CN108178780A - 一种短肽修饰单宁酸纳米抗菌剂及其制备方法 - Google Patents
一种短肽修饰单宁酸纳米抗菌剂及其制备方法 Download PDFInfo
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- CN108178780A CN108178780A CN201711348496.1A CN201711348496A CN108178780A CN 108178780 A CN108178780 A CN 108178780A CN 201711348496 A CN201711348496 A CN 201711348496A CN 108178780 A CN108178780 A CN 108178780A
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- tannic acid
- short peptide
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- Agricultural Chemicals And Associated Chemicals (AREA)
Abstract
本发明公开了一种短肽修饰单宁酸纳米抗菌剂，由短肽修饰单宁酸经交联反应得到，粒径为100‑500nm，该纳米抗菌剂抗菌谱广，对大部分革兰氏阴性菌、革兰氏阳性菌以及耐药菌的最小抑菌浓度小于20μg/mL。本发明还公开了上述短肽修饰单宁酸纳米抗菌剂的制备方法，包括短肽修饰单宁酸的制备和交联制备纳米抗菌剂两个步骤。本发明以超短三肽对单宁酸进行修饰后，经交联得到纳米粒，以纳米结构增强短肽与细菌细胞的相互作用，具有制备简单、高抗菌活性、低细胞毒性、不易耐药等特点，具有潜在的应用前景。
Description
技术领域
本发明属于生物医用材料，特别是涉及一种短肽修饰单宁酸纳米抗菌剂及其制备方法。
背景技术
单宁酸是自然界中存在广泛的一种复杂的多元酚酸，属于典型的葡萄糖桔酰基化合物，富含于多种树木的树皮与果实中。单宁酸分子的酚羟基可与蛋白质、生物碱、多糖、核酸、细胞膜等生物大分子复合，反应机理大多基于胺基、巯基、酰基等官能团与之结合。单宁酸分子的邻位酚羟基则是较强的氢或中子的供给体，在氧化状态下转变为醌类，而醌类化合物被认为是具有抗炎、抗菌、抗病毒及抗癌作用的一类化合物。在生物体内，单宁酸能清除烷氧自由基，通过脱氢反应产生稳定的苯氧自由基，这个过程在消耗氧的同时结合活性氧等自由基以发挥抗氧化的特性，从而对生物组织起到保护作用。
单宁酸还具有显著的抗菌特性，能够有效抑制金黄色葡萄球菌生物膜的形成(Biofouling,2013,29:491.)。Ghafourian等对尿路感染患者的绿脓杆菌分离株进行研究，单宁酸用于抑制绿脓杆菌的最小浓度为35μg/mL，有望作为广谱抗生素的代替物(Journalof Biological Regulators and Homeostatic Agents,2012,26:231.)。单宁酸对金黄色葡萄球菌和肺炎克雷伯菌具有体外抑制作用，进一步研究表明，单宁酸能够使创面收缩并加速肉芽组织及胶原蛋白的形成，血管内皮生长因子的表达也明显高于对照组，能够有效促进大鼠皮肤伤口的愈合(BMC Complementary and Alternative Medicine,2011,11:86)。
抗菌肽是宿主防御体系中天然免疫系统所产生的具有一定杀菌效果的短肽类物质，具有广谱抗菌性。很多抗菌肽不仅对革兰氏阴性菌及革兰氏阳性菌具有杀灭作用，而且对某些真菌、原生生物、甚至肿瘤细胞和病毒也具有一定的抑制作用。由于抗菌肽的作用主要针对细胞膜结构，普遍认为具有较低的抗药性，具有广泛的应用前景。尽管抗菌肽的结构各异，但天然抗菌肽通常是由12-60个氨基酸组成的小分子阳离子多肽，由于富含赖氨酸、精氨酸和组氨酸等碱性氨基酸，抗菌肽通常带有2～7个正电荷，等电点大于7，表现出较强的阳离子特征，这使得抗菌肽能够很好地与呈电负性的细胞膜结合，这是抗菌肽与细菌细胞膜发生相互作用的结构基础。近年来，短肽特别是超短肽引起了研究者的关注，短肽制备简单、生物相容性好、细胞毒性低、体内易降解吸收、易于化学修饰，并且在温和条件下可以自发形成规则的超分子纳米结构。Sttup等利用一种合成的双亲性短肽自组装形成高度规则的纳米线，可模拟酯酶活性(Journal of the American Chemical Society,2007,129:12082.)。Rufo等设计了一种可以用Zn2+调控自组装的七肽分子，该短肽分子与Zn2+分子特异性配位，形成与碳酸酐酶的活性位点类似的空间结构，并表现出较好的仿酶活性(NatureChemistry,2014,6:303.)。
作为新型抗菌剂，基于阳离子结构的工程化短肽往往含有双亲性结构，其疏水区域与脂质结合，然而这同时也导致了溶血的产生。本发明就此进行了深入研究，提出构建纳米粒子负载工程化短肽获得纳米抗菌剂。
发明内容
本发明的目的是提供一种以纳米结构代替脂链作用、联合阳离子短肽和单宁酸的抗菌性能，得到的短肽修饰单宁酸纳米抗菌剂，并提供了所述抗菌剂的制备方法。
技术方案：本发明所述的一种短肽修饰单宁酸纳米抗菌剂，其有效成分为短肽修饰单宁酸。
进一步的，所述短肽为阳离子三肽，所述阳离子三肽的序列包含两个精氨酸以及色氨酸、异亮氨酸、缬氨酸、丙氨酸、甘氨酸、亮氨酸和谷氨酸中的任一种。
进一步的，所述短肽的氮端经赖氨酸或者半胱氨酸修饰后与单宁酸反应得到短肽修饰单宁酸。
所述短肽修饰单宁酸纳米抗菌剂粒径为100-500nm，抗菌谱广，对大部分革兰氏阴性菌、革兰氏阳性菌以及耐药菌的最小抑菌浓度小于20μg/mL。
上述短肽修饰单宁酸纳米抗菌剂的制备方法，包括以下步骤：
(1)短肽修饰单宁酸的制备：通过Fmoc固相合成法合成短肽，短肽氮端经赖氨酸或半胱氨酸修饰后，与单宁酸反应，产物经超滤管浓缩提纯后，冷冻干燥得到短肽修饰单宁酸；
(2)交联制备纳米抗菌剂：将步骤(1)制备所得短肽修饰单宁酸配制为水溶液，然后与交联剂反应，反应结束后离心分离、水洗得到短肽修饰单宁酸纳米抗菌剂。
步骤(1)中，所述短肽为阳离子三肽，所述阳离子三肽的序列包含两个精氨酸以及色氨酸、异亮氨酸、缬氨酸、丙氨酸、甘氨酸、亮氨酸和谷氨酸中的任一种。
步骤(1)中，所述短肽浓度和单宁酸浓度没有具体限定，以能够得到产物三肽修饰单宁酸即可。一般情况下可选择短肽浓度为1～10mg/mL，单宁酸浓度为50～500mg/mL，反应时间1～3小时。
步骤(2)中，所述交联剂选自三羟甲基丙烷三缩水甘油基醚、聚乙二醇二缩水甘油醚、三偏磷酸钠中的任一种。
步骤(2)中，所述短肽修饰单宁酸浓度为1～10mg/mL，交联剂摩尔浓度为单宁酸摩尔浓度的1～3倍，反应时间24～48小时。
优选的，步骤(2)中加入了三乙胺，以提高反应速率。
步骤(1)和步骤(2)均在中性或弱碱性条件下进行。
本发明提出构建纳米粒子负载工程化短肽，基于天然抗菌肽Bactenecin(牛溶菌肽，被认为是自然界中最小的天然阳离子抗菌肽之一)的有效序列，选取超短三肽对单宁酸进行修饰，基于单宁酸的多酚结构，单个分子即具有多个短肽结合位点，短肽修饰的单宁酸经交联得到纳米粒，以纳米结构增强短肽与细菌细胞的相互作用。
有益效果：本发明与现有技术相比，具有如下优点：(1)本发明以交联方法制备单宁酸纳米粒，而非采用与铁离子、钙离子、铝离子、铜离子等金属离子络合的方法，所得纳米粒更加稳定安全可控，通过改变交联剂种类和浓度，可有效调整纳米粒直径及分布，重复性高。(2)本发明选取超短三肽对单宁酸进行修饰，超短肽制备简单，抗菌活性高，生物相容性好。(3)本发明纳米抗菌剂的所有成分(单宁酸和阳离子三肽)均为有效抗菌成分，抗菌谱广，对大部分革兰氏阴性菌、革兰氏阳性菌以及耐药菌的最小抑菌浓度均小于20μg/mL。
具体实施方式
下面结合具体实施例对申请作出详细说明。
所用试剂均为市售购买所得，没有特殊要求。
实施例1
通过Fmoc固相合成法合成四肽KRWR，以pH7.4的磷酸盐缓冲液配成浓度为2.0mg/mL的溶液，在2mL四肽溶液中加入0.25g单宁酸，磁力搅拌下反应3小时，产物经超滤管浓缩提纯后，冷冻干燥。将制得的四肽修饰单宁酸(TA-KRWR)配制成1mL浓度为5.0mg/mL的溶液，强力搅拌，加入38.2μL三羟甲基丙烷三缩水甘油基醚，交联反应36小时，经离心分离、水洗后得TA-KRWR纳米抗菌剂。经透射电镜表征，其直径为350±42nm。以双倍稀释法检验最小抑菌浓度，结果显示，TA-KRWR纳米抗菌剂对金黄色葡萄球菌的最小抑菌浓度为0.25μg/mL，对大肠杆菌的最小抑菌浓度为0.5μg/mL。
实施例2
通过Fmoc固相合成法合成四肽CVRR，以pH7.4的磷酸盐缓冲液配成浓度为5.0mg/mL的溶液，在1mL四肽溶液中加入0.20g单宁酸，磁力搅拌下反应1小时，产物经超滤管浓缩提纯后，冷冻干燥。将制得的四肽修饰单宁酸(TA-CVRR)配制成1mL浓度为2.5mg/mL的溶液，强力搅拌，加入500mg聚乙二醇二缩水甘油醚(Mn 500)，同时加入10μL三乙胺以提高反应速率，交联反应24小时，经离心分离、水洗后得TA-CVRR纳米抗菌剂。经透射电镜表征，其直径为221±22nm。以含苯唑西林和氯化钠的Mueller-Hinton(MH)肉汤增殖培养耐甲氧西林金黄色葡萄球菌(MRSA)，以双倍稀释法检验最小抑菌浓度，结果显示，TA-CVRR纳米抗菌剂对MRSA的最小抑菌浓度为2.0μg/mL。TA-CVRR纳米抗菌剂以平板涂布法评价其抗菌性能，结果显示与MRSA作用10min后，细菌浓度由9.21*107±0.08*107CFU/mL降至3.54*102±0.03*102CFU/mL。
实施例3
通过Fmoc固相合成法合成四肽KRIR，以pH8.0的磷酸盐缓冲液配成浓度为1.0mg/mL的溶液，在10mL四肽溶液中加入0.5g单宁酸，磁力搅拌下反应1小时，产物经超滤管浓缩提纯后，冷冻干燥。将制得的四肽修饰单宁酸(TA-KRIR)配制成1mL浓度为10mg/mL的溶液，强力搅拌，加入200μL 100mg/mL三偏磷酸钠水溶液，交联反应48小时，经离心分离、水洗后得TA-KRIR纳米抗菌剂。经透射电镜表征，其直径为135±26nm。以双倍稀释法检验最小抑菌浓度，结果显示，TA-KRIR纳米抗菌剂对表皮葡萄球菌的最小抑菌浓度为2μg/mL，对绿脓杆菌的最小抑菌浓度为8μg/mL。
实施例4
通过Fmoc固相合成法合成四肽CRLR，以pH7.4的磷酸盐缓冲液配成浓度为3.0mg/mL的溶液，在3mL四肽溶液中加入0.15g单宁酸，磁力搅拌下反应3小时，产物经超滤管浓缩提纯后，冷冻干燥。将制得的四肽修饰单宁酸(TA-CRLR)配制成1mL浓度为3.0mg/mL的溶液，强力搅拌，加入300mg聚乙二醇二缩水甘油醚(Mn 2000)，同时加入10μL三乙胺以提高反应速率，交联反应24小时，经离心分离、水洗后得TA-CRLR纳米抗菌剂。经透射电镜表征，其直径为438±50nm。以含苯唑西林和氯化钠的MH肉汤培养、增殖耐甲氧西林表皮葡萄球菌(MRSE)，由平板涂布法结果显示，TA-CRLR纳米抗菌剂30min的杀菌率达99.996％。
Claims (9)
1.一种短肽修饰单宁酸纳米抗菌剂，其特征在于，其有效成分为短肽修饰单宁酸。
2.根据权利要求1所述的短肽修饰单宁酸纳米抗菌剂，其特征在于，所述短肽为阳离子三肽，所述阳离子三肽的序列包含两个精氨酸和色氨酸、异亮氨酸、缬氨酸、丙氨酸、甘氨酸、亮氨酸、谷氨酸中的任一种。
3.根据权利要求1所述的短肽修饰单宁酸纳米抗菌剂，其特征在于，所述短肽的氮端经赖氨酸或者半胱氨酸修饰后与单宁酸反应得到短肽修饰单宁酸。
4.根据权利要求1所述的短肽修饰单宁酸纳米抗菌剂，其特征在于，所述短肽修饰单宁酸纳米抗菌剂粒径为100-500nm，对大部分革兰氏阴性菌、革兰氏阳性菌以及耐药菌的最小抑菌浓度小于20μg/mL。
5.权利要求1-4中任一所述短肽修饰单宁酸纳米抗菌剂的制备方法，其特征在于，包括以下步骤：
(1)短肽修饰单宁酸的制备：通过Fmoc固相合成法合成短肽，短肽氮端经赖氨酸或半胱氨酸修饰后，与单宁酸反应，产物经超滤管浓缩提纯后，冷冻干燥得到短肽修饰单宁酸；
(2)交联制备纳米抗菌剂：将步骤(1)制备所得短肽修饰单宁酸配制为水溶液，然后与交联剂反应，反应结束后离心分离、水洗得到短肽修饰单宁酸纳米抗菌剂。
6.根据权利要求5所述的制备方法，其特征在于，步骤(1)中，所述短肽为阳离子三肽，所述阳离子三肽的序列包含两个精氨酸以及色氨酸、异亮氨酸、缬氨酸、丙氨酸、甘氨酸、亮氨酸和谷氨酸中的任一种。
7.根据权利要求5所述的制备方法，其特征在于，步骤(2)中，所述交联剂选自三羟甲基丙烷三缩水甘油基醚、聚乙二醇二缩水甘油醚、三偏磷酸钠中的任一种。
8.根据权利要求5所述的制备方法，其特征在于，步骤(2)中，所述短肽修饰单宁酸浓度为1～10mg/mL，交联剂摩尔浓度为单宁酸摩尔浓度的1～3倍，反应时间24～48小时。
9.根据权利要求5所述的制备方法，其特征在于，步骤(2)中，加入三乙胺提高反应速率。
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| CN109224081A (zh) * | 2018-09-12 | 2019-01-18 | 中山大学 | 一种基于氢键络合的多肽或蛋白纳米粒及其制备方法和应用 |
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| CN112933242B (zh) * | 2021-04-08 | 2024-02-02 | 杭州睿导基因科技有限公司 | 儿茶酚与胶原三肽自组装纳米复合物及制备和应用 |
| CN113133513A (zh) * | 2021-04-30 | 2021-07-20 | 西北农林科技大学 | 一种纳米仿生增强的革兰氏阳性菌捕获-分离剂及其制备方法和应用 |
| CN113133513B (zh) * | 2021-04-30 | 2023-07-18 | 西北农林科技大学 | 一种纳米仿生增强的革兰氏阳性菌捕获-分离剂及其制备方法和应用 |
| CN115581773A (zh) * | 2022-09-05 | 2023-01-10 | 东南大学 | 一种聚乙二醇化短肽增容剂及其在制备抗菌制剂中的应用 |
| CN115581773B (zh) * | 2022-09-05 | 2023-10-27 | 东南大学 | 一种聚乙二醇化短肽增容剂及其在制备抗菌制剂中的应用 |
| CN115606596A (zh) * | 2022-11-02 | 2023-01-17 | 中国石油大学(华东) | 一种网状抗菌材料、其制备方法及应用 |
| CN115606596B (zh) * | 2022-11-02 | 2024-02-23 | 中国石油大学(华东) | 一种网状抗菌材料、其制备方法及应用 |
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