CN116474074A - 一种预防hpv感染的多肽消毒剂组合物 - Google Patents
一种预防hpv感染的多肽消毒剂组合物 Download PDFInfo
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- CN116474074A CN116474074A CN202210881560.7A CN202210881560A CN116474074A CN 116474074 A CN116474074 A CN 116474074A CN 202210881560 A CN202210881560 A CN 202210881560A CN 116474074 A CN116474074 A CN 116474074A
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Abstract
本发明公开了一种预防HPV感染的多肽消毒剂组合物及多肽妇科温敏凝胶、多肽妇科栓剂,属于病毒消毒剂技术领域。其有效成分包括由如SEQ ID NO.01所示的第一多肽Gassericin T、如SEQ ID NO.02所示的第二多肽Alloferon‑1组成的混合多肽。本发明中混合多肽组分具有抗炎和抗病毒作用,安全性高,适用范围广,并能有效预防HPV感染和减轻HPV感染引发的炎症。
Description
技术领域
本发明属于病毒消毒剂技术领域,具体涉及一种预防HPV病毒的多肽消毒剂组合物。
背景技术
人乳头瘤病毒(HPV)根据其与癌症的关系分为2类,低危HPV类型与外生殖器疣和复发性呼吸道乳头瘤病(RRP)有关;高危HPV类型的持续感染是癌症发展的最重要风险因素,包括宫颈癌、阴茎癌、肛门癌、阴道癌、外阴癌和口咽癌等。
HPV是最常见的性传播感染病毒。HPV感染导致一系列临床疾病,严重程度从良性疣到转移性肿瘤。目前已经确定200多种HPV分型,大致分为高风险和低风险类型。低风险HPV类型,如HPV 6和11,不具有致癌性,其感染可引起肛门和生殖器区域周围尖锐湿疣以及呼吸道复发性呼吸道状瘤病或喉状瘤病;高危HPV类型包括HPV 16、18、31、33、35、45、51、52、56、58、59和68,其感染具有恶性癌变风险。研究发现,有HPV 6或11感染情况的妇女36个月内生殖器疣累积发生率为64.2%,其中30%的生殖器疣患者继治疗后复发。HPV感染导致患者频繁就诊,医疗成本增加,且引发沉重的社会心理负担。在美国,与HPV相关的疾病(尖锐湿疣、生殖器疱疹、癌前病变、癌症等)相关的年度医疗费用估计超80亿美元。
目前尚缺乏针对HPV的明确有效的预防和治疗药物及措施,临床上暂以支持治疗和对症治疗为主,预防病毒的感染仍是最主要的手段。有效抑制HPV感染和降低HPV感染引发的炎症,对HPV的防治尤为重要。因此,开发预防HPV病毒感染的消毒剂具有重要意义。
HPV E6蛋白是HPV最主要的致病蛋白。E6蛋白能够介导肿瘤抑制因子p53的失活。因此,E6蛋白作为抑制HPV感染的主要靶点,可用于HPV治疗药物的筛选。
发明内容
本发明解决的技术问题是:提出一种预防HPV感染的多肽消毒剂组合物及多肽妇科温敏凝胶、多肽妇科栓剂,本发明成分安全,安全性高,适用范围广,并能有效预防HPV病毒感染和减轻HPV感染引发的炎症。第一多肽、第二多肽及其组合物能够降低IL-1β、IL-2、IL-4、IL-5、IL-12的水平,均具有抗炎作用;二者组合物具有协同抗炎效果,且抗炎作用优于阿司匹林。
为了解决上述技术问题,本发明提出的技术方案是:一种预防HPV感染的多肽消毒剂组合物,其特征在于:其有效成分包括由如SEQ ID NO.01所示的第一多肽Gassericin T、如SEQ ID NO.02所示的第二多肽Alloferon-1的混合多肽,其中,第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。
优选的,所述第一多肽的浓度为6.68μM/Kg,所述第二多肽的浓度为17.39μM/Kg。
优选的,还包括蒲公英、金银花、金盏花、透明质酸钠、甘油和水。
为了解决上述技术问题,本发明提出的另一技术方案是:一种预防HPV感染的多肽妇科温敏凝胶,其有效成分包括由如SEQ ID NO.01所示的第一多肽Gassericin T、如SEQID NO.02所示的第二多肽Alloferon-1的混合多肽,其中,第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。
优选的,所述第一多肽的浓度为6.68μM/Kg,所述第二多肽的浓度为17.39μM/Kg。
优选的,还包括泊洛沙姆P407、P188、透明质酸钠和乳酸-乳酸钠缓冲液,该凝胶在体温成胶,易于在腔道粘附,延长药效。
为了解决上述技术问题,本发明提出的另一技术方案是:一种预防HPV感染的多肽妇科栓剂,其有效成分包括由如SEQ ID NO.01所示的第一多肽Gassericin T、如SEQ IDNO.02所示的第二多肽Alloferon-1的混合多肽,其中,第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。
优选的,所述第一多肽的浓度为6.68μM/Kg。
优选的,所述第二多肽的浓度为17.39μM/Kg。
优选的,还包括甘油、明胶、乳酸-乳酸钠缓冲液,该栓剂有弹性,不易折断,易于在腔道缓慢溶于分泌液,延长药效。
有益效果:
本发明成分安全,安全性高,适用范围广,并能有效预防HPV病毒感染和减轻HPV感染引发的炎症。
第一多肽、第二多肽及其组合物能够显著上调卵巢切除小鼠阴道中lgA和lgM表达,说明第一多肽、第二多肽及其组合物上调免疫球蛋白表达,抑制炎症,具有减轻HPV引发炎症反应的特性。
第二多肽与重组HPV16 E6具有高亲和力;第二多肽可以挽救P53在HPV16阳性癌细胞中的转录和表达活性。
第一多肽在6.68μM/Kg时达到最佳抗炎浓度,第二多肽在17.39μM/Kg到达最佳抗炎浓度;第一多肽和第二多肽的组合物在优选浓度下72h抗炎率可达到13%,96h抗炎率可达到20%,协同抗炎效果显著。
第一多肽、第二多肽及其组合物能够降低IL-1β、IL-2、IL-4、IL-5的水平,因此具有抗炎作用;二者组合物具有协同抗炎效果,且抗炎作用优于阿司匹林。
细胞毒性测定显示,即使较高浓度的第一多肽或第二多肽对人正常卵巢上皮细胞显示无毒性作用。
附图说明
下面结合附图对本发明的作进一步说明。
图1为本发明实施例2中的第一多肽、第二多肽及其组合物对lgA和lgM表达的影响。
图2为本发明实施例3中的第二多肽与HPV E6的结合能力评价。
图3为本发明实施例4中的第二多肽诱导P53及其靶基因表达结果。
图4为本发明实施例5中不同浓度第一多肽和第二多肽的抗炎效果。
图5为本发明实施例6中第一多肽、第二多肽及其组合物上调炎症因子表达结果。
具体实施方式
以下通过具体实施方式结合附图对本发明的技术方案进行进一步的说明和描述。
实施例1:第一多肽(Peptide 1)和第二多肽(Peptide 2)的合成方法
采用固相合成方法分布表合成第一多肽(Peptide1)和第二多肽(Peptide 2)。以二氯树脂为载体树脂,加入所需氨基酸,以N,N-二异丙基乙胺(DIC)和1-羟基苯并三唑(HOBt)为缩合剂,Fmoc-氨基酸为原料缩合,每一步氨基酸连接率用Fmoc法测量。将肽和树脂复合物清洗干燥后加入2mL裂解液,室温反应1小时,抽滤,加过量冰无水乙醚沉淀30min,3000r/min离心5min收集沉淀,反复多次。将收集到沉淀真空干燥沉淀至恒重。经电喷雾离子化质谱(ESI/MS)测定粗肽分量,然后与理论分子量(Peptide 1:7480.5Da;Peptide2:1265.3Da)对照,经真空冷冻干燥后得纯品。
实施例2:第一多肽(Peptide 1)、第二多肽(Peptide 2)及其组合物(Peptide 1+Peptide 2)对lgA和lgM表达的影响
实验方法:
十周龄ICR雌性小鼠随机分为5组,分别为假手术组(Sham)、卵巢切除术组(OVX)、OVX+Peptide 1组、OVX+Peptide 2组和OVX+Peptide 1+Peptide 2组,每组5只。除假手术组外的小鼠均通过卵巢切除术进行去势。小鼠腹腔注射4%水合氯醛溶液麻醉后,俯卧姿势将其固定后清理手术区毛发,用酒精碘伏对小鼠下背部以及侧腹部消毒,在小鼠下背部距两后肢上缘约0.5cm的背中线处向下用手术刀切开一个2-3cm的纵向切口,用圆头剪扩张分离皮肤与肌肉,在左侧约0.5cm后从创口可见肌层和被它覆盖住的白色脂肪组织,用镊子夹起肌层并切开,轻轻拨开脂肪组织找到左侧卵巢,结扎与左侧卵巢紧密相连的子宫角,摘除左侧卵巢、输卵管和部分子宫角并缝合切开的肌层。以相同操作摘除右侧卵巢。缝合右侧肌层后观察是否出血,然后缝合小鼠皮肤,再次在手术区用酒精碘伏消毒。术后对伤口施用局部抗生素以预防感染并降低因手术导致的动物死亡率。假手术组不摘除卵巢,其他操作与实验组相同。每日阴道推注Peptide 1(6.68μM/Kg)、Peptide 2(17.39μM/Kg)及其组合物,持续八周。给药结束后取阴道组织切片进行免疫荧光染色,检测免疫球蛋白lgA和lgM的表达量,分析荧光强度如图1所示。
OVX+Peptide 1、OVX+Peptide 2及其组合物的lgA和lgM荧光强度均显著增加,说明第一多肽、第二多肽及其组合物具有上调免疫球蛋白表达、抑制炎症作用,具有减轻HPV引发炎症反应的特性。
实施例3:基于BIACore分子结合系统检测第二多肽(Peptide 2)与HPV的结合能力
材料及试剂:Series S Sensor Chip CM5(GE Life100530)、HPV16E6纯化蛋白、Peptide 2、Amine Coupling Kit(GELife100050、PBS、甘氨酸-盐酸缓冲溶液(pH 2.5))。
实验方法:
使用BIACore T200仪器研究所选亲和体分子与目标蛋白的实时生物特异性相互作用。靶蛋白HPV16 E6固定在CM5芯片的羧酸葡聚糖表面上,不同浓度的Peptide 2在25℃下以30μL/min的速度通过芯片。如图2所示,检测到共振信号呈浓度依赖性增加,表明Peptide2与重组HPV16 E6结合良好。进一步确定解离平衡常数(KD)、关联速率常数(Kon),以及解离速率常数(Koff),使用BIA评估软件(Biacore)3.0.2通过一对一的Langmuir结合模型进行动力学BIACore分析。
结果如表1及图2所示,Peptide 2的解离平衡常数(KD)值均显著低于阴性对照蛋白;相反,Peptide 2的关联速率常数(Kon)值明显高于阴性对照蛋白亲和体。表明,Peptide2与重组HPV16 E6具有高亲和力。
表1
多肽 | KD(μm) | Kon(1/Ms) | Koff(1/s) |
第二多肽 | 50.60 | 124 | 3.87*10-3 |
阴性对照蛋白 | 1320000 | 6.15*10-4 | 8.65*10-4 |
实施例4:利用免疫印迹法(Western Blot)检测第二多肽(Peptide 2)挽救P53在HPV16阳性癌细胞中的转录和表达活性
实验方法:在6孔板中以每孔1×105的浓度接种人宫颈鳞癌Caski细胞,在含有17.39μM的Peptide 2或阴性对照蛋白的培养基和单独的培养基内进行培养。通过WesternBlot检测P53蛋白及其靶蛋白BAX,BBC3(PUMA)和CDKN1A(P21)的表达,这些蛋白均与细胞凋亡和细胞周期停滞密切相关。
结果显示,与对照相比,Peptide 2能够时间依赖性上调P53、PUMA、BAX和P21的表达(图3)。综上所述,第二多肽可以挽救P53在HPV16阳性癌细胞中的转录和表达活性。
实施例5:第一多肽(Peptide 1)和第二多肽(Peptide 2)的最佳抗炎浓度
实验方法:ICR小鼠随机分组,每组5只小鼠。在λ-角叉菜胶注射前5h每组小鼠分别给予不同浓度Peptide 1和Peptide 2及其组合物,阴性对照组给予0.9%正常生理盐水。测量小鼠足肿胀厚度数据。
结果如图4所示,第一多肽在6.68μM/Kg时达到最佳抗炎浓度,第二多肽在17.39μM/Kg到达最佳抗炎浓度。由此确定第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。优选第一多肽的浓度为6.68μM/Kg。优选第二多肽的浓度为17.39μM/Kg。第一多肽和第二多肽组合物在优选浓度下72h抗炎率可达到13%,96h抗炎率可达到20%,协同抗炎效果显著。
实施例6:利用Luminex液相悬浮芯片检测第一多肽(Peptide 1)、第二多肽(Peptide 2)及其组合物(Peptide 1+Peptide 2)对炎症因子表达的影响
实验仪器:悬液微珠芯片平台Bio-Plex MAGPIX System(Bio-Rad);实验试剂盒:Bio-Plex Pro Mouse Cytokine Grp I Panel 23-plex。
实验方法:将ICR小鼠随机分为对照组(Ctrl)、λ-角叉菜胶(CGN)、阿司匹林(ASA)+λ-角叉菜胶(250mg/kg)和λ-角叉菜胶+Peptide 1(50mg/Kg)组,λ-角叉菜胶+Peptide 2(22mg/Kg)组和λ-角叉菜胶+Peptide 1+Peptide 2组,每组5只小鼠。对照组和λ-角叉菜胶组腹腔注射给予1ml 0.9%正常生理盐水。阳性对照腹腔注射阿司匹林(250mg/kg),2小时后在小鼠左后爪注射30μL 1%的卡拉胶(沿小鼠足底中线,将针头从脚跟处插入并轻轻注射到肌腱下)。在λ-角叉菜胶注射6小时后腹腔注射Peptide 2。λ-角叉菜胶注射7小时后处死小鼠,从小鼠眼眶收集血液,离心取血清,用于炎症因子检测,每组取三个样品进行评估。应用Bio-Plex Pro Mouse Cytokine Grp I Panel23-plex检测试剂盒,经过样品孵育、孵育检测抗体及显色,送入已校正的Bio-Plex机器中读值,获得的荧光由软件自动计算优化。
结果如图5所示,第一多肽和第二多肽及其组合物均能够降低IL-1β、IL-2、IL-4、IL-5的水平,均具有抗炎作用(P<0.05);二者组合物具有协同抗炎效果,且抗炎作用优于阿司匹林。
实施例7:第一多肽(Peptide 1),第二多肽(Peptide 2)的细胞毒性检验
实验方法:使用MTT测定法测定Peptide 1和Peptide 2对人正常卵巢上皮细胞的毒性。将细胞接种在96孔板中,密度为3×103细胞/孔,并用纯化的Peptide 1、Peptide2或缓冲液单独在不同时间点培养。将10μl MTT溶液(5mg/mL)加入到每个孔中,并在37℃下在5%CO2细胞培养箱中孵育24小时。在3000g下离心15分钟后,除去上清液,并加入体积为150μl的二甲亚砜以溶解甲苯肼晶体。使用酶标仪在570nm处测量吸光度。结果所示,细胞毒性测定显示,即使较高浓度的Peptide 1(1mg/ml)和Peptide 2(1mg/ml)及其组合物与阴性对照相比,对人正常卵巢上皮细胞均显示无毒性作用。
实施例8
一种预防HPV感染的消毒剂组合物,由混合多肽、蒲公英、金银花、金盏花、透明质酸钠、甘油和注射用水组成,其中,第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。所述蒲公英的含量为1.0%,金银花的含量为17%,金盏花的含量为2%,透明质酸钠的含量为0.03%,甘油的含量为15%,余量为无菌去离子水。
该消毒剂组合物的制备方法为:先将注射用水溶解蒲公英、金银花、金盏花、透明质酸钠、甘油充分溶解后配置成辅料母液,之后用辅料母液溶解上述多肽,最后以注射用水补足。
实施例9
一种预防HPV感染的多肽妇科温敏凝胶,由混合多肽、泊洛沙姆P407、P188、透明质酸钠组成,其中,第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。所述泊洛沙姆P407的含量为25%,P188含量为8%,透明质酸钠的含量为0.3%,其余为乳酸-乳酸钠缓冲溶液。
该妇科温敏凝胶的制备方法为:先将泊洛沙姆P407、P188和透明质酸钠溶于乳酸-乳酸钠缓冲溶液,置于4℃下用冷溶法溶解,制成辅料母液,之后用辅料母液溶解上述多肽,补足乳酸-乳酸钠缓冲溶液,调整pH在3.8左右即成。
实施例10
一种预防HPV感染的多肽妇科栓剂,由混合多肽、甘油、明胶、和乳酸-乳酸钠缓冲液组成。其中,第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。所述甘油的含量为34%,明胶含量为60%,余量为乳酸-乳酸钠缓冲液。
该妇科栓剂的制备方法为:先将明胶置于乳酸-乳酸钠缓冲液中在室温溶胀后加热至60℃~70℃使其完全溶解,再加入处方量的甘油降温至40℃~45℃,制成辅料母液。用辅料母液溶解上述多肽,倒入涂有润滑剂的模具静置成型即成。
以上所述,仅为本发明的较佳实施例而已,故不能此限定本发明实施的范围,即依本发明专利范围及说明书内容所作的等效变化与修饰,皆应仍属本发明涵盖的范围。
Claims (10)
1.一种预防HPV感染的多肽消毒剂组合物,其特征在于:其有效成分包括由如SEQ IDNO.01所示的第一多肽Gassericin T、如SEQ ID NO.02所示的第二多肽Alloferon-1的混合多肽,其中,第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。
2.根据权利要求1所述的多肽消毒剂组合物,其特征在于:所述第一多肽的浓度为6.68μM/Kg,所述第二多肽的浓度为17.39μM/Kg。
3.根据权利要求1或2所述的预防HPV感染的多肽消毒剂组合物,其特征在于:还包括蒲公英、金银花、金盏花、透明质酸钠、甘油和水。
4.一种预防HPV感染的多肽妇科温敏凝胶,其特征在于:其有效成分包括由如SEQ IDNO.01所示的第一多肽Gassericin T、如SEQ ID NO.02所示的第二多肽Alloferon-1的混合多肽,其中,第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。
5.根据权利要求4所述的多肽妇科温敏凝胶,其特征在于:所述第一多肽的浓度为6.68μM/Kg,所述第二多肽的浓度为17.39μM/Kg。
6.根据权利要求4或5所述的多肽妇科温敏凝胶,其特征在于:还包括泊洛沙姆P407、P188、透明质酸钠和乳酸-乳酸钠缓冲液,该凝胶在体温成胶,易于在腔道粘附,延长药效。
7.一种预防HPV感染的多肽妇科栓剂,其特征在于:其有效成分包括由如SEQ ID NO.01所示的第一多肽Gassericin T、如SEQ ID NO.02所示的第二多肽Alloferon-1的混合多肽,其中,第一多肽的浓度为6-8μM/Kg,第二多肽的浓度为17-19μM/Kg。
8.根据权利要求7所述的多肽妇科栓剂,其特征在于:所述第一多肽的浓度为6.68μM/Kg。
9.根据权利要求7所述的多肽妇科栓剂,其特征在于:所述第二多肽的浓度为17.39μM/Kg。
10.根据权利要求7至9中任一所述的多肽妇科栓剂,其特征在于:还包括甘油、明胶、乳酸-乳酸钠缓冲液,该栓剂有弹性,不易折断,易于在腔道缓慢溶于分泌液,延长药效。
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