可在其他的组合中使用或单独使用,而未脱离本发明的范围。
附图中示出本发明的实施例,并且在下面的说明中进行了详细解释。其中:
图1 示出了各种肽(七肽(a);八肽(b) (c))对细菌青春双歧杆菌(Bifidobacterium adolescentis)或大肠杆菌的抗微生物活性的研究结果。字母以单字母代码给出氨基酸。肽ac-RGKAKCCK-NH2 (c) (SEQ ID No.4) 具有乙酰化的氨基末端和酰胺化的羧基末端。抑制区的直径代表抗微生物活性;在这里,在琼脂板中仅含有载体液体(阴性对照)的一个空白冲孔的直径为2.5毫米的直径。该实验至少重复三次,并示出平均值+标准偏差;
图2示出根据本发明的肽作为对抗不同病原体的抗生素的多种实施方式的检验:检验了下列肽:改性八肽(SEQ
ID No. 4),野生型八肽(SEQ ID No.1),丙氨酸-突变的八肽(SEQ ID No.7)和七肽(SEQ ID No.8)(各50μg/ ml)分别在流式细胞术-抗微生物效果实验中对大肠杆菌、金黄色葡萄球菌、白色念珠菌和脆弱拟杆菌进行测试。字母再次以单字母代码表示各氨基酸。将实验一式两份重复两次,示出平均值+标准偏差表示;
图3示出由D-氨基酸构成的根据本发明的八肽相较于由L-氨基酸构成的八肽对大肠杆菌K12 (a)和青春双歧杆菌(b)的检验结果;
图4示出在径向扩散试验中不同的根据本发明的八肽对抗病原性细菌和真菌的活性的进一步检验的结果;和
图5示出八肽对肠细胞系CaCo-2的细胞毒性的检验结果。
如前所述,几乎所有的生物体均产生抗微生物肽(AMP),并且抗微生物肽(AMP)是对抗微生物感染的第一屏障。许多AMP具有抗革兰氏阳性细菌和抗革兰氏阴性细菌、以及抗真菌和一些带有外壳的病毒的抗微生物活性。人体产生不同类别的AMP,其中如前已述及的防御素既是其中之一。它们以其微小的尺寸(3-5 kDa)、净阳离子电荷和6个保存的半胱氨酸残基为特点,所述半胱氨酸残基经由三个二硫桥键彼此相连。根据这些桥键的连接将防御素划分为α-和β-防御素。迄今为止,仅功能性研究了四种β-防御素(hBD-1 至hBD-4),尤其也作为有抗生素效果的候选。
但是,迄今,如前所述,具有3个天然二硫桥键的β-防御素的化学合成在其制备方法的成本和复杂性方面均是巨大的挑战。
由本发明首次提供的肽是一种防御素hBD-1的C-端末端的八肽,其包含两个游离的半胱氨酸,并且其以其抗微生物活性证实为相较于hBD-1出色的以及更短的得自hBD-1的C-末端的肽序列,如下文中提及的实验所示。
细菌-和真菌菌株
由Ardeypharm(德国)得到细菌菌株青春双歧杆菌Ni3, 29c(临床分离),短双歧杆菌(Bifidobacterium breve)PZ1343,长双歧杆菌(Bifidobacterium longum)DSM20219T(临床分离),嗜酸乳杆菌(Lactobacillus
acidophilus)PZ1138(临床分离),发酵乳杆菌(Lactobacillus fermentum)PZ1162(临床分离)和唾液链球菌嗜热亚种(Streptococcus
salivarius spp. termophilus)DSM20617,并且由DSMZ(德国微生物和细胞生产收藏中心)购得普通拟杆菌(Bacteroides vulgatus)DSM1447。从粪便中分离出白色念珠菌(Candida albicans)菌株526,并由Eichert医学院,检验医学研究所(Göppingen,德国)提供。 “美国典型培养物保藏中心(ATCC)的对照菌株大肠杆菌ATCC25922,金黄色葡萄球菌ATCC25923和脆弱拟杆菌(Bacteroides fragilis)ATCC25285由Eichert医学院,检验医学研究所(Göppingen,德国)提供。此外,测试菌株粪肠球菌(Enterococcus faecalis)ATCC29212,白色念珠菌ATCFC为10231和铜绿假单胞菌(Pseudomonas aeruginosa)ATCC27853,它们在给出的ATCC编号下,在美国典型培养物保藏中心得到。
肽
人β-防御素得自肽研究所,Osaka,
日本;化学合成羧基-末端的七肽和八肽以及还原的 hBD-1 (EMC Micro Collections Tübingen, 德国)。
抗微生物实验
如先前所述般进行厌氧细菌的抗微生物径向扩散实验(参见Schröder等人"Reduction of disulfide bonds unmasks potent
antimicrobial activity of human beta-defensin
1", Nature, 469: 419-423 (2011))。简言之,厌氧培养所述细菌(Oxoid AnaeroGen™,英国),更确切地说在37℃下在哥伦比亚-琼脂板上厌氧培养24小时,随后接种到液体TSB(“胰蛋白胨大豆肉汤”)培养基中,并再培养24小时。接着,洗涤该细菌培养物并稀释到光密度(OD620 nm)= 0.1,其中使用150μl用于效果测定。温育在10毫升pH为7.4的10mM磷酸钠中进行,其具有0.3毫克/毫升的TSB粉末和具有0或2 mM二硫苏糖醇(DTT, Sigma Aldrich)的1%(w/v)低EEO-琼脂糖(具有非常低的EEO-值的琼脂糖)(Appli-Chem),更确切地说在厌氧条件下,用1μg合成的氧化hBD-1(肽研究所,日本)或者合成肽进行超过3小时。在该板上提供覆盖凝胶,所述覆盖凝胶带有6% (w/v) TSB-粉末、1%琼脂糖和10mM磷酸钠缓冲液(pH-值7.4或5.7),其带有或没有DTT。在37℃下温育48小时后,测量抑制区的直径。该实验至少重复三次。
如前所述进行用于测定细菌和真菌的膜去极化的流式细胞术抗微生物实验(参见Nuding等人的“A flow cytometric assay to
monitor antimicrobiol activity of defensines
and cationic tissue extracts", Journal of Microbiological Methods, 65:
335-380 (2006))。简言之,在1:6稀释的 Schaedler-培养基中于37℃用肽以50μl的最终体积温育1.5×106个细胞/ml。将所述防御素溶解于0.01%的乙酸中,并用给定的最终浓度加入到细菌-/真菌-悬液液中。用溶剂(0.01%乙酸)温育的细菌-或真菌-悬浮液在此充当生活力对照。90分钟后,用1毫克/毫升的膜电位敏感染料DiBAC4(3)([双(1,3-二丁基巴比妥酸酯)三甲烷氧杂菁])(Invitrogen,美国)温育该悬浮液10分钟。将悬浮液离心,并将沉淀重新悬浮在300毫升的磷酸盐缓冲盐水中。借助FACSCalibur-流式细胞仪(Becton-Dickinson,美国),使用Cell
Quest软件(Becton-Dickinson)测定悬浮液中偶极化的荧光细菌或者真菌的百分比。将该实验重复两次,并且各次一式两份。
HPLC-
分析
为用HPLC(“高效液相色谱法)分析,将所述八肽与0.1%(v/ v)的三氟乙酸(TFA)混合并用Agilent1200系统(Agilent)和“Synergi
reversed phase”(RP)柱(250 x
4,6 mm, 4 μm, Phenomenex,
德国)分析。在25℃和0.8毫升/分钟下,梯度经24分钟从0%B升至12%B,(溶剂A,水+0.18%(v/ v)TFA;溶剂B,乙腈+0.15%(v/ v)TFA)。
离子
-
抑制实验
在室温下,用4.5 mM NaCl, 氯化镁MgCl2,
氯化铁FeCl2, 氯化锌ZnCl2或者硫酸锌ZnSO4
温育0.25 μg/ml所述肽或防御素45 min。随后,在径向扩散实验中分析该混合物对青春双歧杆菌和大肠杆菌的抗微生物活性。该实验重复至少3次。
结果
最近,Schröder等人("Reduction of disulfid
bonds unmasks potent antimicrobial activity of human beta-defensine
1", Nature, 469: 419-423 (2011))发现,人β-防御素1在还原条件下表现出提高的抗微生物活性。
当前已进一步研究了hBD-1及其抗微生物活性。为此测试了三种人β-防御素hBD-1、2和3对人肠内菌群的共生细菌的抗微生物活性,即在标准条件(pH
7.4)和微酸性条件(pH5.7)下,其中在这两个条件下也测试还原条件,在所述还原条件中向生长培养基中添加2mM的化学还原剂二硫苏糖醇(DTT)。在此表明(数据未显示),在大部分细菌的情况中,所述β-防御素的活性在标准条件下是最高的,例外的是hBD-1,其在此条件下在很大程度上无活性,并且通过还原激活。然而,在pH值5.7的情况中不能观察到该活化。与此相反,已证实hBD-2不会受还原影响,相反pH-值的变化对其抗微生物活性具有非常负面的影响。
在大多数情况中,hBD-3相较于另外两种防御素对测试的共生菌具有最强的活性。
总之,可以说周围环境的因素,例如氧化还原电位和pH-值,可调制β-防御素对共生肠细菌的抗微生物活性。然而,这种调制对于各个防御素 -细菌-关系而言是特异性的,并且与细菌的革兰氏状态或者菌属均不相关。
用已经表现出对青春双歧杆菌的抗微生物活性的代表hBD-1的七个末端氨基酸的七肽进行的实验表明,野生型的羧基末端的七肽具有对青春双歧杆菌的最高活性,而具有相反的氨基酸序列的肽活性较低。通过用丙氨酸置换半胱氨酸残基完全抑制活性。hBD-1的孤立的氨基端是无活性的。
在此,测试作为下一个的根据本发明的肽,包含hBD-1的羧基末端的八个末端氨基酸的八肽:其表现出比之前测试的七肽更强的抗微生物活性(参见图1)。如果置换Cys6或Cys7,对青春双歧杆菌的活性大大降低,即以相同的程度,而置换两个半胱氨酸使活性完全停顿。与先前测试的七肽相反,八肽对大肠杆菌也具有抗微生物活性(参见图1b)。令人惊讶地,在此通过丙氨酸置换Cys6或Cys7提高了抗微生物活性,而置换两个半胱氨酸又几乎使抗微生物活性完全消失。
为了优化所述八肽和改善其对蛋白酶的稳定性,在随后的步骤中通过乙酰化稳定所述八肽的氨基末端,并且用酰胺化稳定羧基末端。相较于野生型肽,对大肠杆菌的活性没有显著区别,而对青春双歧杆菌的活性则大大提高(参见图1c)。
借助该新确定并提供的八肽可以提供简单经济地制造的具有抗菌效果的肽,其可以用作治疗药剂。因此研究了经修饰和未经修饰的肽杀灭(机会)病原微生物的能力。为此进行流式细胞术分析,(参见图2),由其表明,野生型八肽以及丙氨酸-突变肽和野生型七肽的作用在大多数情况中仅在边缘。与此相反,经修饰的八肽具有出色的抗病原微生物金黄色葡萄球菌和白色念珠菌的活性,但对大肠杆菌和脆弱类杆菌却没有。
由此表明,通过稳定化端基不仅提高了对共生肠细菌青春双歧杆菌的抗微生物活性,而且提高了对临床相关的至少两种病原微生物的抗微生物活性。
在进一步的实验中进行反相HPLC分析,以研究测试的肽的疏水性(数据未示出)。所述经修饰的八肽作为最后的物质从柱中洗脱出来,这表明疏水性最大;在其之前洗脱出野生型肽、各丙氨酸-氨基酸-置换变体和双丙氨酸-氨基酸置换变体(数据未示出)。
为了进一步研究电荷和离子相互作用的作用,用一价和二价阳离子温育经氧化的和经还原的hBD-1和野生型和经修饰的八肽(数据未示出)。就大肠杆菌而言,整个防御素的活性通过用氯化镁或氯化铁预温育完全关闭,而羧基末端肽的活性被大大抑制,但用这些金属离子预温育后尚能检测到。与此相反,NaCl不影响对大肠杆菌的抗微生物活性。
在研究青春双歧杆菌时再次证实,用氯化钠预温育对活性没有强烈影响,而氯化铁、氯化锌和硫酸锌却完全关闭或大大降低活性。不同于大肠杆菌,用氯化镁温育不影响对双歧杆菌的抗菌活性。
在进一步的实验中研究由除甘氨酸以外的D-氨基酸构成的具有序列RGKAKCCK(SEQ ID No.1)的本发明的八肽-与由L-氨基酸构成的具有序列RGKAKCCK(SEQ ID No.1)的八肽,也就是说具有经修饰的或未经修饰的末端(图3)相比较。由D-氨基酸构成的具有经修饰的末端的肽(N-端:乙酰化;C-端:酰胺化)对大肠杆菌K12表现出较弱的活性(参见图3a),而这种肽,以未经修饰的形式和经修饰的形式,对青春双歧杆菌表现出相较于由L-氨基酸构成的肽升高的活性(参见图3b)。
因此这些数据总体上也表明,在肽和阳离子之间的相互作用不仅基于正电荷,而且更确切地说特定的离子能影响对某些细菌的活性。
本发明的八肽抗病原细菌和真菌的活性也在另外的径向扩散实验中得以证实:测试了对菌株大肠杆菌25922、金黄色葡萄球菌25923、粪肠球菌29212、白色念珠菌10231和铜绿假单胞菌27853的活性(参见图4),其中一方面使用由L-氨基酸构成的(参见图4;图中左侧的五个条柱)或由除甘氨酸以外的D-氨基酸构成的(参见图4,图中右侧的五个条柱)具有序列RGKAKCCK(SEQ
ID No.1)的本发明的八肽,也就是说各自一次具有经修饰的和一次具有未经修饰的末端(N-端:乙酰化;C-端:酰胺化)。在此,除了出色的对大肠杆菌和金黄色葡萄球菌的活性而外,尤其也显示出测试的八肽的所有变体对白色念珠菌的出色活性。
该进一步的MTT-((3-[4,5-二甲基噻唑-2-基]-2,5-二苯基四唑鎓溴化物;噻唑蓝)实验中还研究了末端稳定化的八肽的细胞毒性,更确切地说随增加的各八肽(SEQ ID no. 1;L-或D-氨基酸(除甘氨酸外),具有经修饰的末端:N-端:乙酰化,和C-端:酰胺化)的浓度,相较于增加的0.01%醋酸的浓度对人细胞系CaCo-2
(ATCC HTB-37)的细胞毒性。对此的结果示于图5中,由其表明,稳定化的八肽不具有超过溶剂0.01%醋酸的细胞毒性。因此,本发明的八肽也适合用于治疗应用中。
但是,上述结果和数据清楚表明,在此首次提供的八肽,即以野生型-形式,与氨基酸置换,和/或以稳定化的形式,是出色的具有抗菌效果的药剂。这些结果是令人惊讶的,并且基于迄今可用的现有技术是不可预期的。
序列表
<110> Robert Bosch GmbH
<120> 抗微生物肽
<130> R. 342354
<160> 12
<170> PatentIn version 3.3
<210> 1
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成制备的肽,包含hBD-1的C-端的序列
<400> 1
Arg Gly Lys Ala Lys Cys Cys Lys
1 5
<210> 2
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的具有抗微生物活性的肽
<400> 2
Arg Gly Lys Ala Lys Cys Ala Lys
1 5
<210> 3
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的具有抗微生物活性的肽
<400> 3
Arg Gly Lys Ala Lys Ala Cys Lys
1 5
<210> 4
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 具有经修饰的末端的合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 乙酰化
<220>
<221> MOD_RES
<222> (8)..(8)
<223> 酰胺化
<400> 4
Arg Gly Lys Ala Lys Cys Cys Lys
1 5
<210> 5
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 具有经修饰的末端的合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 乙酰化
<220>
<221> MOD_RES
<222> (8)..(8)
<223> 酰胺化
<400> 5
Arg Gly Lys Ala Lys Cys Ala Lys
1 5
<210> 6
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 具有经修饰的末端的合成的肽
<220>
<221> MOD_RES
<222> (1)..(1)
<223> 乙酰化
<220>
<221> MOD_RES
<222> (8)..(8)
<223> 酰胺化
<400> 6
Arg Gly Lys Ala Lys Ala Cys Lys
1 5
<210> 7
<211> 8
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 7
Arg Gly Lys Ala Lys Ala Ala Lys
1 5
<210> 8
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 8
Gly Lys Ala Lys Cys Cys Lys
1 5
<210> 9
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 9
Gly Lys Ala Lys Ala Ala Lys
1 5
<210> 10
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 10
Lys Cys Cys Lys Ala Lys Gly
1 5
<210> 11
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 11
Cys Lys Lys Cys Lys Ala Gly
1 5
<210> 12
<211> 7
<212> PRT
<213> 人工序列
<220>
<223> 合成的肽
<400> 12
Asp His Tyr Asn Cys Val Ser
1 5
Claims (12)
1.肽或其衍生物,其具有抗微生物活性,并且具有C-端和N-端,并且其由至少8个和最多12个连续的氨基酸构成,其中所述肽具有下式I的序列:
Ter1-X1-B1-X2-B2-X3-Z1-Z2-X4-Ter2,
(式I)
其中
Ter1是N-端氨基酸X1的游离N-端氨基基团,或者是经修饰的N-端氨基基团;
X1、X2和X3各自相同或不同并且彼此独立地各自选自具有碱性侧链的氨基酸,优选选自下述之一:精氨酸、赖氨酸、6-羟基赖氨酸、高精氨酸、2,4-二氨基丁酸、[β]-高精氨酸、D-精氨酸、精氨醛、2-氨基-3-胍基丙酸、硝基精氨酸、N-甲基-精氨酸、[ε]-N-甲基赖氨酸、别羟基赖氨酸、2,3-二氨基丙酸、2,2'-二氨基庚二酸、鸟氨酸、对称性二甲基精氨酸、不对称性二甲基精氨酸,
B1和B2相同或不同,并且各为具有脂族侧链或碱性侧链的氨基酸,并且优选选自丙氨酸或甘氨酸,
Z1和Z2各自是半胱氨酸,或者是半胱氨酸和丙氨酸,和
Ter2是C-端氨基酸X4的游离C-端羧基基团,或者是经修饰的C-端羧基基团。
2.根据权利要求1的肽,其特征在于,所述肽由8个连续的氨基酸构成,并且所述肽具有式I的序列。
3.根据权利要求1或2的肽或其衍生物,其特征在于,所述肽选自SEQ ID No.1-6或其衍生物之一,其中所述衍生物是通过至少一个氨基酸被所述氨基酸的衍生物取代形成的。
4.根据权利要求1-3任一项的肽,其特征在于,其由D-或L-氨基酸或者它们的混合物构成。
5.根据权利要求1-4任一项的肽,其特征在于,所述肽在C-端和/或N-端被乙酰化、酰胺化、甲酰化、磷酸化修饰。
6.根据权利要求1-5任一项的肽作为抗生素和/或在消毒剂或清洁剂中的用途。
7.根据权利要求6的用途,其用于治疗和/或预防由微生物引发的炎性疾病或感染性疾病。
8.根据权利要求7的用途,其特征在于,所述炎性疾病或感染性疾病由微生物引起,所述微生物是细菌、病毒或者酵母菌。
9.根据权利要求6-8任一项的用途,其特征在于,所述炎性疾病或感染性疾病由微生物引起,所述微生物选自双歧杆菌属种(Bifidobacterium sp.)、乳杆菌属种(Lactobacillus sp.)、大肠杆菌、链球菌属种(Streptococcus sp.)、葡萄球菌属种(Staphylococcus sp.)、拟杆菌属种(Bacteroides sp.)、假丝酵母菌属种(Candida sp.)、假单胞菌属种(Pseudomonas sp.)、丙酸杆菌属种(Propionibakterium sp.)、密螺旋体属种(Treponema sp.)。
10.根据权利要求6-9任一项的用途,其特征在于,所述炎性疾病或感染性疾病选自慢性炎性肠道疾病、口腔/咽腔的炎性疾病、肺病、泌尿生殖道的疾病、胰腺疾病、女性生殖系统的疾病、皮肤的疾病或损伤或烧伤。
11.药物组合物,其包含至少一种根据权利要求1-5任一项的肽和药学上可接受的载体。
12.多核苷酸,其编码根据权利要求1-5任一项的肽。
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CA (1) | CA2866520C (zh) |
CL (1) | CL2014002180A1 (zh) |
DE (1) | DE102012203547A1 (zh) |
MX (1) | MX359084B (zh) |
RU (1) | RU2660351C2 (zh) |
WO (1) | WO2013132005A1 (zh) |
Cited By (1)
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CN109311939A (zh) * | 2016-06-14 | 2019-02-05 | 赛德玛公司 | 肽、包含所述肽的组合物及其用途、尤其是化妆品用途 |
Families Citing this family (6)
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DE102012203547A1 (de) * | 2012-03-07 | 2013-09-12 | Robert Bosch Gesellschaft Für Medizinische Forschung Mbh | Antimikrobielle Peptide |
KR101804847B1 (ko) | 2014-10-27 | 2017-12-07 | 경희대학교 산학협력단 | 항균 펩타이드 헥사머를 포함하는 구강 질환 예방 및 치료용 약학적 조성물 및 이의 용도 |
EP3317294B1 (en) | 2015-07-02 | 2023-03-15 | Dana-Farber Cancer Institute, Inc. | Stabilized anti-microbial peptides |
AU2017228333C1 (en) | 2016-02-29 | 2022-03-10 | Dana-Farber Cancer Institute, Inc. | Stapled intracellular-targeting antimicrobial peptides to treat infection |
AU2018304230A1 (en) | 2017-07-19 | 2020-02-06 | Dana-Farber Cancer Institute, Inc. | Stabilized anti-microbial peptides for the treatment of antibiotic-resistant bacterial infections |
KR102558956B1 (ko) * | 2019-12-30 | 2023-07-24 | 주식회사 아이젤 | 양친매성 펩타이드 및 이를 포함하는 항균용 또는 항염증용 조성물 |
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CN101528248A (zh) * | 2006-07-10 | 2009-09-09 | 奥地利科学院 | 抗微生物肽 |
US8071285B1 (en) * | 2003-05-14 | 2011-12-06 | Carl Henry Lawyer | Zinc finger protein derivatives and methods of using same |
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BR0014740A (pt) * | 1999-10-12 | 2002-06-18 | Blis Technologies Ltd | Lantibiótico |
AU2003215257A1 (en) * | 2002-02-19 | 2003-09-09 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of | Modified defensins and their use |
CN1183960C (zh) * | 2003-02-27 | 2005-01-12 | 四川大学 | 双歧杆菌细胞壁蛋白在制药中的应用 |
KR20090111307A (ko) * | 2006-07-03 | 2009-10-26 | 엑손히트 써라퓨틱스 에스에이 | 전립선 특이적 전사물 및 전립선암의 치료 및 진단에 사용되는 이의 용도 |
EP2077274A1 (en) * | 2008-01-02 | 2009-07-08 | Ceinge Biotecnologie Avanzate s.c. a r.l. | Synthetic analogs of human beta-defensins having antimicrobial, antiviral and chemotactic activity |
CN101959429B (zh) * | 2008-01-08 | 2014-09-10 | 阿克塞利亚制药公司 | 抗微生物肽系统的激动剂 |
US20090298707A1 (en) * | 2008-03-18 | 2009-12-03 | The Regents Of The University Of California | Sparse matrix system and method for identification of specific ligands or targets |
DE102010040153A1 (de) * | 2010-09-02 | 2012-03-08 | Robert Bosch Gesellschaft Für Medizinische Forschung Mbh | Stoffkombination zur Behandlung von entzündlichen oder infektiösen Erkrankungen |
DE102012203547A1 (de) * | 2012-03-07 | 2013-09-12 | Robert Bosch Gesellschaft Für Medizinische Forschung Mbh | Antimikrobielle Peptide |
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2012
- 2012-03-07 DE DE102012203547A patent/DE102012203547A1/de not_active Withdrawn
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- 2013-03-07 CN CN201380012350.3A patent/CN104245721A/zh active Pending
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- 2013-03-07 WO PCT/EP2013/054599 patent/WO2013132005A1/de active Application Filing
- 2013-03-07 EP EP13708150.1A patent/EP2822958B1/de active Active
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- 2013-03-07 CN CN201810643582.3A patent/CN108822201A/zh active Pending
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US8071285B1 (en) * | 2003-05-14 | 2011-12-06 | Carl Henry Lawyer | Zinc finger protein derivatives and methods of using same |
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---|---|---|---|---|
CN109311939A (zh) * | 2016-06-14 | 2019-02-05 | 赛德玛公司 | 肽、包含所述肽的组合物及其用途、尤其是化妆品用途 |
CN109311939B (zh) * | 2016-06-14 | 2022-10-04 | 赛德玛公司 | 肽、包含所述肽的组合物及其用途、尤其是化妆品用途 |
Also Published As
Publication number | Publication date |
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DE102012203547A1 (de) | 2013-09-12 |
MX2014010655A (es) | 2015-03-06 |
AU2013229486A1 (en) | 2014-10-23 |
JP2017148045A (ja) | 2017-08-31 |
EP2822958A1 (de) | 2015-01-14 |
JP6157514B2 (ja) | 2017-07-05 |
CA2866520A1 (en) | 2013-09-12 |
WO2013132005A1 (de) | 2013-09-12 |
KR20140142700A (ko) | 2014-12-12 |
RU2014140231A (ru) | 2016-04-27 |
CL2014002180A1 (es) | 2015-04-17 |
MX359084B (es) | 2018-09-03 |
CA2866520C (en) | 2019-05-21 |
JP2015510874A (ja) | 2015-04-13 |
AU2013229486B2 (en) | 2017-10-19 |
RU2660351C2 (ru) | 2018-07-05 |
US20150087579A1 (en) | 2015-03-26 |
CN108822201A (zh) | 2018-11-16 |
US20170073371A1 (en) | 2017-03-16 |
EP2822958B1 (de) | 2018-12-19 |
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