CN104974228B - 一种小分子多肽zy4及其应用 - Google Patents
一种小分子多肽zy4及其应用 Download PDFInfo
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- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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Abstract
本发明公开了一种小分子多肽ZY4在制备治疗痤疮、抗感染、抗肿瘤药物及化妆品中的应用。它包含17个氨基酸残基，分子量为2374.0 Da，等电点为10.74，其氨基酸序列如SEQ ID:1所示。本发明中的多肽ZY4为人工合成，具有分子量小、人工合成方便的优点，本发明的多肽ZY4通过实验证明抑菌效果明显，对痤疮具有显著的治疗效果；该多肽还能抑制肿瘤细胞的生长，对肿瘤细胞具有杀伤作用；小分子多肽ZY4能够在制备抗感染、抗肿瘤和治疗痤疮药物及化妆品中应用。
Description
技术领域
本发明属于生物医学技术领域，具体涉及小分子多肽ZY4在制备治疗痤疮、抗感染抗肿瘤药物及化妆品中的应用。
背景技术
痤疮是一种毛囊性皮脂腺的慢性炎症，是青少年时期常见的炎性皮肤病，好发生于面颊、额部、颊部和鼻唇沟，其次是胸部、背部和肩部，其发病主要与性激素水平、皮脂腺大量分泌、痤疮丙酸杆菌增殖、毛囊皮脂腺导管的角化异常及炎症等因素相关。***的皮肤表面脂质成分有所改变，雄性激素增多，造成皮脂毛囊导管角化过度，毛囊壁上脱落的上皮细胞与皮脂混合，栓塞在毛囊口内，形成粉刺，再受丙酸菌等作用，加上细菌感染，引起炎症，产生脓疮，患后异常痛苦。
肿瘤是机体在各种致癌因素作用下，局部组织的某一个细胞在基因水平上失去对其生长的正常调控，导致其克隆性异常增生而形成的新生物。根据肿瘤对人体危害的大小及其生长特性而分为良性肿瘤和恶性肿瘤两类。恶性肿瘤生长迅速，生长时常向周围组织浸润，表面几无包膜，常有全身转移。目前，恶性肿瘤的发病率有逐年升高的趋势，在各种疾病的死亡原因中也占前几位，因而是重点防治的一种疾病。
抗菌肽是生物体内经诱导产生的一种具有生物活性的小分子多肽，分子量在1000～7000左右，由10～60个氨基酸残基组成。抗菌肽是当生物受到微生物侵入后机体迅速产生的高效、光谱的抗菌肽类分子，来参与机体的免疫反应。抗菌肽作为机体有效的防御分子是广泛存在的，目前已从微生物、植物、昆虫、节肢动物、两栖动物、哺乳动物甚至人体内鉴定出上千种抗菌肽。抗菌肽抗菌机理复杂，但大多数理论都认为其机制涉及到抗菌肽的阳离子性和疏水性与带负电荷的微生物胞膜的作用，抗菌肽和细菌的细胞膜接触后，引起膜通透性改变，或在细菌细胞膜上形成跨膜的孔洞，最后导致细菌内容物外泄而死亡。因此，抗菌肽在杀灭细菌的速度上要远远高于传统的抗生素，且不像抗生素在低浓度下抑制细菌的生长，抗菌肽对细菌的作用几乎都是致死性的。研究表明：抗菌肽与传统抗生素相比，不易诱导耐药菌株的产生；抗菌谱光，对细菌、真菌、病毒、原虫及癌细胞均有作用。已经在家禽体内发现了3个家族的抗菌肽，包括cathelicidin，liver-expressed antimicrobialpeptide(LEAP)，andβ-defensin。这些抗菌肽对于家禽抵抗细菌性、病毒性疾病具有至关重要的作用，相关这些基因的突变或者缺失对于家禽抗微生物感染的能力将有显著的影响；这些抗菌肽除了具有光谱抗菌活性，同时还有高效的抗真菌、抗病毒、抗原虫和(或)抗肿瘤活性，如Bat5和IMc7能杀灭钩端螺旋体，对白色念珠菌、隐球菌和胞膜病毒和寄生虫都有较好的杀灭作用；一些抗菌肽对疱疹病毒、流感病毒、艾滋病病毒有囊膜病毒有明显的杀伤力；此外，有些抗菌肽同时还具有多种其他的调控功能，如Cathelicidin还具有促进伤口愈合、组织损伤修复、化学趋化作用、促血管生成和抗寄生虫等功能，在调节动物机体免疫上有着重要生物学活性。
发明内容
本发明的目的在于克服现有技术的缺点，提供一种小分子多肽ZY4；
本发明的另一个目的在于提供一种小分子多肽ZY4在制备治疗痤疮、抗感染、抗肿瘤药物及化妆品中的应用。
本发明的目的通过以下技术方案来实现：小分子多肽ZY4，它包含17个氨基酸残基，分子量为2374.0Da，等电点为10.74，其氨基酸序列如SEQ ID:1所示，为缬氨酸-半胱氨酸-赖氨酸-精氨酸-色氨酸-赖氨酸-赖氨酸-色氨酸-赖氨酸-精氨酸-赖氨酸-色氨酸-赖氨酸-赖氨酸-色氨酸-半胱氨酸-缬氨酰胺(ValCysLysArgTrpLysLysTrpLysArgLysTrpLysLysTrpCysVal-NH2),所述基因序列中两个半胱氨酸形成一个分子内二硫键，C-末端的Val酰胺化。
本发明的小分子多肽ZY4在制备治疗痤疮、抗感染、抗肿瘤药物及化妆品中的应用。
本发明的有益效果是：本发明中的多肽ZY4为人工合成，具有分子量小、人工合成方便的优点，本发明的多肽ZY4通过实验证明抑菌效果明显，对痤疮具有显著的治疗效果；该多肽还能抑制肿瘤细胞的生长，对肿瘤细胞具有杀伤作用；小分子多肽ZY4能够在制备抗感染、抗肿瘤和治疗痤疮药物及化妆品中应用。
附图说明
图1为小分子多肽ZY4对小鼠耳痤疮模型的治疗作用示意图。
图2为小分子多肽ZY4对小鼠耳痤疮模型炎症的治疗作用示意图。
图3为小分子多肽ZY4抗肺癌细胞A549活性的示意图。
图4为小分子多肽ZY4抗乳腺癌细胞MDA-435活性的示意图。
图5为小分子多肽ZY4抗黑色素瘤细胞A357活性的示意图。
图6为小分子多肽ZY4抗肝癌细胞HepG2活性的示意图。
图7为小分子多肽ZY4抗胃癌细胞SGC7901活性的示意图。
具体实施方式
下面结合附图和实施例对本发明做进一步的描述，本发明的保护范围不局限于以下所述：
实施例1：小分子多肽ZY4的制备
1.称取树脂0.2g放置于干燥洁净的反应管中，加入适量的N,N-二甲基酰胺(DMF)，活化30min。称取第一氨基酸残基1mmol，4-二甲氨基吡啶(DMAP)150mg加入到反应管中，DMF做为溶剂反应3h，反应完毕后用DMF洗3-6次，加入适当的吡啶和乙酸酐，体积比为1:1，反应30min，反应完毕后DMF洗3-6次。然后用哌啶洗脱氨基酸的保护基团Fmoc，洗脱两次，每次15min，再用DMF洗4次，甲醇洗2次；
2.称第二个氨基酸3mmol，HBTU 3mmol于反应管中，加入DIEA 0.5ml，反应40min，用DMF洗3-6次，加入哌啶溶液两次洗脱氨基酸的保护基团Fmoc，每次10min，再用DMF洗4次，甲醇洗2次；
3.重复第二个步骤直到最后一个氨基酸残基；
4.最后一个氨基酸反应完毕后，用三氟乙酸切割2h，反应抽滤，得到多肽的三氟乙酸溶液，用***沉淀，离心，再用***洗3-5遍，得到白色固体，经过HPLC脱盐冻干得到多肽样本。
实施例2：小分子多肽ZY4抗菌实验
1.分别制备大肠杆菌、白色念珠菌、金黄色葡萄球菌、枯草芽孢杆菌、溶血性葡萄球菌、表皮葡萄球菌、科氏葡萄球菌菌液，37℃恒温培养18h，备用；
2.配制浓度为0.8～20μg/ml小分子多肽ZY4溶液，将直径为5～7mm的圆形定性滤片消毒烘干后浸入上述不同浓度的小分子多肽ZY4溶液中；
3.制备高柱肉汤琼脂培养基，灭菌，备用；
4.溶化高柱肉汤琼脂培养基，冷却至50℃，分别加入大肠杆菌、白色念珠菌、金黄色葡萄球菌、枯草芽孢杆菌、溶血性葡萄球菌、表皮葡萄球菌、科氏葡萄球菌菌液1ml，轻摇均匀，倒入无菌平皿，轻晃使培养基均匀平铺在平皿上；
5.用消毒过的镊子将滤片整齐、有序的放入冷却的平皿内，盖上陶瓦盖，并做标记，置于37℃恒温培养箱内培养24h；
6.用卡尺测量抑菌圈大小，并比较不同浓度小分子多肽ZY4对不同细菌的作用强度，结果如表1、表2。
表1：
| 微生物 | 最低抑菌浓度(μg/ml) |
| 大肠杆菌 | 12.15 |
| 白色念珠菌 | 2.12 |
| 金黄色葡萄球菌 | 2.14 |
| 枯草杆菌 | 1.10 |
如表1所示：小分子多肽ZY4对大肠杆菌、白色念珠菌、金黄色葡萄球菌和枯草芽孢杆菌的最低抑菌浓度分别为12.15μg/ml、2.12μg/ml、2.14μg/ml、1.10μg/ml。
表2：
| 微生物 | 最低抑菌浓度(μg/ml) |
| 金黄色葡萄球菌(09B2499) | 2.25 |
| 溶血性葡萄球菌(09A4394抗氨苄) | 2.17 |
| 表皮葡萄球菌(09A3726抗氨苄) | 2.45 |
| 科氏葡萄球菌(09B2490抗氨苄) | 1.10 |
如表2所示：小分子多肽ZY4对痤疮有关的金黄色葡萄球菌、溶血性葡萄球菌、表皮葡萄球菌、科氏葡萄球菌的最低抑菌浓度分别为2.25μg/ml、2.17μg/ml、2.45μg/ml、1.10μg/ml。实验结果表明：小分子多肽ZY4具有显著的抑菌作用。
实施例3：小分子多肽ZY4对小鼠耳痤疮模型的治疗作用
1.用脑心浸液培养基培养痤疮丙酸杆菌ATCC11817，培养至对数期，生理盐水洗涤2次，生理盐水重悬至5×108CFU/ml；
2.选取重量为18g的雄性小鼠，昆明种，随机分为3组，每组6只，分别为治疗组、阳性对照组、阴性对照组，每只腹腔注射120μl、1％的戊巴比妥钠进行麻醉，然后在小鼠左耳皮内注射重悬后的菌液20μl/只；
3.用聚乙二醇、甘油将小分子多肽ZY4、克林霉素分别配制成2mg/ml软膏，其中聚乙二醇与甘油的重量份比为5:1，涂擦小鼠左耳皮肤表面，治疗组涂擦小分子多肽ZY4，阳性对照组涂擦克林霉素，阴性对照组涂擦聚乙二醇，每8h一次，共给药3次，24h后处死小鼠；
4.用干净的酒精棉球消毒小鼠左耳，剪下左耳并剪碎，转移至匀浆器中充分匀浆，1只耳朵加入1ml生理盐水匀浆；
5.稀释匀浆液至1000倍，取50μl稀释液涂脑心浸液培养基平板，37℃厌氧培养72h，计数菌落。结果如图1所示：给予2mg/ml的小分子多肽ZY4治疗后痤疮丙酸杆菌的菌落数为2.1×105，给予2mg/ml克林霉素治疗后痤疮丙酸杆菌的菌落数为5.6×105，给予聚乙二醇治疗后痤疮丙酸杆菌的菌落数为9.44×105，表明：ZY4对小鼠耳痤疮治疗效果明显好于克林霉素。
实施例4：小分子多肽ZY4对小鼠耳痤疮模型炎症的治疗作用
1.用脑心浸液培养基培养痤疮丙酸杆菌ATCC6919，培养至对数期，生理盐水洗涤2次，生理盐水重悬至5×108CFU/ml；
2.选取重量为18g的雄性小鼠，昆明种，随机分为3组，每组9只，分别为治疗组、阳性对照组、阴性对照组，每只腹腔注射50μl的***进行麻醉，然后在小鼠左耳皮内注射重悬后的菌液20μl/只；
3.用聚乙二醇将小分子多肽ZY4、克林霉素分别配制成2mg/ml软膏，其中聚乙二醇与甘油的重量份比为5:1，涂擦小鼠左耳皮肤表面，治疗组涂擦小分子多肽ZY4，阳性对照组涂擦克林霉素，阴性对照组涂擦聚乙二醇，每8h一次，共给药3次，24h后处死小鼠；
4.用干净的酒精棉球消毒小鼠左耳，测量小鼠耳朵厚度，结果如图2所示：治疗前的小鼠耳朵厚度均为0.20mm，给予2mg/ml的小分子多肽ZY4治疗1天后小鼠耳朵的厚度0.25mm，给予2mg/ml克林霉素治疗1天后小鼠耳朵厚度为0.34mm，给予聚乙二醇治疗1天后小鼠耳朵的厚度为0.43mm,表明：ZY4消炎效果明显好于克林霉素。
实施例5：小分子多肽ZY4抗肺癌肿瘤细胞A549活性实验
1.收集对数期肺癌肿瘤细胞A549，制成细胞悬液，调整其浓度至5×106～10×106个/ml，每孔加入100μl，铺板使待测细胞调密度至1000-10000孔，边缘孔用无菌PBS填充；
2. 5％CO2、37℃孵育，至细胞单层铺满96孔平地板孔底，待细胞贴壁2～12h后加入浓度为100μg/ml、200μg/ml的小分子多肽ZY4、浓度为10μg/ml和5μg/ml的紫杉醇，5％CO2、37℃孵育16～48h，倒置显微镜下观察；
3.每孔加入20μl、5mg/ml的MTT溶液，继续培养4h，吸取孔内培养液；
4.每孔加入150μl二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解，在酶联免疫检测仪OD490nm处测量各孔的吸光值，同时设置调零孔、对照孔，结果如图3所示：200μg/ml的ZY4作用于肺癌细胞A549后OD值为0.3，100μg/ml的ZY4作用于肺癌细胞A549后OD值为0.5；10μg/ml的紫杉醇作用于癌细胞肺癌细胞A549后OD值为0.5，10μg/ml的紫杉醇作用于癌细胞肺癌细胞A549后OD值为0.7，表明：ZY4对肺癌肿瘤细胞A549有明显的抑制作用。
实施例6：小分子多肽ZY4抗乳腺癌细胞MDA-435活性实验
1.收集对数期乳腺癌细胞MDA-435制成细胞悬液，调整其浓度至5×106～10×106个/ml，每孔加入100μl，铺板使待测细胞调密度至1000～10000孔，边缘孔用无菌PBS填充；
2. 5％CO2、37℃孵育，至细胞单层铺满96孔平地板孔底，待细胞贴壁2～12h后加入浓度为50～300μg/ml的小分子多肽ZY4、对照为同体积的生理盐水，5％CO2、37℃孵育16～48h，倒置显微镜下观察；
3.每孔加入20μl、5mg/ml的MTT溶液，继续培养4h，吸取孔内培养液；
4.每孔加入150μl二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解，在酶联免疫检测仪OD490nm处测量各孔的吸光值，同时设置调零孔、对照孔，结果如图4所示：300μg/ml的ZY4作用乳腺癌细胞MDA-435后OD值为0.17，200μg/ml的ZY4作用乳腺癌细胞MDA-435后OD值为0.20，100μg/ml的ZY4作用乳腺癌细胞MDA-435后OD值为0.61，50μg/ml的ZY4作用乳腺癌细胞MDA-435后OD值为0.7，表明：ZY4对乳腺癌细胞MDA-435的抑制具有浓度依赖性。
实施例7：小分子多肽ZY4抗黑色素瘤细胞A357活性实验
1.收集对数期黑色素瘤细胞A357，制成细胞悬液，调整其浓度至5×106～10×106个/ml，每孔加入100μl，铺板使待测细胞调密度至1000～10000孔，边缘孔用无菌PBS填充；
2. 5％CO2、37℃孵育，至细胞单层铺满96孔平地板孔底，待细胞贴壁2～12h后加入浓度为100μg/ml、200μg/ml的小分子多肽ZY4、对照为同体积的生理盐水，5％CO2、37℃孵育16～48h，倒置显微镜下观察；
3.每孔加入20μl、5mg/ml的MTT溶液，继续培养4h，吸取孔内培养液；
4.每孔加入150μl二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解，在酶联免疫检测仪OD490nm处测量各孔的吸光值，同时设置调零孔、对照孔，结果如图5所示：100μg/ml的ZY4作用黑色素瘤细胞A357后OD值为1.0，200μg/ml的ZY4作用黑色素瘤细胞后OD值为0.72，生理盐水作用黑色素瘤细胞后OD值为1.0。表明：200μg/ml的ZY4对黑色素瘤有明显抑制作用。
实施例8：小分子多肽ZY4抗肝癌细胞HepG2活性实验
1.收集对数期肝癌细胞HepG2，制成细胞悬液，调整其浓度至5×106～10×106个/ml，每孔加入100μl，铺板使待测细胞调密度至1000～10000孔，边缘孔用无菌PBS填充；
2. 5％CO2、37℃孵育，至细胞单层铺满96孔平地板孔底，待细胞贴壁2～12h后加入浓度为100μg/ml、200μg/ml的小分子多肽ZY4、对照为同体积的生理盐水，5％CO2、37℃孵育16～48h，倒置显微镜下观察；
3.每孔加入20μl、5mg/ml的MTT溶液，继续培养4h，吸取孔内培养液；
4.每孔加入150μl二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解，在酶联免疫检测仪OD490nm处测量各孔的吸光值，同时设置调零孔、对照孔，结果如图6所示：100μg/ml的ZY4作用肝癌细胞HepG2后OD值为0.89，200μg/ml的ZY4作用肝癌细胞HepG2后OD值为0.6，生理盐水作用肝癌细胞HepG2后OD值为1.0，表明：200μg/ml和100μg/ml的ZY4对肝癌细胞HepG2有明显的抑制作用。
实施例9：小分子多肽ZY4抗胃癌细胞SGC7901活性实验
1.收集对数期胃癌细胞SGC7901，制成细胞悬液，调整其浓度至5×106～10×106个/ml，每孔加入100μl，铺板使待测细胞调密度至1000～10000孔，边缘孔用无菌PBS填充；
2. 5％CO2、37℃孵育，至细胞单层铺满96孔平地板孔底，待细胞贴壁2～12h后加入浓度为50～300μg/ml的小分子多肽ZY4、对照为同体积的生理盐水，5％CO2、37℃孵育16～48h，倒置显微镜下观察；
3.每孔加入20μl、5mg/ml的MTT溶液，继续培养4h，吸取孔内培养液；
4.每孔加入150μl二甲基亚砜，置摇床上低速振荡10min，使结晶物充分溶解，在酶联免疫检测仪OD490nm处测量各孔的吸光值，同时设置调零孔、对照孔，结果如图7所示：50μg/ml的ZY4作用胃癌细胞SGC7901后OD值为0.65，100μg/ml的ZY4作用胃癌细胞SGC7901后OD值为0.57，200μg/ml的ZY4作用胃癌细胞SGC7901后OD值为0.2，300μg/ml的ZY4作用胃癌细胞SGC7901后OD值为0.09，表明：ZY4对肝癌细胞胃癌细胞SGC7901有明显的抑制作用。
Claims (4)
1.小分子多肽ZY4，其特征在于，它包含17个氨基酸残基，分子量为2374.0 Da，等电点为10.74，其氨基酸序列如SEQ ID:1所示，为缬氨酸-半胱氨酸-赖氨酸-精氨酸-色氨酸-赖氨酸-赖氨酸-色氨酸-赖氨酸-精氨酸-赖氨酸-色氨酸-赖氨酸-赖氨酸-色氨酸-半胱氨酸-缬氨酰胺，所述氨基酸序列中两个半胱氨酸形成一个分子内二硫键。
2.一种如权利要求1所述小分子多肽ZY4在制备抗感染大肠杆菌、白色念珠菌、金黄色葡萄球菌、枯草芽孢杆菌、溶血性葡萄球菌、表皮葡萄球菌或科氏葡萄球菌药物中的应用。
3.一种如权利要求1所述小分子多肽ZY4在制备治疗痤疮的药物或化妆品中的应用。
4.一种如权利要求1所述小分子多肽ZY4在制备抗肺癌、乳腺癌、黑色素瘤、肝癌或胃癌药物中的应用。
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