CN106540339B - 一种脂肽自组装凝胶及其制备方法和应用 - Google Patents

一种脂肽自组装凝胶及其制备方法和应用 Download PDF

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CN106540339B
CN106540339B CN201610954741.2A CN201610954741A CN106540339B CN 106540339 B CN106540339 B CN 106540339B CN 201610954741 A CN201610954741 A CN 201610954741A CN 106540339 B CN106540339 B CN 106540339B
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姚琛
周宾
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Abstract

本发明的一种脂肽自组装凝胶及其制备方法和应用，其中脂肽由活性肽片段、间隔臂、交联臂、疏水片段组成，基于亲疏水以及巯基相互作用，调节脂肽溶液pH值即可自组装成凝胶。本发明的一种脂肽自组装凝胶的制备方法包括下列步骤：通过固相合成法分别合成活性肽片段、间隔臂、交联臂三种短肽；采用碳二亚胺法偶联活性肽片段和间隔臂，偶联交联臂和疏水片段，得到两种中间产物，进一步将中间产物偶联得到含活性肽片段、间隔臂、交联臂和疏水片段的脂肽产物；配制脂肽水溶液，调节pH值，制得脂肽凝胶。脂肽自组装凝胶易于涂覆生物材料表面，应用范围广，对浮游细菌和生物膜细菌均有较强作用，有效减少感染的发生，且不易产生耐药性。

Description

一种脂肽自组装凝胶及其制备方法和应用
技术领域
本发明是一种脂肽自组装凝胶及其制备方法和应用，涉及一种可用于生物医药等方面的材料及其制备方法，属于生物医用材料领域。
背景技术
细菌在材料表面的黏附广泛存在于自然界、工业及健康医疗等众多领域，特别在医学领域，细菌极易黏附在植入患者体内的生物材料上形成顽固的生物膜，是生物材料伴生感染(Bacteria associated infections,BAI)的根源，导致疾病的发生。常规药物可杀灭浮游细菌和表层细菌，临床症状可控制，但一般不能穿透细菌生物膜。研究表明，同一种细菌在生物膜中抵抗抗生素和杀菌剂的能力比在浮游状态下高500-5000倍，由于这种抵御抗菌药物作用，致使细菌生物膜在宿主体内长期存在。在环境允许时，细菌生物膜再次释放浮游细菌，导致症状再次复发，成为急性感染发病的“细菌孵化所”。并且，细菌生物膜由于在宿主体内持续存在，其内细菌产生超抗原，影响宿主的免疫系统，刺激周围粘膜，不时释放炎性介质，导致局部炎症反应，是造成临床上难治性疾病原因之一。
随着微生物耐药性或抗药性增强等问题日渐突出，开发新的抗菌资源已成为研究者关注的焦点。抗菌肽与传统抗生素、药物的作用机制不同，具有抗菌谱广、作用强时间短、不易产生耐药性等特点，受到越来越多的重视。
因此，为了减少感染的发生，减少抗生素使用带来的影响，在生物材料表面使用抗菌肽凝胶涂层是一种有效可行的方法。
目前抗菌肽作用机制的研究模型较多(桶板模型、毯式模型、环形孔模型、凝聚模型等)，然而大部分的理论认为抗菌肽的生物活性与它所具有的阳离子性和两亲性有着密切的关系。阳离子性决定了抗菌肽的选择性，使其可与表面带负电荷的细菌膜发生静电吸引产生相互作用。疏水性氨基酸残基使得抗菌肽能够有效的渗透到菌膜脂质双分子层的内部，从而形成了疏水通道，导致菌膜完整性的破坏，造成菌膜裂解，菌体死亡。所以，设计抗菌肽类似物时，常常以天然抗菌肽构效关系为基础，对肽序列的氨基酸进行替换、缩短肽链的长度、将不同序列的抗菌肽进行片段组合形成杂合肽，或将脂肪链引入抗菌肽，或通过抗菌肽骨架环化或分子内侧链环化等方式，得到抗菌谱更广、活性更高的抗菌肽。
发明内容
技术问题：本发明的目的是提供一种脂肽自组装凝胶及其制备方法和应用。在生物材料表面使用抗菌凝胶涂层，应用范围广，对浮游细菌和生物膜细菌均有较强作用，有效减少感染的发生，且不易产生耐药性。
技术方案：一种脂肽自组装凝胶，为脂肽在碱性水溶液中自组装为水凝胶；所述的脂肽由活性肽片段、间隔臂、交联臂、疏水片段组成，其中，活性肽片段的序列为RLARIVVIRVAR、RIWVIWRR、KRWWKWWRR、IRWRIRVWVRRI、KRWRIRVRVIRK、KKWKIVVIKWKK、WIVVIWRRKRRR中的任一种，交联臂为含有两个及两个以上半胱氨酸残基的短肽。
所述的间隔臂为含有两个及两个以上甘氨酸残基的短肽。
所述的疏水片段为月桂酸、肉豆蔻酸、棕榈酸或硬脂酸中任意一个的脂质部分。
一种制备所述的脂肽自组装凝胶的方法，包括下列步骤：
步骤1).合成活性肽片段、间隔臂、交联臂：通过固相合成法分别合成活性肽片段、间隔臂、交联臂三种短肽；
步骤2).合成脂肽：采用碳二亚胺法偶联活性肽片段和间隔臂、交联臂和疏水片段，得到两种中间产物，进一步将两种中间产物偶联得到含活性肽片段、间隔臂、交联臂和疏水片段的脂肽产物；
步骤3).制备脂肽凝胶：配制脂肽水溶液，用碱液调节溶液为弱碱性得到脂肽凝胶。
所述的脂肽水溶液的质量体积百分比浓度为5-20mg/mL。
所述的碱液为氢氧化钠水溶液。
所述的脂肽自组装凝胶作为生物材料表面抗菌涂层的应用。
所述的脂肽自组装凝胶作为制备抗浮游细菌和生物膜细菌生物材料表面抗菌涂层的应用。
有益效果：
1.本发明基于脂肽亲疏水结构以及交联臂的巯基相互作用，调节脂肽溶液pH值即可自组装成凝胶。
2.本发明抗菌脂肽凝胶具有较高抗菌活性，细菌细胞接触破裂后释放谷胱甘肽等，可进一步还原释放抗菌脂肽。
3.本发明抗菌脂肽凝胶在生物材料表面使用，应用范围广，对浮游细菌和生物膜细菌均有较强作用，有效减少感染的发生，且不易产生耐药性。
具体实施方式
本发明由活性肽片段、间隔臂、交联臂、疏水片段合成抗菌脂肽，基于亲疏水以及巯基相互作用，调节脂肽溶液pH值即可自组装成凝胶。所得的凝胶易于涂覆生物材料表面。
本发明的脂肽自组装凝胶的制备方法具体依次包括下列步骤：
1).通过固相合成法分别合成活性肽片段、间隔臂、交联臂三种短肽；
2).采用碳二亚胺法偶联活性肽片段和间隔臂，偶联交联臂和疏水片段，得到两种中间产物，进一步将中间产物偶联得到含活性肽片段、间隔臂、交联臂和疏水片段的脂肽产物；
3).配制质量体积百分比浓度为5-20mg/mL的脂肽水溶液，用氢氧化钠水溶液调节pH值至7.5左右，制得脂肽凝胶。
所得的凝胶易于涂覆生物材料表面。
实施例1
通过Fmoc(9-芴甲氧羰基)固相合成法分别合成活性肽(RLARIVVIRVAR)、间隔臂(GGG)、交联臂(CC)三种短肽。采用1-乙基-3-(3-二甲基氨丙基)碳二亚胺(EDC)和N-羟基琥珀酰亚胺(NHS)分别偶联得到中间产物RLARIVVIRVARGGG和交联臂-棕榈酸(CC-Palm)，进一步将中间产物偶联得到脂肽产物RLARIVVIRVARGGGCC-Palm。配制质量体积百分比浓度为10mg/mL的脂肽水溶液，用氢氧化钠水溶液调节pH值至7.5左右，制得脂肽凝胶。所得的凝胶易于涂覆生物材料表面，具有较高的抗菌活性。
采用平板涂布法，以不同作用时间下细菌悬浮液中活细菌的浓度的对数值与作用时间关系评价脂肽凝胶对革兰氏阳性细菌金黄色葡萄球菌(S.aureus)和革兰氏阴性细菌大肠杆菌(E.coli)的抗菌性能，结果见表1。
表1不同作用时间下脂肽凝胶的杀菌率
实施例2
通过固相合成法分别合成活性肽(RIWVIWRR)、间隔臂(GGG)、交联臂(CCCCC)三种短肽。采用1-乙基-3-(3-二甲基氨丙基)碳二亚胺(EDC)和N-羟基琥珀酰亚胺(NHS)偶联得到RIWVIWRRGGG，交联臂-硬脂酸(CCCCC-Stearic)，进一步偶联得到脂肽产物RIWVIWRRGGGCCCCC-Stearic。配制质量体积百分比浓度为20mg/mL的脂肽水溶液，用氢氧化钠水溶液调节pH值至7.5左右，制得脂肽凝胶。所得的凝胶易于涂覆生物材料表面，具有较高的抗菌活性。
实施例3
通过固相合成法分别合成活性肽(KRWWKWWRR)、间隔臂(GGGGGG)、交联臂(CCC)三种短肽。采用1-乙基-3-(3-二甲基氨丙基)碳二亚胺(EDC)和N-羟基琥珀酰亚胺(NHS)偶联得到KRWWKWWRRGGGGGG，交联臂-月桂酸(CCC-Lauric)，进一步偶联得到脂肽产物KRWWKWWRRGGGGGGCCC-Lauric。配制质量体积百分比浓度为8mg/mL的脂肽水溶液，用氢氧化钠水溶液调节pH值至7.5左右，制得脂肽凝胶。所得的凝胶易于涂覆生物材料表面，具有较高的抗菌活性。
SEQNO.1: RLARIVVIRVAR
SEQNO.2: RIWVIWRR
SEQNO.3: KRWWKWWRR
SEQNO.4: IRWRIRVWVRRI
SEQNO.5: KRWRIRVRVIRK
SEQNO.6: KKWKIVVIKWKK
SEQNO.7: WIVVIWRRKRRR

Claims (6)

1.一种脂肽自组装凝胶，其特征在于，为脂肽在碱性水溶液中自组装为水凝胶；所述的脂肽由活性肽片段、间隔臂、交联臂、疏水片段组成，其中，活性肽片段的序列为RLARIVVIRVAR、RIWVIWRR、KRWWKWWRR、IRWRIRVWVRRI、KRWRIRVRVIRK、KKWKIVVIKWKK、WIVVIWRRKRRR中的任一种，交联臂为含有两个及两个以上半胱氨酸残基的短肽；所述的间隔臂为含有两个及两个以上甘氨酸残基的短肽；所述的疏水片段为月桂酸、肉豆蔻酸、棕榈酸或硬脂酸中任意一个的脂质部分；所述的碱性水溶液为pH值为7.5的弱碱性溶液。
2.一种制备权利要求1所述的脂肽自组装凝胶的方法，其特征在于：包括下列步骤：
步骤1).合成活性肽片段、间隔臂、交联臂：通过固相合成法分别合成活性肽片段、间隔臂、交联臂三种短肽；
步骤2).合成脂肽：采用碳二亚胺法偶联活性肽片段和间隔臂、交联臂和疏水片段，得到两种中间产物，进一步将两种中间产物偶联得到含活性肽片段、间隔臂、交联臂和疏水片段的脂肽产物；
步骤3).制备脂肽凝胶：配制脂肽水溶液，用碱液调节溶液为弱碱性得到脂肽凝胶，弱碱性是指pH值为7.5。
3.根据权利要求2所述的制备脂肽自组装凝胶的方法，其特征在于：所述的脂肽水溶液的质量体积百分比浓度为5-20 mg/mL。
4.根据权利要求2所述的制备脂肽自组装凝胶的方法，其特征在于：所述的碱液为氢氧化钠水溶液。
5.权利要求1所述的脂肽自组装凝胶作为生物材料表面抗菌涂层的应用。
6.权利要求1所述的脂肽自组装凝胶作为制备抗浮游细菌和生物膜细菌生物材料表面抗菌涂层的应用。
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