CN1161372C - 具有生物学活性的新肽 - Google Patents
具有生物学活性的新肽 Download PDFInfo
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- CN1161372C CN1161372C CNB998035041A CN99803504A CN1161372C CN 1161372 C CN1161372 C CN 1161372C CN B998035041 A CNB998035041 A CN B998035041A CN 99803504 A CN99803504 A CN 99803504A CN 1161372 C CN1161372 C CN 1161372C
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- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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Abstract
本发明涉及比常规的抗微生物肽活性更强或活性相同的肽，其在高盐浓度下具有强抗微生物活性。
Description
技术领域
本发明的肽具有比常规的抗微生物肽更强的活性，其在高盐浓度下具有这种活性。
背景技术
本发明涉及生物学活性肽。地球上的每个动物均具有生物防御系统以防御或保护其不受病毒或细菌的感染。这种系统之一是利用抗微生物肽的非特异性免疫。
由于下述杰出的性质，抗微生物肽被认为是一类新的药物。首先，抗微生物肽显示出比常规抗生素更强的抗广谱微生物的活性。第二，抗微生物肽具有有益于人体的高度工业实用性，因为抗微生物肽显示抗外来病原体而不破坏宿主细胞的抗微生物活性。第三，产生微生物抗性的可能性较小，因为抗微生物肽的活性机制与产生严重抗药性的常规抗生素的活性机制完全不同。对抗微生物肽的研究最初是在具有发育不全的免疫系统的一种昆虫中分离了杀菌肽。在首次发现杀菌肽之后，从两栖动物中发现了爪蟾抗菌肽和铃蟾抗菌肽，从哺乳动物中分离了防卫素。对抗微生物肽的研究很活跃，目前已鉴定和报道了来自从微生物到人的各种物种的约2000种抗微生物肽。
但是，开发作为药物的上述抗微生物肽有若干障碍。首先，常规抗微生物肽在相对较高浓度起作用。例如，从两栖动物表皮分离的抗微生物肽爪蟾抗菌肽虽然有效抗革兰氏阳性和革兰氏阴性细菌及真菌，但其活性浓度为50-200μg/ml(Zasloff M.(1987)美国科学院院刊84：5449-5453)。相对于常规抗生素在0.1-1μg/ml范围抗特异微生物，上述浓度范围非常高。第二，抗微生物肽的抗微生物活性对盐浓度敏感。在侵袭人肺部的囊性纤维化中，例如，抗微生物肽无效，因为在侵袭部位盐浓度异常增高(Goldman，M.J.等(1997)细胞，88：553-560)。本发明人在生物化学生物物理研究通讯218，408-413(1996)中报道了分离自韩国蟾蜍的抗微生物肽。这些已知称为buforin I和buforin II的抗微生物肽显示抗广谱微生物包括革兰氏阳性和革兰氏阴性细菌和真菌的强抗微生物活性。Buforin I和buforinII在1-4μg/ml浓度也有抗微生物活性，其比常规抗微生物肽的活性强。但是这些抗微生物肽也对盐浓度敏感。因此，仍需要开发具有增强的抗微生物活性并对盐浓度不敏感的在体内具有抗微生物活性的抗微生物肽。
发明描述
本发明的一个目的是提供新的生物学活性肽。
本发明的另一个目的是提供具有较强的抗微生物活性的抗广谱微生物的肽。
本发明的再一目的是提供对增强抗微生物活性的盐浓度不敏感的肽。
本发明的又一目的在于提供对增强抗微生物活性的盐浓度不敏感的肽的二级结构。
本发明的再一目的在于提供可以制备生物学活性肽的前体肽。
本发明的再一目的在于提供可编码生物学活性肽的cDNA。
附图简述
图1是在作为结构形成剂的50％三氟乙醇存在下由NMR光谱确定的buforin II的二级结构。
图2是显示作为盐浓度的函数的最小抑制浓度的曲线。
发明详述
本发明的肽包括具有两亲性α-螺旋结构的肽。
本发明的肽还包括具有改变的buforin II(生物化学生物物理研究通讯218，408-413(1996))二级结构的肽。
本发明人已示出buforin II的二级结构从N-末端开始包括一随机卷曲(1-4个残基)，延伸螺旋(5-10个残基)和正常α-螺旋(11-21个残基)结构。
在buforin II的结构中，具有正常α-螺旋结构(11-21个残基)的肽序列，即PVGRVHRLLRK具有强的抗微生物活性。本发明人已发现一种肽、特别是至少除去形成随机卷曲结构(1-4个残基)的序列的肽具有非常强的抗微生物活性。因此，本发明的一组肽由含有buforin II的α-螺旋结构的肽、特别是具有PVGRVHRLLRK序列的肽组成。这些形成α-螺旋的序列，例如序列PVGRVHRLLRK还可另外含有C-末端或N-末端额外氨基酸，优选在N-末端具有形成延伸螺旋或正常螺旋的氨基酸，在C-末端为酰胺化肽。
本发明的另一组肽包括具有重复单位[RLLR]n(n是1-6之间的整数)的肽(RLLR是在buforin II的氨基酸序列中发现的特异重复形式)，并优选n＝2-5的肽。
所述的肽还可包括C-末端或N-末端额外氨基酸，N-末端氨基酸可包括不形成随机卷曲的氨基酸，优选形成延伸螺旋的氨基酸。例如，这一组氨基酸序列包括RAGLQFPVG[RLLR]1、RAGLQFPVG[RLLR]2、RAGLQFPVG[RLLR]3、[RLLR]3、[RLLR]4、[RLLR]5等。
本发明的肽可用本领域熟知的技术合成，例如，用自动化肽合成仪或用遗传工程技术。例如，肽的产生可通过构建由融合配偶体和肽基因组成的融合基因，将其转化宿主微生物，在宿主中表达融合蛋白，用蛋白酶和化学制剂切割融合蛋白，并纯化抗微生物肽而进行。为此，例如，可将一DNA序列插入融合配偶体和肽基因之间以引入编码可被蛋白酶如因子Xa和肠激酶或被化学制剂如CNBr和羟胺切割的加工位点的序列。
为引入编码CNBr切割位点的DNA序列，例如，通过将在3′-末端消化的融合配偶体基因与识别序列含有Met密码子(ATG)的限制性内切酶连接，所述的酶如AflIII，BsmI，BspHI，BspLU11I，NcoI，NdeI，NsiI，Ppu10I，SphI，StyI或其同切点酶，以及将在其5′-末端消化的肽基因与具有与融合配偶体的切割位点相容的切割位点的限制性内切酶连接，而将融合配偶体和抗微生物肽基因框内融合。对于另一个例子，即引入编码羟胺切割位点的DNA序列，编码Asn-Gly的DNA序列可被引入融合配偶体和肽基因之间。例如，通过将在3′-末端用识别序列中含有Asn密码子的限制性内切酶或其同切点酶消化的融合配偶体基因与在其5′-末端用识别序列中含有Gly密码子的限制性内切酶或其同切点酶消化的肽基因经相容的粘端或钝端连接而框内融合。
本发明的基因结构可通过克隆入表达载体如质粒、病毒或可插入或掺入基因的群体常规载体而导入宿主细胞。
本发明的肽含有C-末端酰胺化的形式。
本发明的肽显示出对各种微生物包括革兰氏阴性和革兰氏阳性细菌、真菌和原生动物的强抗微生物活性。
本发明的肽可与其它生物学活性药物制剂如生物学活性化学品、其它肽等一起给药。
本发明的氨基酸缩写依如下IUPAC_IUB命名规则缩写。
氨基酸 缩写
丙氨酸 A
精氨酸 R
天冬酰胺 N
天冬氨酸 E
半胱氨酸 C
谷氨酸 D
谷氨酰胺 Q
甘氨酸 G
组氨酸 H
异亮氨酸 I
亮氨酸 L
赖氨酸 K
甲硫氨酸 M
苯丙氨酸 F
脯氨酸 P
丝氨酸 S
苏氨酸 T
色氨酸 W
酪氨酸 Y
缬氨酸 V
本发明将通过如下实施例详细描述。本领域技术人员应理解的是所述实施例仅为更清楚地描述本发明而给出，而不是限制本发明。
实施例1 肽的制备
构建表1所述序列，用自动肽合成仪合成各种肽，并用C18反相高效液相层析法(Waters Associates，USA)纯化。
表1 buforin II及其衍生物的氨基酸序列
| 肽 | 氨基酸序列 |
| SEQ ID NO.1 | RAGLQFPVGRVHRLLRK |
| SEQ ID NO.2 | AGLQFPVGRVHRLLRK |
| SEQ ID NO.3 | GLQFPVGRVHRLLRK |
| SEQ ID NO.4 | LQFPVGRVHRLLRK |
| SEQ ID NO.5 | QFPVGRVHRLLRK |
| SEQ ID NO.6 | FPVGRVHRLLRK |
| SEQ ID NO.7 | PVGRVHRLLRK |
| SEQ ID NO.8 | TRSSRAGLQFPVGRVHR |
| SEQ ID NO.9 | RAGLQFPVGRVHRLLR |
| SEQ ID NO.10 | RAGLQFPVGRVHRLL |
| SEQ ID NO.11 | RAGLQFPVGRVHRL |
| SEQ ID NO.12 | RKGLQKLVGRVHRLLRK |
| SEQ ID NO.13 | RLLRRLLRRLLRRLLRRLLR |
| SEQ ID NO.14 | RVHRLLRRVHRLLRRVHRLLR |
| SEQ ID NO.15 | RAGLQFPVGRLLRRLLRRLLR |
| SEQ ID NO.16 | RAGLQFPVGRVHRLLRK-NH2 |
| SEQ ID NO.17 | RAGLQFPVGRLLR |
| SEQ ID NO.18 | RAGLQFPVGRLLRRLLR |
| SEQ ID NO.19 | RLLRRLLRRLLR |
| SEQ ID NO.20 | RLLRRLLRRLLRRLLR |
实施例2 抗微生物活性的检测
测定实施例1的肽抗各种微生物的最小抑制浓度。分别在37℃和30℃在Mller-Hinton和Saboraud培养基中过夜培养细菌和真菌，并接种培养基培养2小时至中对数期。将细菌和真菌稀释至104-105/ml之后，用其接种含有连续稀释的肽的96孔平板，并再保温18小时。最小抑制浓度是通过测定光吸收而确定的抑制微生物生长的浓度。结果示于表2。
表2 肽的抗微生物活性
| 微生物 | 最小抑制浓度(μg/ml) | |||||||||||
| BuforinII | SeqNo.1 | SeqNo.2 | SeqNo.3 | SeqNo.4 | SeqNo.5 | SeqNo.6 | SeqNo.7 | SeqNo.8 | SeqNo.9 | SeqNo.10 | SeqNo.11 | |
| 革兰氏阳性 | ||||||||||||
| 枯草芽孢杆菌 | 2 | 1 | 4 | 4 | 8 | 18 | 32 | 25 | ＞200 | 12 | 50 | 100 |
| 金黄色葡萄球菌 | 4 | 2 | 8 | 8 | 18 | 62 | 32 | 50 | ＞200 | 50 | 200 | 200 |
| 变异链球菌 | 2 | 1 | 4 | 4 | 8 | 36 | 32 | 25 | ＞200 | 25 | 50 | 100 |
| 肺炎链球菌 | 4 | 2 | 4 | 4 | 18 | 18 | 32 | 50 | ＞200 | 25 | 100 | 100 |
| 革兰氏阴性 | ||||||||||||
| 大肠杆菌 | 4 | 2 | 2 | 2 | 8 | 36 | 32 | 25 | ＞200 | 12 | 50 | 200 |
| 沙雷氏菌 | 1 | 2 | 2 | 2 | 4 | 18 | 16 | 25 | ＞200 | 12 | 25 | 100 |
| 恶臭假单胞菌 | 4 | 2 | 2 | 2 | 8 | 36 | 32 | 25 | ＞200 | 25 | 50 | 200 |
| 鼠伤寒沙门氏菌 | 2 | 1 | 4 | 4 | 18 | 18 | 64 | 50 | ＞200 | 25 | 50 | 200 |
| 真菌 | ||||||||||||
| 白色假丝酵母 | 1 | 1 | 8 | 8 | 36 | 62 | 32 | 50 | ＞200 | 50 | ＞200 | ＞200 |
| 新型隐球酵母 | 1 | 1 | 8 | 8 | 62 | 62 | ＞100 | 50 | ＞200 | 50 | 100 | 200 |
| 酿酒酵母 | 1 | 1 | 8 | 8 | 36 | 62 | ＞100 | 50 | ＞200 | 100 | ＞200 | ＞200 |
表2(续)
| 微生物 | 最小抑制浓度(μg/ml) | ||||||||||
| BuforinII | SeqNo.12 | SeqNo.13 | SeqNo.14 | SeqNo.15 | SeqNo.16 | 爪蟾抗菌肽2 | Buf(5-13)[RLLR] | Buf(5-13)[RLLR]2 | (RLLR)3 | (RLLR)4 | |
| 革兰氏阳性 | |||||||||||
| 枯草芽孢杆菌 | 2 | 18 | 2 | 6 | 1 | 1 | 50 | 32 | 4 | 16 | 2 |
| 金黄色葡萄球菌 | 4 | 18 | 1 | 50 | 1 | 1 | 50 | 64 | 8 | 16 | 1 |
| 变异链球菌 | 2 | 36 | 2 | 25 | 0.5 | 0.5 | 100 | 16 | 16 | 16 | 2 |
| 肺炎链球菌 | 4 | 18 | 2 | 100 | 1 | 1 | 50 | 32 | 8 | 16 | 2 |
| 革兰氏阴性 | |||||||||||
| 大肠杆菌 | 4 | 18 | 2 | 100 | 1 | 2 | 100 | 32 | 8 | 32 | 2 |
| 沙雷氏菌 | 1 | 4 | 1 | 3 | 1 | 1 | 25 | 32 | 8 | 16 | 1 |
| 恶臭假单胞菌 | 4 | 36 | 2 | 50 | 1 | 2 | 50 | 32 | 16 | 16 | 2 |
| 鼠伤寒沙门氏菌 | 2 | 18 | 2 | 50 | 1 | 2 | 50 | 16 | 4 | 16 | 2 |
| 真菌 | |||||||||||
| 白色假丝酵母 | 1 | 16 | 8 | ＞200 | 2 | 2 | 25 | 32 | 4 | 32 | 8 |
| 新型隐球酵母 | 1 | 8 | 8 | 100 | 1 | 1 | 12 | 32 | 4 | 32 | 8 |
| 酿酒酵母 | 1 | 4 | 8 | ＞200 | 4 | 2 | 25 | 32 | 8 | 32 | 8 |
在(RLLR)3的N-末端融合有形成延伸α-螺旋的氨基酸序列的肽RAGLQFPVG(RLLR)3显示具有特别强的抗微生物活性，分别具有4个和5个RLLR重复的肽(RLLR)4和(RLLR)5也显示强抗微生物活性。
缺失了buforin II的形成随机卷曲结构的序列的肽也显示强抗微生物活性，并且在N-末端酰胺化的肽显示更强的抗微生物活性。
实施例3 抗微生物活性作为盐浓度的函数的测定
以作为盐浓度的函数测定肽的最小抑制浓度，从而确定抗微生物活性是否依赖于盐浓度。测定最小抑制浓度的方法同实施例2，除了改变氯化钠的浓度。结果示于图2。本发明的肽的抗微生物活性不作为盐浓度的函数变化，而buforin和爪蟾抗菌肽的抗微生物活性作为盐浓度的函数而敏感地变化。
<110>株式会社三养吉尼克斯，金善昌
<120>生物学活性肽
<130>PA/SYG99049
<150>KR 1998-1797
<151>1998-01-22
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Claims (9)
1、由序列[RLLR]n组成的肽，其中n是2-6之间的整数。
2、权利要求1的肽，其中该肽包含融合于其N-末端的一个额外的Gly残基。
3、权利要求1的肽，其中该肽的C-末端是酰胺化的。
4、由选自RAGLQFPVGRVHRLLRK、AGLQFPVGRVHRLLRK、GLQFPVGRVHRLLRK、LQFPVGRVHRLLRK、QFPVGRVHRLLRK、FPVGRVHRLLRK和PVGRVHRLLRK的一种氨基酸序列组成的肽。
5、权利要求4的肽，其中该肽的C-末端是酰胺化的。
6、权利要求4的肽，其中该肽包含融合于其N-末端的一个额外的Gly残基。
7、包含氨基酸序列RKGLQKLVGRVHRLLRK的肽。
8、包含氨基酸序列RAGLQFPVG[RLLR]m的肽，其中m是1-3之间的整数。
9、一种抗微生物制剂，其包括权利要求1至8中任一项的肽。
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|---|---|---|---|
| KR1998/1797 | 1998-01-22 | ||
| KR19980001797 | 1998-01-22 |
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| CN1161372C true CN1161372C (zh) | 2004-08-11 |
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| US (1) | US6531446B1 (zh) |
| EP (1) | EP1049709B1 (zh) |
| JP (1) | JP2002501079A (zh) |
| KR (1) | KR100314721B1 (zh) |
| CN (1) | CN1161372C (zh) |
| CA (1) | CA2318398C (zh) |
| DE (1) | DE69911579T2 (zh) |
| WO (1) | WO1999037664A1 (zh) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL146411A0 (en) * | 1999-05-14 | 2002-07-25 | Us Army Med Res Mat Command | Buforin i as a specific inhibitor and therapeutic agent for botulinum toxin b and tetanus neurotoxins |
| US6573244B1 (en) | 1999-05-17 | 2003-06-03 | The United States Of America As Represented By The Secretary Of The Army | Previns as specific inhibitors and therapeutic agents for Botulinum toxin B and Tetanus neurotoxins |
| US7235521B1 (en) | 1999-05-17 | 2007-06-26 | United States Of America As Represented By The Secretary Of The Army | Previns as specific inhibitors and therapeutic agents for botulinum toxin B and tetanus neurotoxins |
| EP1280822A2 (en) * | 2000-04-24 | 2003-02-05 | Novartis AG | Histone h2a-derived peptides useful in gene delivery |
| KR20020051124A (ko) * | 2000-12-22 | 2002-06-28 | 이한웅 | 부포린 유도체를 포함하는 함암제 |
| FR2818981A1 (fr) * | 2001-01-03 | 2002-07-05 | Synt Em | Peptides amphipathiques et leur utilisation pour le transfert de substances d'interet dans les cellules |
| KR100441402B1 (ko) * | 2002-03-26 | 2004-07-23 | 한국과학기술원 | 항균 활성을 갖는 펩타이드, 이들의 유도체 및 이들을포함하는 항균 조성물 |
| CN1269837C (zh) * | 2002-09-02 | 2006-08-16 | 上海高科联合生物技术研发有限公司 | 一组合成抗菌肽 |
| US7091185B2 (en) * | 2003-02-24 | 2006-08-15 | Dow Global Technologies Inc. | Periodic antimicrobial peptides |
| GB0404374D0 (en) | 2004-02-27 | 2004-03-31 | Univ Manchester | Treatment of bacterial infections |
| GB0513096D0 (en) | 2005-06-28 | 2005-08-03 | Strathclyde | Treatment of microbial infections |
| KR100958095B1 (ko) | 2007-12-31 | 2010-05-14 | 한국과학기술원 | 번역 동반 시스템을 이용한 항균 펩타이드의 대량 발현방법 |
| JP2010154842A (ja) * | 2008-12-03 | 2010-07-15 | Koji Kawakami | Ｅｇｆｒを標的にした新規抗がんキメラペプチド |
| KR101677959B1 (ko) | 2011-08-10 | 2016-11-21 | 한국과학기술원 | 리파아제 활성이 증대된 양친매성 펩타이드-리파아제 결합체 및 이의 용도 |
| CN107041140A (zh) | 2014-10-01 | 2017-08-11 | 植物保健公司 | 具有破坏的过敏反应盒的激发子肽及其用途 |
| EP3201341A4 (en) * | 2014-10-01 | 2018-06-27 | Plant Health Care, Inc. | Hypersensitive response elicitor peptides and use thereof |
| KR101811437B1 (ko) | 2015-09-17 | 2018-01-25 | 서울대학교산학협력단 | 그람 음성균에 대한 항균 활성을 나타내는 끊어진 또는 꺾어진 나선 펩타이드 또는 펩타이드 유사체 및 이의 용도 |
| US20170247423A1 (en) * | 2016-02-29 | 2017-08-31 | Dana-Farber Cancer Institute, Inc. | Stapled intracellular-targeting antimicrobial peptides to treat infection |
| US11371011B2 (en) | 2016-04-06 | 2022-06-28 | Plant Health Care, Inc. | Beneficial microbes for delivery of effector peptides or proteins and use thereof |
| WO2017176587A1 (en) | 2016-04-06 | 2017-10-12 | Plant Health Care, Inc. | Hypersensitive response elicitor-derived peptides and use thereof |
| US11325955B2 (en) | 2017-07-19 | 2022-05-10 | Dana-Farber Cancer Institute, Inc. | Stabilized anti-microbial peptides for the treatment of antibiotic-resistant bacterial infections |
| CN110256573A (zh) * | 2019-05-08 | 2019-09-20 | 吉林农业大学 | 一种杂合抗菌肽bm16r及其制备方法和应用 |
| CN110305193B (zh) * | 2019-07-18 | 2021-10-08 | 河南科技大学 | 一种抗牙龈卟啉单胞菌多肽及应用 |
| CN112679594B (zh) * | 2020-12-29 | 2022-03-25 | 潍坊医学院 | 一种抗菌肽Buforin IIB的改造体镇痛肽BRL及其应用 |
| WO2022262942A1 (en) | 2021-06-15 | 2022-12-22 | Panvir Therapeutics | Anti-tumour peptides |
| CN114605517B (zh) * | 2022-05-12 | 2022-09-27 | 广东海洋大学 | 一种具有广谱抗癌作用的多肽lxp-7及其应用 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5177189A (en) * | 1989-08-18 | 1993-01-05 | The Scripps Research Institute | Polypeptide analogs of Apolipoprotein E |
| WO1995019370A1 (en) * | 1994-01-18 | 1995-07-20 | Magainin Pharmaceuticals Inc. | Ion-channel forming amphiphilic peptides having n-terminal modifications |
| FR2715847B1 (fr) * | 1994-02-08 | 1996-04-12 | Rhone Poulenc Rorer Sa | Composition contenant des acides nucléiques, préparation et utilisations. |
| GB9504761D0 (en) * | 1995-03-09 | 1995-04-26 | Unilever Plc | Amphiphilic peptide and analogs thereof |
| US5994306A (en) * | 1995-11-22 | 1999-11-30 | Intrabiotics Pharmaceuticals, Inc. | Fine-tuned protegrins |
| US5981221A (en) * | 1997-03-26 | 1999-11-09 | Incyte Pharmaceuticals, Inc. | Histone fusion protein |
-
1999
- 1999-01-21 KR KR1019990001813A patent/KR100314721B1/ko not_active IP Right Cessation
- 1999-01-22 WO PCT/KR1999/000036 patent/WO1999037664A1/en active IP Right Grant
- 1999-01-22 DE DE69911579T patent/DE69911579T2/de not_active Expired - Lifetime
- 1999-01-22 US US09/600,710 patent/US6531446B1/en not_active Expired - Lifetime
- 1999-01-22 EP EP99900698A patent/EP1049709B1/en not_active Expired - Lifetime
- 1999-01-22 CA CA002318398A patent/CA2318398C/en not_active Expired - Fee Related
- 1999-01-22 JP JP2000528585A patent/JP2002501079A/ja active Pending
- 1999-01-22 CN CNB998035041A patent/CN1161372C/zh not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| KR100314721B1 (ko) | 2001-11-23 |
| WO1999037664A1 (en) | 1999-07-29 |
| EP1049709B1 (en) | 2003-09-24 |
| CA2318398C (en) | 2007-11-13 |
| KR19990068053A (ko) | 1999-08-25 |
| DE69911579T2 (de) | 2004-06-24 |
| EP1049709A1 (en) | 2000-11-08 |
| CN1291991A (zh) | 2001-04-18 |
| US6531446B1 (en) | 2003-03-11 |
| CA2318398A1 (en) | 1999-07-29 |
| DE69911579D1 (de) | 2003-10-30 |
| JP2002501079A (ja) | 2002-01-15 |
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