CN111925422A - 抗菌肽及其在制备药物或化妆品中的应用 - Google Patents
抗菌肽及其在制备药物或化妆品中的应用 Download PDFInfo
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- CN111925422A CN111925422A CN202010975688.0A CN202010975688A CN111925422A CN 111925422 A CN111925422 A CN 111925422A CN 202010975688 A CN202010975688 A CN 202010975688A CN 111925422 A CN111925422 A CN 111925422A
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- antibacterial peptide
- trichophyton rubrum
- peptide
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Abstract
本发明涉及抗菌肽及其在制备药物或化妆品中的应用。该抗菌肽对人体致病真菌红色毛癣菌具有显著的抑制活性，而且本发明化合物还具有毒性低的优点，因此可用于制备抗真菌药物和化妆品。
Description
技术领域
本发明属于药物领域，具体的涉及一种抗菌肽及其在制备药物或化妆品中的应用。
背景技术
真菌性皮肤病，又称皮肤癣菌病，系由浅部真菌侵入人体皮肤、毛发、甲板引起的感染，简称癣。手癣和足癣病因致病真菌主要为红色毛癣菌、须癣毛癣菌、石膏样小孢子菌和絮状表皮癣菌，其中红色毛癣菌占60%以上，已成为我国当前手、足癣的主要致病菌。红色毛癣菌(Trichophy ton rubrum )属于有丝分裂孢子真菌， 是一种最常见的亲人性致病性皮肤癣菌。为世界性分布， 也是我国最常见的一种皮肤癣菌。红色毛癣菌可以引起皮肤、毛发感染;而且经常引起足和指(趾)甲的慢性难治性感染。有研究统计90%的皮肤癣菌慢性感染是由该菌所致。
目前针对现抗红色毛癣菌的药物研究已经有一些。吡咯类抗真菌药的作用靶酶为甾醇-14-α-去甲基酶。麦角甾醇是真菌细胞膜的主要组成部分，它能够维持细胞膜的流动性，并且是细胞膜的结构骨架。麦角甾醇有一个结构特点，其C-4 位是去甲基化的。吡咯类抗真菌药主要作用于14-α-去甲基酶，吡咯类药物中的氮原子与甾醇-14-α-去甲基酶上的细胞色素P450 蛋白中的铁原子特异性的结合，P450 可以催化形成14-甲基化甾醇而不形成14-去甲基化甾醇，进而阻止麦角甾醇的合成，从而改变细胞膜的通透性，导致细胞膜破裂，进而使真菌死亡。可以用于治疗由红色毛癣菌引起的皮肤癣菌病的吡咯类抗真菌药有咪康唑、酮康唑、益康唑、布康唑、硫康唑、噻康唑、克霉唑和伊曲康唑等。此类药物是临床上使用最为广泛的，其中，伊曲康唑是三氮唑类药物，其余为咪唑类药物。相对于咪唑类药物，三唑类在体内的代谢较慢，对真菌细胞色素P-450 蛋白的选择性更高，对人体的毒性作用更小，疗效较好，伊曲康唑是作用最强的唑类抗真菌药。丙烯胺类抗真菌药作用靶酶为角鲨烯环氧化酶( squalene epoxidase) 。此类药物主要是作用于麦角甾醇合成的前期，它们可以抑制角鲨烯环氧化酶的活性，阻断鲨烯环氧化，导致鲨烯的大量积累，使麦角甾醇合成不足，对菌体产生毒性作用，从而导致菌体死亡。可以用于治疗由红色毛癣菌引起的皮肤癣菌病的丙烯胺类药物有布替萘芬和特比萘芬。尽管目前开发出了多种结构不同的新型抗真菌药物，但是抗真菌药物仍然存在着毒副作用大以及耐药性问题。一些生物活性提取物在用于皮肤癣的治疗也是研究颇多，但是抑制效果并不是特别显著。
抗菌肽具有广谱抗菌活性，可以快速查杀靶标，并且其中很多是纯天然的肽，使它迅速成为潜在的治疗药物。抗菌肽的治疗范围为:革兰氏阴性细菌、革兰氏阳性细菌、真菌、寄生虫、肿瘤细胞等。抗菌肽是由基因编码在核糖体内合成的多肽，不同种类的抗菌肽通常有共同的特点:短肽(30～60个氨基酸)，强阳离子性(等电点范围为8．9～10．7)，热稳定性好(100℃，15min)，分子质量约为4ku，无药物屏蔽且不影响真核细胞。当今，抗菌肽已经可以由原核生物到人类的大部分有机生物体中成功分离和分类。抗菌肽通常作用于细菌，在真核生物的天然免疫方面发挥着重要作用由于全球抗生素药物的滥用，越来越多的细菌可能发展成为对传统抗生素耐药的菌株。人们迫切地寻找能够代替传统抗生素的药物，使得抗菌肽受到广泛的重视许多抗菌肽除了抗细菌之外还有抗真菌的功能，其中一个重要因素就是抗菌肽与质膜的相互作用。目前已经发现的抗真菌肽有cecropins、果蝇抗菌肽、线肽素、贻贝素、蝎血素以及人工改造的各种抗菌肽等。研究证明，抗菌肽抗真菌能力与真菌的属、种和孢子的状态有关。
虽然抗菌肽研究很多，但是针对能够特异性抗红色毛癣菌的抗菌肽还没有筛选获得，也没有相关的研究。
发明内容
本发明克服了现有技术的缺陷，提供了一种能够特异性抗红色毛癣菌的抗菌肽，具体的，所述抗菌肽的氨基酸序列如SEQ ID NO：1所示。
通过分析，发现，所述抗菌肽出了能够作用于细胞膜之外，还能够特异性的促进NADPH氧化酶的表达，诱导产生一系列氧化应应，造成ROS和MDA的含量增加，从而导致细胞损伤和死亡。
作为本发明的一种实施方式，所述的红色毛癣菌为分离的，或者已知的标准株。
本发明另外一方面，提供所述抗菌肽的筛选制备方法，其采用磷脂细胞膜固相萃取联用HPLC筛选抗菌肽的方法获得的。
本发明还提供了所述的抗菌肽在制备治疗由红色毛癣菌引起的皮肤病的药物中的用途。
此外，本发明还提供了一种治疗皮肤病的药物，所述药物包含上述抗菌肽和药学上可接受的载体或助剂。
更进一步的，所述药物还还有治疗皮肤病的其他药物包括但不限于化药、抗体药、ADC等。
所述药物可以片剂，膏剂，贴剂等剂型。
本发明还提供一种抑制红色毛癣菌生长的方法，所述方法通过所述抗菌肽靶向红色毛癣菌来促使红色毛癣菌损伤及凋亡，抑制红色毛癣菌的生长。
更进一步的，本发明还提供一种化妆品，所述化妆品是洗面奶，所述洗面奶中含有所述的抗菌肽，
最后，本发明还提供了抗菌肽在制备用于治疗由红色毛癣菌引起的皮肤病的化妆品中的用途。
本发明优点在于：本发明合成了一种新的抗菌肽，该抗菌肽对人体致病真菌红色毛癣菌具有显著的抑制活性，而且本发明化合物还具有毒性低的优点，因此可用于制备抗真菌药物。
附图说明
图1收集物的抑菌实验结果图
图2活性峰的RP-HPLC分析图
图3抗菌肽治疗皮肤癣的结果图
具体实施方式
下面通过实施例对本发明进行具体的描述，有必要在此指出的是以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，该领域的技术人员可以根据上述本发明内容对本发明做出一些非本质的改进和调整。
实施例1 抗红色毛癣菌杀菌肽的筛选
1、菌培养
红色毛癣菌 ATCC®28188 标准株点种于沙氏葡萄糖琼脂SDA平皿上，于27℃黑暗培养，挑取单菌落接入250mL PDA培养基的摇瓶中，150r/min，27℃黑暗培养，随后3000 r/min，4℃，离心10 min，收集得到菌体收获菌体备用。
2、脂质提取
将收集得到菌体8g，重复PBS洗涤、离心，并采用60mL Tris-HCl缓冲液(25 mmol/L，pH7.5)重悬，超声破壁，离心后加入180 mL氯仿-甲醇(1:2，v/v)混合溶剂，混合搅拌100min。之后，再加入40mL氯仿和40 mL蒸馏水，继续搅拌混30min。采用分液漏斗将氯仿相分离，旋转蒸发除去溶剂，即得红色毛癣菌脂质。
3、红色毛癣菌模拟细胞膜的制备
将上述操作得到的红色毛癣菌脂质复溶于氯仿-甲醇混合溶液中，旋转蒸发干成薄膜，真空过夜除去剩余溶剂。脂膜采用Tris-HCl缓冲液(10 mmol/L，pH 7.2)水化超声处理，脂浓度控制为70mg/mL。Zetasizer nano ZS纳米粒度分析测得模拟细胞膜的粒径大小范围为405～678nm之间。
4、模拟细胞膜固相萃取联用HPLC筛选抗菌肽
将模拟细胞膜固定相和本实验构建的多肽随机库进行(15mg/mL)混合，于37℃下轻微振荡(50r/min)反应50 min。离心(3000 r/min，4℃，15 min)收集滤液，此滤液即为固相萃取后的多肽混合物，冷冻干燥，复溶至原始体积。RP-HPLC检测亲和吸附前后的多肽混合物的液相指纹图谱。色谱条件为：色谱柱，Lichrospher C18: 250×4.6 mm；柱温，25℃；进样体积，10 µL；流动相流速，0.6mL/min；流动相，溶剂A，含0.15%(v/v)TFA的水溶液，溶剂B，含0.12%(v/v)TFA的80%(v/v)乙腈溶液；洗脱程序，线性梯度洗脱(0-30min，0%-100%溶剂B)；检测波长215 nm。根据抗菌肽的膜结合特性，潜在的抗菌肽会吸附在模拟细胞膜固定相上，因此，在固相萃取后其峰面积较未萃取的原始样品中对应峰的峰面积会减小。通过比较吸附前后的样品图谱，可迅速定位峰面积减小的差异峰。通过实验发现与萃取前样品的RP-HPLC指纹图谱相比，主要有4组差异峰，其中差异最显著的是峰1和峰4几乎消失。而其它色谱峰的峰形、面积、保留时间在吸附前后均一致。将峰1和峰4的收集物通过简单的抑菌实验初步证明对红色毛癣菌有明显抑菌活性（结果如图1所示），因此，后续实验中以峰1和峰4作为目标物进行进一步分离。本发明以峰4作为研究对象进行分析。
经透析后的峰4组分的RP-HPLC分析图谱如图2所示，该组分约在流动相中乙腈浓度为47.5%时出峰，暗示其具有一定疏水性，符合大多数抗菌肽的疏水性特征。疏水相互作用在抗菌肽与细菌细胞膜磷脂双分子层的互作中发挥作用，是调节肽-膜作用的重要影响因素。
5、抗菌肽序列鉴定
采 用 基 质 辅 助 激 光 解 析 电 离 四 级 杆 飞 行 时 间 质 谱(MALDI Q-TOF MS)对纯化所得肽进行质谱分析。质谱采用正离子(ESI+)采集模式。毛细管电压，3.5kV；锥孔电压，40 V；源温度，100℃，脱溶剂温度，300℃；脱溶剂气流，300 L/h；锥孔气流，500 L/h；碰撞能量，6 eV；检测电压，1700 V；选择离子，m/z 1350.63。质谱所得数据采用仪器自带软件Masslynx V4.1进行肽序分析。采用分子模拟软件Hyperchem 8.0进行肽的最低能量构象空间结构模拟。发 现 其 氨 基 酸 序 列 为FEEQRPPRITPARFTFWKQPIEPIRKE，分子量为3397.88Da，等电点为10.55，显示较强的阳离子多肽特性。
5、抗菌肽的化学合成
根据已知肽序，采用固相合成法，委托上海生工有限公司合成。合成粗肽采用HPLC进行纯化(≥95%)，采用MALDI Q-TOF MS验证合成肽的氨基酸序列，经验证与SEQ ID NO：1一致。
实施例2抗菌肽最小抑菌浓度的测定
采用微量稀释法测定抗菌肽对指示菌的最小抑菌浓度(Minimalinhibitoryconcentrations，MICs)。
所测试菌株分别是：（1）大肠杆菌ATCC25922；（2）须癣毛癣菌，北京华越洋生物NRR00060；（3）红色毛癣菌 ATCC®28188。将所述菌株按照常规的培养方法进行培养。培养到对数期后，离心(3000 r/min，4℃，10 min)收集对数期细菌菌体，并采用灭菌PBS清洗、重悬至OD600在0.3左右。将肽采用灭菌PBS配制成1024 µg/mL的母液，0.22 µm滤膜过滤除菌，并采用灭菌PBS梯度稀释。依次将100 µL培养基、100 µL受试菌液和50 µL不同浓度的的抗菌肽溶液加入到灭菌平底96孔板。37℃培养18 h。酶标仪测定每孔内OD600值。对照组采用等量PBS缓冲溶液代替抗菌肽。与初始值相比，OD600不再增加的肽的最小浓度为抗菌肽的最小抑菌浓度。PBS缓冲液代替多肽作为空白对照。培养结束后，测量其OD600。抑菌率计算公式为：抑菌率(%) = (A0−A)/A0×100，式中，A和A0 分别代表样品和空白的OD600 值。实验重复三次，结果以其平均值±标准差表示，结果如表1所示。
表1 抗菌肽对菌的最小抑菌浓度
| 菌株 | MIC（μg/mL） |
| 大肠杆菌 | 8μg/mL |
| 须癣毛癣菌 | 32μg/mL |
| 红色毛癣菌 | 16μg/mL |
从表1的结果可以看出，本发明的抗菌肽对于红色毛癣菌具有较好的抑制活性，其最小抑制浓度达到了16μg/mL。此外，对于大肠杆菌和须癣毛癣菌也有一定的抑制效果。
实验例3 抗菌肽治疗和预防皮肤癣的作用
将红色毛癣菌活化后接种于SDA培养基，30℃培养7天，无菌生理盐水洗脱后充分震荡混匀，调整菌株混合菌悬液浓度为1.0×108CFU/mL。腹腔注射麻醉剂，豚鼠背部双侧分别剪毛后脱毛，各形成约2.5×2.5cm的无毛区，用无菌砂纸在无毛区打磨至点状渗血后，均匀涂抹菌悬液100μL。在接种菌液第3天，将造模成功的25只豚鼠分别编号，按随机数字表法分为5组(阴性对照组/5％乙醇溶剂组/8μg/mL抗菌肽/32μg/mL抗菌肽/阳性对照组1％TBF)，每组5只。每天定时涂药1次，每次 100μL连续14天。 每天定时观察红斑、丘疹、鳞屑情况，记录每只豚鼠皮损评分。标准为:4分:皮损红肿，皮肤增厚、皮屑致密，布满整个皮损部位；3分:皮损红肿，皮屑间有点状的正常皮肤，正常皮肤累计小于1/4；2分:皮损微红、不肿，皮屑间有线状正常皮肤，正常皮肤累计小于1/2；1分:皮损不红、不肿，有少许皮屑，1/2以上正常皮肤；0分:皮损不红、不肿，基本为正常皮肤。 实验结果如图3所示：阴性对照组(NC)与5％乙醇组之间无明显差异，即溶剂组对患病豚鼠无治愈作用的影响。 NC与阳性对照组(PC/1％TBF)、抗菌肽组之间都具有极显著差异。 而且抗菌肽的治愈效果具有剂量依赖性。实验结果说明，本发明抗菌肽在8μg/mL浓度下的皮损得分为4.5左右，可以有效预防和治疗红色毛癣菌引起的皮肤癣。
实施例4 多肽的生物安全性检测
通过观察多肽对人口腔上皮细胞(Human oral keratinocytes，HOK)活力的影响，检测多肽是否具有细胞毒性。HOK的活力通过Cell Counting Kit-8(CCK-8)进行测定。.
具体步骤如下：
1、HOKs接种96孔板中，每孔2×103个细胞，培养覆盖面积大约为50％。使用20％胎牛血清(FBS)DMEM培养基培养。
2、将含有终浓度为8和32ug/mL的多肽的培养液加入细胞中，将多肽处理过的和未处理(阴性对照)的细胞在CO2培养箱中(5％CO2，37℃恒温)培养24h。未加多肽的细胞培养基为阴性对照。
3、按照Am-blue试剂盒指导手册对于每个时间点的细胞进行操作。
4、使用酶标仪在450nm处读取数值。
实验结果显示，显微镜下观察多肽组处理的细胞形态和阴性对照组无明显差别，在处理时间24h后，多肽处理对细胞增殖几乎没有影响，说明多肽处理后对细胞活力几乎无影响，具有较好的安全性。
序列表
<110> 北京欣颂生物科技有限公司
<120> 抗菌肽及其在制备药物或化妆品中的应用
<160> 1
<170> SIPOSequenceListing 1.0
<210> 1
<211> 27
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Phe Glu Glu Gln Arg Pro Pro Arg Ile Thr Pro Ala Arg Phe Thr Phe
1 5 10 15
Trp Lys Gln Pro Ile Glu Pro Ile Arg Lys Glu
20 25
Claims (8)
1.一种抗红色毛癣菌的抗菌肽，其特征在于氨基酸序列如SEQ ID NO：1所示。
2.一种抗真菌药物，其特征在于含有权利要求1所述的抗菌肽。
3.如权利要求2所述的药物，其特征在于还含有药学可用的载体。
4.一种化妆品，其特征在于含有权利要求1所述的抗菌肽。
5.如权利要求4所述的化妆品，其特征在于所述化妆品是洗面奶。
6.SEQ ID NO：1所示的抗菌肽在制备治疗由红色毛癣菌引起的皮肤病的药物中的用途。
7.SEQ ID NO：1所示的抗菌肽在制备治疗由红色毛癣菌引起的皮肤病的化妆品中的用途。
8.如权利要求7所述的用途，其特征在于所述化妆品是洗面奶。
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| CN113827701A (zh) * | 2021-11-08 | 2021-12-24 | 北京戴域生物技术有限公司 | 抑制烫伤病菌的多肽在制备化妆品或药物组合物中的用途 |
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