三类杀微生物剂候选物抗HIV-1_（IIIB）活性及机制研究
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摘要
艾滋病是严重危害人类健康的疾病。人类在同艾滋病的斗争中,从发现艾滋病的病因后,已开发出抗艾滋病病毒的药物,减轻了HIV/AIDS的发病率和死亡率,但是该病还不能够治愈。目前,性传播是HIV感染的最主要途径。全球90%的感染者是通过性传播而感染上HIV病毒的,其中女性感染者比例呈逐渐增加的趋势。HIV/AIDS的流行趋势仍然没有减弱的迹象,发展预防HIV感染的新技术十分紧迫。人们已经意识到,应用杀微生物剂预防HIV感染是目前所有手段中最有效的方法。国际社会对于开发一种由女性自己控制使用的杀微生物剂十分重视,把它看成与艾滋病疫苗研究同等重要的课题。在过去的15年里,杀微生物剂的研究和开发取得了显著的进展,已有30多种化合物或制剂进入临床前或临床研究阶段。但是面对“聪明的病毒”,我们的武器库显然还很单薄,我们还需要不断的研究新的化合物以满足需要。在本文中我们将对来源于中药的化合物、凝集素和稀土元素抗HIV-1_(ⅢB)活性进行探讨。
酯化多糖D2、D3、D6、D8、D9的IC_(50)值分别为(10.28±1.12)μg/ml、(10.90±1.08)μg/ml、(8.72±1.08)μg/ml、(15.10±1.08)μg/ml、(11.10±1.09)μg/ml,选择指数(SI)的值分别为261、331、313、213、203。稀土元素CCYCN也表现出了一定的抗HIV-1_(ⅢB)活性,其IC_(50)值为(4.02±1.07)μg/ml,选择指数(SI)的值为229。采用不同方法得到的化合物未酯化DN、未酯化DN1、未酯化DN2也对HIV-1_(ⅢB)有一定的活性,IC_(50)值分别为(33.12±1.08)μg/ml、(27.19±1.08)μg/ml、(10.68±1.08)μg/ml,选择指数(SI)的值分别为22、28、87。
通过初筛实验,我们得到酯化多糖D2、D3、D6、D8、D9对HIV-1_(ⅢB)有较好的抗性,为了了解酯化多糖D2、D3、D6、D8、D9作用机理,我们采取时间过程、融合阻断和化合物不同方法预处理病毒或宿主细胞等实验方法来进行作用机制的初步研究。实验结果表明:酯化多糖D2、D3、D6、D8、D9可能作用在HIV病毒复制的早期,即阻断HIV病毒吸附到宿主细胞上,进而抑制HIV-1_(ⅢB)宿主细胞。
我们又对酯化多糖D3、D6进行了稳定性实验。用SPSS15.0软件对所得数据进行分析,结果表明:经过一段时间,D3、D6在水溶液中的抗HIV-1_(ⅢB)活性随时间的增加而明显降低,有待进一步研究。
综上所述,酯化多糖D3、D6显示了较好的抗HIV-1_(ⅢB)活性,值得对它们的作用机制和稳定性做更进一步研究。
AIDS is the most serious disease for human health.During the struggle against AIDS,people revealed out the pathogen of AIDS,developed many antiviral drugs,which reduced the incidence of AIDS and mortality rate,but AIDS is not cured yet.At present,sexual transmission plays a major role in the spread of HIV in the world.More than 90%of new HIV infections are spreading through unprotected intercourse in whole world.The relentlessness of the HIV/AIDS epidemic and its growing feminization have prompted people to acknowledge the urgency to develop new prevention technologies. Microbicides are now recognized as among the most promising prevention technologies on the horizon.To develop a microbicide used under women control has been recognized as an important method as vaccine of HIV to control transmission of HIV-1.There has been significant progress in microbicide research and development in the past 15 years.Over 30 compounds or formulations are undergoing preclinical or clinical studies. However,the number of potential products is not large enough.Discovery of novel compounds for use as potential microbicide candidates is a long-term task.In this paper,we focused on the developing novel microbicides from traditional Chinese medicine,lectins and rare earth elements.
The IC_(50)values of sulfated polysaccharide D2,D3,D6,D8,D9 were (10.28±1.12)μg/ml,(10.90±1.08)μg/ml,(8.72±1.08)μg/ml,(15.10±1.08)μg/ml, (11.10±1.09)μg/ml,and the SI values were 261,331,313,213,203, respectively.The rare earth element CCYCN had anti-HIV-1_(ⅢB)activity,its IC_(50)value was(4.02±1.07)μg/ml,and its selective index(SI)value was 229. The unsulfated polysaccharide compounds DN,DN1,DN2,which were obtained by different methods,also could inhibit HIV-1_(ⅢB)activity,their IC_(50)values were(33.12±1.08)μg/ml,(27.19±1.08)μg/ml,(10.68±1.08)μg/ml, their selective indexs(SIs)values were 22,28,87,respectively.
According to anti-HIV-1_(ⅢB)activity experiment,we knew the sulfated polysaccharide compounds D2,D3,D6,D8,D9 had better anti-HIV-1_(ⅢB) activities than other compounds.In order to know the antiviral mechanisms of the compounds D2,D3,D6,D8,D9,time-addition assay,fusion and different pre-treatments were used.The results showed that the sulfated polysaccharide D2,D3,D6,D8,D9 may affect the early stage of HIV life cycle.
We also studied on the stabilities of the sulfated polysaccharide compounds D3 and D6.SPSS15.0 was used to analyze data we acquired,the results showed the IC_(50)values of D3 and D6 had the notable relation of linearity.
In a word,the sulfated polysaccharide compounds D3 and D6 demonstrated strong anti-HIV-1_(ⅢB)activities,and may be potential candidates for microbicides development.They shoud be further studied on antiviral mechanism and stability in the future.
酯化多糖D2、D3、D6、D8、D9的IC_(50)值分别为(10.28±1.12)μg/ml、(10.90±1.08)μg/ml、(8.72±1.08)μg/ml、(15.10±1.08)μg/ml、(11.10±1.09)μg/ml,选择指数(SI)的值分别为261、331、313、213、203。稀土元素CCYCN也表现出了一定的抗HIV-1_(ⅢB)活性,其IC_(50)值为(4.02±1.07)μg/ml,选择指数(SI)的值为229。采用不同方法得到的化合物未酯化DN、未酯化DN1、未酯化DN2也对HIV-1_(ⅢB)有一定的活性,IC_(50)值分别为(33.12±1.08)μg/ml、(27.19±1.08)μg/ml、(10.68±1.08)μg/ml,选择指数(SI)的值分别为22、28、87。
通过初筛实验,我们得到酯化多糖D2、D3、D6、D8、D9对HIV-1_(ⅢB)有较好的抗性,为了了解酯化多糖D2、D3、D6、D8、D9作用机理,我们采取时间过程、融合阻断和化合物不同方法预处理病毒或宿主细胞等实验方法来进行作用机制的初步研究。实验结果表明:酯化多糖D2、D3、D6、D8、D9可能作用在HIV病毒复制的早期,即阻断HIV病毒吸附到宿主细胞上,进而抑制HIV-1_(ⅢB)宿主细胞。
我们又对酯化多糖D3、D6进行了稳定性实验。用SPSS15.0软件对所得数据进行分析,结果表明:经过一段时间,D3、D6在水溶液中的抗HIV-1_(ⅢB)活性随时间的增加而明显降低,有待进一步研究。
综上所述,酯化多糖D3、D6显示了较好的抗HIV-1_(ⅢB)活性,值得对它们的作用机制和稳定性做更进一步研究。
AIDS is the most serious disease for human health.During the struggle against AIDS,people revealed out the pathogen of AIDS,developed many antiviral drugs,which reduced the incidence of AIDS and mortality rate,but AIDS is not cured yet.At present,sexual transmission plays a major role in the spread of HIV in the world.More than 90%of new HIV infections are spreading through unprotected intercourse in whole world.The relentlessness of the HIV/AIDS epidemic and its growing feminization have prompted people to acknowledge the urgency to develop new prevention technologies. Microbicides are now recognized as among the most promising prevention technologies on the horizon.To develop a microbicide used under women control has been recognized as an important method as vaccine of HIV to control transmission of HIV-1.There has been significant progress in microbicide research and development in the past 15 years.Over 30 compounds or formulations are undergoing preclinical or clinical studies. However,the number of potential products is not large enough.Discovery of novel compounds for use as potential microbicide candidates is a long-term task.In this paper,we focused on the developing novel microbicides from traditional Chinese medicine,lectins and rare earth elements.
The IC_(50)values of sulfated polysaccharide D2,D3,D6,D8,D9 were (10.28±1.12)μg/ml,(10.90±1.08)μg/ml,(8.72±1.08)μg/ml,(15.10±1.08)μg/ml, (11.10±1.09)μg/ml,and the SI values were 261,331,313,213,203, respectively.The rare earth element CCYCN had anti-HIV-1_(ⅢB)activity,its IC_(50)value was(4.02±1.07)μg/ml,and its selective index(SI)value was 229. The unsulfated polysaccharide compounds DN,DN1,DN2,which were obtained by different methods,also could inhibit HIV-1_(ⅢB)activity,their IC_(50)values were(33.12±1.08)μg/ml,(27.19±1.08)μg/ml,(10.68±1.08)μg/ml, their selective indexs(SIs)values were 22,28,87,respectively.
According to anti-HIV-1_(ⅢB)activity experiment,we knew the sulfated polysaccharide compounds D2,D3,D6,D8,D9 had better anti-HIV-1_(ⅢB) activities than other compounds.In order to know the antiviral mechanisms of the compounds D2,D3,D6,D8,D9,time-addition assay,fusion and different pre-treatments were used.The results showed that the sulfated polysaccharide D2,D3,D6,D8,D9 may affect the early stage of HIV life cycle.
We also studied on the stabilities of the sulfated polysaccharide compounds D3 and D6.SPSS15.0 was used to analyze data we acquired,the results showed the IC_(50)values of D3 and D6 had the notable relation of linearity.
In a word,the sulfated polysaccharide compounds D3 and D6 demonstrated strong anti-HIV-1_(ⅢB)activities,and may be potential candidates for microbicides development.They shoud be further studied on antiviral mechanism and stability in the future.
引文
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