CN113754784A - 一种细胞穿透抗菌肽及其应用 - Google Patents
一种细胞穿透抗菌肽及其应用 Download PDFInfo
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- CN113754784A CN113754784A CN202111138564.8A CN202111138564A CN113754784A CN 113754784 A CN113754784 A CN 113754784A CN 202111138564 A CN202111138564 A CN 202111138564A CN 113754784 A CN113754784 A CN 113754784A
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明涉及抗菌肽技术领域,具体涉及一种细胞穿透抗菌肽及其应用。本发明提供的抗菌肽为由包含氨基酸序列如SEQ ID NO.1所示的多肽和氨基酸序列如SEQ ID NO.2所示的多肽形成的嵌合肽。该抗菌肽兼具细胞穿透和抗菌功能,具有广谱的抗菌效果,对大肠杆菌、金黄色葡萄球菌、沙门氏菌等均具有良好的抑菌活性,且该肽能够进入细胞,对胞内细菌具有强的抑制作用;同时,本发明的肽具有较低的细胞毒性,具备良好的生物相容性,应用前景广泛。
Description
技术领域
本发明涉及抗菌肽技术领域,具体涉及一种细胞穿透抗菌肽及其应用。
背景技术
抗生素的频繁和不规则使用加剧了病原微生物的变异和不断进化,使其耐药性不断增强,从而导致超级细菌的产生。如今,抗生素在畜牧业中正在迅速失去效力,抗生素耐药性问题也越来越严重。抗生素除了耐药性问题外,其使用还具有一定的局限性:由于细胞膜的生物屏障作用阻止抗生素进入细胞内,使其难以对胞内细菌发挥作用。
胞内细菌是一类能够侵入宿主细胞,并能在细胞内生长和繁殖的病原微生物,主要包括金黄色葡萄球菌、沙门氏菌、布鲁氏菌等。这些病原微生物适应了胞内的生存方式,利用自身分泌的毒力因子和蛋白来逃避宿主的免疫反应和大部分抗生素的杀伤作用,从而引起机体长期或反复感染,引起多种严重并发症。因此,有效清除细胞内病原微生物,并且不破坏宿主细胞是解决胞内细菌感染的关键。
抗菌肽具有广谱抗菌、不易产生耐药性等特点。细胞穿透肽是可以穿透生物膜并能携带各种物质进入细胞内的小分子多肽,且具有较低的细胞毒性。因此,设计具有细胞穿透能力的抗菌肽是清除胞内细菌的一种策略。
发明内容
本发明的目的之一是提供一种细胞穿透抗菌肽,该抗菌肽对于胞内细菌具有较好的抑菌、杀菌作用。本发明的另一目的是提供该抗菌肽的应用以及含有该抗菌肽的产品。
本发明的抗菌肽设计的整体构思如下:本发明通过对具有抗菌活性的多肽的筛选,最终确定选择富含脯氨酸的猪源抗菌肽PR-39,该抗菌肽中,脯氨酸由于其形成主链氢键的不稳定性,可用作螺旋结构的破坏氨基酸,使得肽段趋于形成无规则结构,这种无规则结构对细胞膜的破坏较小,有利于降低细胞毒性。进一步分析并截取该抗菌肽的疏水核心,同时选择疏水性氨基酸异亮氨酸替换序列中的精氨酸和脯氨酸进一步增强序列的疏水性。为了实现肽的细胞穿透能力,对细胞穿透肽进行筛选,最终确定选择六个精氨酸的细胞穿透肽与上述抗菌肽相连形成嵌合肽。六个精氨酸不仅使肽段具有细胞穿透能力,还增加了序列的电荷数,进一步增强肽的抗菌活性。上述嵌合肽具有较高的抗胞内细菌活性。经抗菌活性测试,发现获得的抗菌肽具备广谱抗菌活性,且对细胞内的金黄色葡萄球菌等细菌具有较强的抑制作用。此外,该肽的细胞毒性低,具备良好的生物相容性,表明其具备临床应用潜力。
基于上述发现,本发明提供以下技术方案:
本发明提供一种细胞穿透抗菌肽,其为由包含氨基酸序列如SEQ ID NO.1所示的多肽和氨基酸序列如SEQ ID NO.2所示的多肽形成的嵌合肽。
以上所述的多肽中,序列如SEQ ID NO.1所示的多肽为细胞穿透肽,序列如SEQ IDNO.2所示的多肽为具有抗菌活性的多肽。
以上所述的抗菌肽中,氨基酸序列如SEQ ID NO.1和SEQ ID NO.2所示的多肽直接共价连接。
SEQ ID NO.1所示的多肽和SEQ ID NO.2所示的多肽可以通过共价连接直接串联形成所述抗菌肽。
本领域技术人员可以理解,加入连接接头通常不会对嵌合肽的功能、活性产生影响。通过接头连接的抗菌肽也同样具有抗菌和细胞穿透功能,能够发挥抗胞内细菌的功能,因此也在本发明的保护范围内。
优选地,所述抗菌肽具有如SEQ ID NO.3所示的氨基酸序列。
进一步优选地,所述抗菌肽的氨基酸序列如SEQ ID NO.3所示。
本发明所述的抗菌肽的氨基酸序列具体如下:Arg Arg Arg Arg Arg Arg PhePhe Ile Pro Ile Leu Ile Pro Ile Ile,分子量为2121.66。
优选地,本发明所述的抗菌肽的C末端含有酰胺化修饰。C末端的酰胺化修饰可进一步提高肽的阳离子性和稳定性。
本发明还提供以上所述的抗菌肽的衍生物,其为将所述抗菌肽经疏水化修饰或标签化修饰得到的修饰物,或者为将所述抗菌肽与载体连接形成的偶联物,或者为将所述抗菌肽经偶联形成的多聚物。
以上所述的疏水化修饰可为在抗菌肽的N末端或C末端连接疏水基团。
以上所述的标签化修饰可为在抗菌肽的N末端或C末端连接标签序列(例如:组氨酸标签等)。
以上所述的载体可为药物载体。
本发明还提供编码所述抗菌肽的核酸分子。
根据所述抗菌肽的氨基酸序列,本领域技术人员可以确定编码该抗菌肽的核酸分子的序列。
本发明提供含有所述核酸分子的生物材料,所述生物材料包括表达盒、载体或宿主细胞。
以上所述的表达盒为在所述核酸分子的上游、下游连接用于转录、翻译的调控元件得到的重组核酸分子。
以上所述的载体为携带所述核酸分子且能够在宿主细胞中复制或整合的质粒载体、病毒载体、噬菌体载体或转座子。
以上所述的宿主细胞为微生物细胞或可用于多肽表达的动物细胞或细胞系。上述动物细胞或细胞系不具备繁殖为动物个体的潜力。
基于本发明提供的抗菌肽的功能,本发明提供所述抗菌肽或所述抗菌肽的衍生物或所述核酸分子或所述生物材料在制备抗菌产品中的应用。
优选地,所述产品为药物、保健品、饲料、饲料添加剂、消毒剂、清洁剂、防腐剂、日化用品或纺织品。
所述抗菌产品为用于抑制、杀灭细菌的产品或用于预防或治疗细菌感染的产品。
所述产品优选为用于预防或治疗胞内细菌感染的产品。
本发明提供的抗菌肽具有广谱抗菌活性,对于革兰氏阳性菌和革兰氏阴性菌均具有良好的抗菌活性,包括肠杆菌属细菌、沙门氏菌属细菌、葡萄球菌属细菌等。
以上所述的胞内细菌包括但不限于葡萄球菌属细菌(金黄色葡萄球菌等)、沙门氏菌属细菌(鼠伤寒沙门氏菌等)、布鲁氏杆菌属细菌(各种布鲁氏杆菌等)。
本发明提供一种药物组合物,其包含所述抗菌肽或其盐或所述抗菌肽的衍生物。
以上所述的药物组合物还可包含其他活性成分以及药学领域允许的辅料。
本发明还提供一种饲料或饲料添加剂,其包含所述抗菌肽或其盐或所述抗菌肽的衍生物。
以上所述的饲料或饲料添加剂还可包含其他活性成分以及饲料领域允许的辅料。
本发明还提供一种消毒剂、清洁剂或防腐剂,其包含所述抗菌肽或其盐或所述抗菌肽的衍生物。
本发明的有益效果至少在于:
本发明提供一种兼具杀菌和细胞穿透双功能的抗菌肽,该肽具有广谱的抗菌活性,对大肠杆菌、沙门氏菌、金黄色葡萄球菌等细菌具有良好的抗菌效果,对侵染细胞内的细菌也表现出强的抑制作用,且不易产生耐药性,而且,该肽的细胞毒性较低,还具有肽链短、化学合成方法简单、成本低廉的优势,该抗菌肽对于治疗胞内细菌感染具有较高的应用价值。
附图说明
图1为本发明实施例1中合成的抗菌肽的质谱图。
图2为本发明实施例1中合成的抗菌肽的高效液相色谱图,其中,最高峰的出峰时间为13.967分钟。
图3为本发明实施例3中抗菌肽的胞内抑菌活性检测结果。
图4为本发明实施例4中抗菌肽的细胞毒性检测结果。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。
以下实施例中所使用的实验方法如无特殊说明,均为常规方法。下述实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1固相化学合成法合成抗菌肽
本实施例采用固相化学合成法合成抗菌肽,抗菌肽的氨基酸序列如SEQ ID NO.3所示,具体方法如下:
1、抗菌肽的制备从C端到N端逐一进行,通过多肽合成仪来完成。首先将Fmoc-X(X是每个抗菌肽的C端第一个氨基酸)接入到Wang树脂,然后脱去Fmoc基团后得到X-Wang树脂;再将Fmoc-Y-Trt-OH(9-芴甲氧羧基-三甲基-Y脱去保护基,Y为每个抗菌肽C端第二个氨基酸);按照这个程序依次从C端合成到N端,直至合成完毕,得到脱去Fmoc基团的侧链保护的树脂;
2、在上述得到的肽树脂中,加入切割试剂,20℃避光下反应2h,过滤;沉淀TFA(三氟乙酸)洗涤,将洗液与上述滤液混合,旋转蒸发仪浓缩,再加入10倍左右体积的预冷无水乙醚,-20℃沉淀3h,析出白色粉末物,以2500g离心10min,收集沉淀,再用无水乙醚洗涤沉淀,真空干燥,得到多肽,其中切割试剂由TFA、水和TIS(三异丙基氯硅烷)按照质量比95:2.5:2.5混合而成;
3、使用0.2mol/L硫酸钠(磷酸调节至pH 7.5)进行柱平衡30min,用90%乙腈水溶液溶解多肽,过滤,C18反相常压柱,采用梯度洗脱(洗脱剂为甲醇和硫酸钠水溶液按照体积比为30:70~70:30混合),流速为1mL/min,检测波长为220nm,收集主峰,冻干;再利用反相C18柱进一步纯化,洗脱液A为0.1%TFA/水溶液;洗脱液B为0.1%TFA/乙腈溶液,洗脱浓度为25%B~40%B,洗脱时间为12min,流速为1mL/min,再同上收集主峰,冻干;
4、抗菌肽的鉴定:将上述得到的抗菌肽经过电喷雾质谱法分析,质谱图(图1)中显示的分子量与理论分子量2121.66基本一致;抗菌肽的纯度大于95%(图2,液相色谱柱为Kromasil C18-5(4.6×250mm,220nm,10μL),使用非线性梯度的水/乙腈(含0.1%三氟乙酸),流速为1.0mL/min)。
以上结果显示,经化学合成制备得到氨基酸序列如SEQ ID NO.3所示的抗菌肽(命名为P3I7)。
实施例2肽的抗菌活性的测定
利用微量稀释法测定实施例1制备得到的抗菌肽(P3I7)对细菌的最小抑菌浓度,具体如下:
用含有0.01%乙酸的0.2%胎牛血清白蛋白作为稀释液加入96孔板中,使用倍比稀释法依次配制系列梯度的抗菌肽溶液,使每个孔中的溶液体积为50μL。然后分别添加50μL的待测菌液(~105CFU/mL)于各孔中,培养基为MHB(pH=7.0)。分别设置阳性对照(含有菌液而不含有抗菌肽)和阴性对照(既不含菌液也不含肽)。于37℃恒温培养18h,然后用酶标仪在492nm处测定光吸收值,以数值大于0.1为菌株生长的判定标准,确定肽对细菌的最小抑菌浓度。试验设定两个平行,重复三次。结果见表1。待测细菌Escherichia coli ATCC25922,Staphylococcus aureus CVCC 1882,Staphylococcus aureus ATCC 6538,Salmonella typhimurium ATCC14028购自北京百欧博伟生物技术有限公司,Staphylococcus aureus ATCC 29213购自上海鲁微科技有限公司,Escherichia coliK88,Staphylococcus aureus ATCC 43300来源于中国兽医微生物菌种保藏管理中心。
表1抗菌肽P3I7对细菌的抑菌活性(μM)
由表1可以看出,肽P3I7对革兰氏阴性菌和革兰氏阳性菌都具有良好的抗菌效果,表现出广谱抗菌活性,并且对耐甲氧西林金黄色葡萄球菌(S.aureus 43300)也表现出抑菌活性,表明肽P3I7具备杀灭耐药菌的潜力。
实施例3肽的胞内抑菌活性测定
对实施例1制备的抗菌肽的胞内抑菌活性进行测定,具体如下:
S.aureus 6538菌株在培养基中生长4h,3000×g离心10min,收集细菌细胞,PBS洗涤三次,用不含胎牛血清的培养基重悬。浓度为105个细胞/孔的巨噬细胞均匀铺至96孔板中,加入S.aureus6538(107CFU/孔),在37℃下共培养1h,吸去培养上清并用PBS洗涤,加入含有100μg/mL庆大霉素全培养基在37℃作用2h以杀死细胞外细菌,用PBS洗涤细胞。之后分别加入100μL倍比稀释的抗菌肽和万古霉素(Vancomycin)处理6h,再用0.1%TritonX-100孵育15min裂解细胞释放胞内细菌。将溶解产物稀释10倍后均匀涂布于固体培养基中,并在37℃下培养过夜。统计菌落个数以确定细胞内细菌的数量。分别设定阳性对照(含有细胞而不含有抗菌肽)和阴性对照(只含有培养基)。试验设定两个平行,重复三次。结果如图3所示。
结果显示,抗菌肽在64μM和32μM时,能够杀灭90%的胞内金黄色葡萄球菌,且效果优于相同浓度下的万古霉素。
实施例4肽细胞毒性的测定
对实施例1制备的抗菌肽的细胞毒性进行测定,具体如下:
抗菌肽对真核细胞的毒性采用MTT比色法测定。将冻存于液氮中的小鼠单核巨噬细胞株RAW264.7细胞复苏后接种于含有10%胎牛血清的培养基中,在37℃、5%CO2条件下传代培养。待细胞进入到快速生长期,然后加2mL、0.25%胰蛋白酶对细胞进行消化。用培养基调整细胞浓度,使其终浓度约为1×105个细胞/孔。将50μL细胞悬液与50μ倍比稀释的抗菌肽混合于96孔板中,在37℃、5%CO2条件下孵育6h,随后每孔加入25μL MTT(5mg/mL),继续孵育2h。孵育结束后,弃去上清。用150μL DMSO溶解孔底结晶,用酶标仪在570nm处测定吸光度值。分别设定阳性对照(含有细胞而不含有抗菌肽)和阴性对照(只含有培养基)。试验设定两个平行,重复三次。结果见图4。细胞存活率根据下面公式进行计算:
细胞存活率=[(测试孔OD570-阴性对照OD570)/(阳性对照OD570-阴性对照OD570)]×100%。
结果显示,用64μM浓度的抗菌肽P3I7处理小鼠巨噬细胞RAW264.7时,细胞存活率为85%,表明P3I7的细胞毒性较小,具有一定的临床应用潜力。
综合以上结果显示,抗菌肽P3I7具备广谱抗菌活性,并且对杀灭细胞内细菌也具有较强作用,细胞毒性低,具有广泛的应用潜力。
虽然,上文中已经用一般性说明及具体实施方案对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
序列表
<110> 中国农业大学
<120> 一种细胞穿透抗菌肽及其应用
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Claims (10)
1.细胞穿透抗菌肽,其特征在于,其为由包含氨基酸序列如SEQ ID NO.1所示的多肽和氨基酸序列如SEQ ID NO.2所示的多肽形成的嵌合肽。
2.根据权利要求1所述的抗菌肽,其特征在于,所述抗菌肽中,氨基酸序列如SEQ IDNO.1和SEQ ID NO.2所示的多肽直接共价连接。
3.根据权利要求1或2所述的抗菌肽,其特征在于,所述抗菌肽具有如SEQ ID NO.3所示的氨基酸序列。
4.权利要求1~3任一项所述的抗菌肽的衍生物,其特征在于,其为将权利要求1~3任一项所述的抗菌肽经疏水化修饰或标签化修饰得到的修饰物,或者为将权利要求1~3任一项所述的抗菌肽与载体连接形成的偶联物,或者为将权利要求1~3任一项所述的抗菌肽经偶联形成的多聚物。
5.编码权利要求1~3任一项所述的抗菌肽的核酸分子。
6.含有权利要求5所述的核酸分子的生物材料,其特征在于,所述生物材料包括表达盒、载体或宿主细胞。
7.权利要求1~3任一项所述的抗菌肽或权利要求4所述的抗菌肽的衍生物或权利要求5所述的核酸分子或权利要求6所述的生物材料在制备抗菌产品中的应用。
8.根据权利要求7所述的应用,其特征在于,所述产品为药物、保健品、饲料、饲料添加剂、消毒剂、清洁剂、防腐剂、日化用品或纺织品。
9.一种药物组合物,其特征在于,包含权利要求1~3任一项所述的抗菌肽或其盐或权利要求4所述的衍生物。
10.一种饲料或饲料添加剂,其特征在于,包含权利要求1~3任一项所述的抗菌肽或其盐或权利要求4所述的衍生物。
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