CN106974904B - 杨梅素及其衍生物的新用途和一种抗hiv感染的杀微生物剂 - Google Patents

杨梅素及其衍生物的新用途和一种抗hiv感染的杀微生物剂 Download PDF

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CN106974904B
CN106974904B CN201710151080.4A CN201710151080A CN106974904B CN 106974904 B CN106974904 B CN 106974904B CN 201710151080 A CN201710151080 A CN 201710151080A CN 106974904 B CN106974904 B CN 106974904B
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myricetin
hiv
microbicide
sevi
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李琳
任茹霞
张萱萱
殷淑文
丁永桢
梁太珍
刘叔文
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Guangzhou South Medical University Science Park Co ltd
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Abstract

本发明公开了杨梅素及其衍生物的新用途和一种抗HIV感染的杀微生物剂。杨梅素能够抑制SEVI的形成，破坏成熟SEVI的结构，直接阻断SEVI引起的HIV感染增强，并且杨梅素本身还具有良好的抗HIV活性，可开发为具有拮抗SEVI和抗HIV的双功能杀微生物剂，最大程度地避免因精液中淀粉样纤维的存在而导致临床疗效不佳的可能；在精液存在的条件下，杨梅素能分别与叠氮胸苷、雷特格韦、马拉维若、替诺福韦、奈韦拉平、依法韦仑任意一种抗逆转录病毒药物协同抗HIV，可开发出含有杨梅素和抗逆转录病毒药物的多组分抗HIV感染杀微生物剂，同时作用于精液和病毒两个方面，发挥更好的临床抗HIV感染疗效。

Description

杨梅素及其衍生物的新用途和一种抗HIV感染的杀微生物剂
技术领域
本发明涉及杀微生物剂领域，更具体地涉及杨梅素及其衍生物的新用途和一种抗HIV感染的杀微生物剂。
背景技术
艾滋病(AIDS)是人免疫缺陷病毒(HIV)引起的病毒性传染病，性传播是HIV的主要传播途径，虽然理论上来说，预防HIV感染最好的手段是使用艾滋病疫苗；然而，艾滋病疫苗的研究还需要较长时间的摸索，短期内有效的艾滋病疫苗还难以问世。
杀微生物剂是一类含有抗HIV成分的凝胶、乳脂、栓剂、药膜或海绵，在性交前置入阴道或肛门内，以预防艾滋病病毒和其它性传播疾病的性传播，是一种可由女性所控制的预防HIV性传播的有效措施，这对于女性地位比较低下的发展中国家(如大部分的非洲国家)预防艾滋病传播有非常重要的意义。为此，杀微生物剂的研究开发已被联合国艾滋病规划署和世界卫生组织定为全球优先发展的策略。
迄今为止，大约有20个杀微生物剂产品已进入临床试验的各个阶段，其中，大部分多聚阴离子类和表面活性剂类杀微生物剂因临床抑制效果不甚理想，或存在一定的安全问题，均先后宣布失败或被中止。
由于杀微生物剂的用药部位为阴道或直肠，不能忽视精液对其药效的影响。精液中存在淀粉样纤维，促进HIV的感染，在存在生理浓度精液衍生肽时，1到3个病毒颗粒就可导致HIV感染。其中，前列腺酸性磷酸酶(prostatic acidic phosphatase,PAP)多肽片段(PAP248-286)形成的淀粉样纤维被命名为精液源性病毒感染增强因子(Semen-derivedEnhancer of Virus Infection,SEVI)，SEVI促进HIV感染的作用机理主要是：1)富含阳离子氨基酸残基的SEVI能通过静电作用降低HIV病毒颗粒与靶细胞之间的静电排斥；2)SEVI在人体体液中呈无序状态，利于病毒颗粒与靶细胞膜相互作用；3)SEVI直接捕获HIV病毒颗粒，提高病毒在靶细胞表面沉降速度，促进病毒与靶细胞吸附和融合。因此，在精液或PAP248-286存在时，SEVI会抑制杀微生物剂的抗HIV感染能力，这意味着，开发一种能拮抗SEVI对HIV感染的增强能力，又具有抗HIV病毒活性的双功能杀微生物剂，非常有现实意义。
杨梅素(Myricetin，简称Myr)是一种黄酮类化合物，化学式为C15H10O8，存在于壳斗科、豆科、报春花科、葡萄科、菊科等植物中，现有研究表明，杨梅素具有抗肿瘤、降低神经毒性、影响淋巴细胞活化与增殖、拮抗血小板活化因子、降血糖、抗氧化、保肝护肝等药理学活性。另外，杨梅素来源广泛，且相对价格低廉，安全可靠，有利于后续广泛开发上市。
发明内容
本发明的目的在于提供杨梅素及其衍生物的新用途和一种抗HIV感染的杀微生物剂。
本发明所采取的技术方案是：
杨梅素或杨梅素衍生物在预防HIV感染中的应用。
作为上述应用的进一步限定，所述杨梅素衍生物为杨梅素在药学上可以接受的盐、脂及糖基化的衍生物。
一种抗HIV感染的杀微生物剂，其特征在于：含有杨梅素和/或杨梅素衍生物。
作为上述杀微生物剂的进一步优选，还含有抗逆转录病毒药物。
作为上述杀微生物剂的进一步优选，所述抗逆转录病毒药物为叠氮胸苷、雷特格韦、马拉维若、替诺福韦、奈韦拉平、依法韦仑中至少一种。
作为上述杀微生物剂的进一步优选，杨梅素衍生物为杨梅素在药学上可以接受的盐、脂及糖基化的衍生物。
本发明的有益效果是：
(1)杨梅素能单独作为抗HIV感染的杀微生物剂。杨梅素能抑制PAP248-286多肽自聚集形成SEVI淀粉样纤维；能够剂量依赖性抑制SEVI淀粉样纤维的形成；能够破坏已经成熟的SEVI结构，导致纤维二级结构的改变；在TZM-b1感染增强细胞模型上，还可直接阻断SEVI引起的HIV病毒感染。综上所述，杨梅素能够抑制SEVI的形成，破坏成熟SEVI的结构，直接阻断SEVI引起的HIV感染增强，并且杨梅素本身还具有良好的抗HIV活性，可开发为具有拮抗SEVI和抗HIV病毒的双功能杀微生物剂，最大程度地避免因精液中淀粉样纤维的存在而导致临床疗效不佳的可能。
(2)杨梅素能与抗逆转录病毒药物(简称，ARVs)联合作为抗HIV感染的杀微生物剂。在精液存在的条件下，杨梅素能分别与叠氮胸苷、雷特格韦、马拉维若、替诺福韦、奈韦拉平、依法韦仑任意一种抗逆转录病毒药物协同抗HIV，可开发出含有杨梅素和抗逆转录病毒药物的多组分抗HIV感染杀微生物剂，同时作用于精液和病毒两个方面，发挥更好的临床抗HIV感染疗效。
附图说明
图1：硫黄素T染色法检测梅素对PAP248-286自聚集形成SEVI淀粉样纤维的影响；
图2：透射电子显微镜观察杨梅素对PAP248-286自聚集形成SEVI淀粉样纤维的影响；
图3：圆二色谱法检测杨梅素对成熟SEVI二级结构的破坏作用，其中，图A、B、C分别为杨梅素处理1min、24h、48h的检测结果；
图4：TZM-b1细胞感染模型检测杨梅素拮抗SEVI增强HIV病毒感染的能力，其中，图A、B分别为X4嗜性HIV病毒和R5嗜性HIV病毒感染的增强倍数结果。
具体实施方式
下面将结合实验，对本发明进一步描述。
需要说明的是，本实例在以本发明技术方案为前提下进行实施，给出了详细的实施方式和具体的操作过程，但本发明的保护范围不限于此。
实验例1、硫磺素T染色法观察杨梅素对SEVI淀粉样纤维形成的影响
(1)梯度稀释的杨梅素(终浓度为75,37.5,18.75及0μg/mL)与3mg/mL PAP248-286溶液混匀，置于恒温振荡仪中，37℃，1400rpm转速下恒温振荡；
(2)于振荡的不同时间点(0,6,12,18,24及48h)分别取出10μL样品与190μL硫磺素T溶液混合，荧光酶标仪测定荧光强度(激发波长为440nm，发射波长为485nm)。
实验结果如图1所示，75μg/mL的杨梅素可在48h内完全抑制PAP248-286自聚集形成SEVI淀粉样纤维。
实验例2、透射电子显微镜观察杨梅素对SEVI淀粉样纤维的形态的影响
(1)梯度稀释的杨梅素(75,37.5,18.75及0μg/mL)与3mg/mL PAP248-286溶液混匀，置于恒温振荡仪中，37℃，1400rpm转速下恒温振荡；
(2)于不同时间点(0,12及24h)，取5μL样品滴于铜网上，2min后用滤纸从铜网边缘吸去多余的液体；
(3)滴加磷钨酸(3％,pH 7.0)于铜网，2min后用滤纸从铜网边缘吸去多余染液；
(4)滴加纯水于铜网，用滤纸从铜网边缘吸取多余水，待干后即用于电镜观察。
实验结果如图2所示，50μg/mL的杨梅素在24h内完全抑制3mg/ml PAP248-286自聚集形成SEVI淀粉样纤维。
实验例3、圆二色谱法检测杨梅素对成熟SEVIβ-sheet二级结构的影响
(1)梯度稀释的杨梅素(500,250,125及0μg/mL)与3mg/mL预形成SEVI溶液混匀，置于恒温振荡仪中，37℃，1400rpm转速下反应；
(2)于不同时间点(1min,24h及48h)，取出样品与PBS混匀稀释至多肽终浓度为300μg/mL；
(3)于圆二色谱仪上扫描200～260nm波段的光谱图。
实验结果如图3所示，杨梅素处理1min后，淀粉样纤维特征结构β-sheet在220nm处的峰消失了，说明杨梅素能迅速的破坏成熟SEVI的二级结构。
实验例4、在TZM-b1细胞感染模型上检测，杨梅素能够直接抑制SEVI介导的HIV病毒感染增强作用
(1)SEVI样品预处理：将3mg/mL PAP248-286溶液，置于37℃振荡器中，在1400rpm转速下，振摇48h或更长，直至观察到淀粉样纤维形成，将溶液离心，将上清和沉淀部分分别保存；
(2)将1×104个/孔TZM-b1细胞进入96孔细胞培养板中37℃,5％CO2条件下培养过夜；
(3)将系列梯度稀释杨梅素(50，25，12.5，6.25，3.13，1.56，0.78，0.39mg/mL)分别与50μg/mL SEVI混合，37℃共孵育1h后，离心去上清，DMEM重悬后，分别与X4、R5两种嗜性的HIV-1病毒混合，加入到TZM-b1细胞中，感染3h后更换新鲜的DMEM培养基。
(4)37℃，5％CO2条件下培养48h，荧光素酶报告基因实验检测病毒感染率
实验结果如图4所示，杨梅素能剂量依赖性地抑制SEVI介导的HIV病毒感染增强作用。
实验例5、在TZM-b1细胞感染模型上检测，精液环境下杨梅素和ARVs药物发挥协同抗HIV作用
(1)将1×104个/孔TZM-b1细胞进入96孔细胞培养板中37℃,5％CO2条件下培养过夜。
(2)在10％精液的环境下，将最高终浓度为10μg/mL杨梅素(Myricetin，简称Myr)倍比稀释后分别和抗逆转录病毒药物(简称ARVs)单独或者共同与R5嗜性的HIV-1病毒混合，37℃共孵育30min后，加入到TZM-b1细胞中，感染3h更换新鲜的DMEM培养基；上述各ARVs药物包括叠氮胸苷(zidovudine，简称AZT)、雷特格韦(raltegravir，简称RAL)，马拉维若(maraviroc，简称MAR)，替诺福韦(tenofovir，简称TNF)，奈韦拉平(nevirapine，简称NVP)，依法韦仑(efavirenz，简称EFV)。
(3)37℃，5％CO2条件下培养48h，荧光素酶报告基因实验检测病毒感染率，计算杨梅素和各ARVs药物的协同指数；已知两药合用，联用指数CI值能直观的反应出联用的药物之间是否存在协同作用。其中CI＜0.1，联用药物之间存在着很强的协同作用，0.10～0.30代表着强的协同,0.30～0.70代表着两药协同，0.70～0.85两药在某种程度上协同和0.85～0.90代表着较弱的协同作用。
表1精液环境下杨梅素和ARVs药物协同抗HIV-1
Figure BDA0001245599190000051
注：CI为联用指数。
结果如表1所示，杨梅素与叠氮胸苷、雷特格韦、马拉维若、替诺福韦、奈韦拉平、依法韦仑这六种ARVs分别的协同指数都低于0.4，表明两药有协同作用，能发挥较强的协同抗HIV感染的效果，有望开发出含有杨梅素和抗逆转录病毒药物的多组分抗HIV感染杀微生物剂，同时作用于精液和病毒两个方面，发挥更好的临床抗HIV感染疗效。

Claims (1)

1.杨梅素联合叠氮胸苷在制备抗HIV感染的杀微生物剂中的应用。
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