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.
引文
[1]杰伊A,利维.艾滋病毒与艾滋病的发病机制.北京:科学出版社,2000.
[2]张云武,张亚平,贲昆龙.人免疫缺陷病毒(HIV-1)辅助受体研究进展.病毒学报,1999,(15)282-288.
[3]张兴权,范江.艾滋病毒感染与艾滋病.北京:人民卫生出版社,1999.
[4]Hoffmann C,Kamps BE.HIV medicine.Paris:Flying Publisher,2003.
[5]Little SJ,Holte S,Routy JP et al.Antiretroviral-drug resistance among patients recently infected with HIV.N Engl J Med,2002,347(6):385-394.
[6]More JP,Doms RW.The entry of entry inhibitors:a fusion of science and medicine.Proc Natl Acad Sci USA,2003,100(19):10598-10602.
[7]Jiang S,Sidiqui P,Liu S.Blocking of viral entry,a complimentary strategy forHIV therapy.DrugDiscov Today:Ther Strateg,2004,1(4):497-450.
[8]Berger EA.Chemokine receptors as HIV-1 coreceptors:roles in viral entry,tropism,and disease.Annu.Rev.Immunol,1999,17:657-700.
[9]吴钦梅.HIV-1进入细胞机制及进入抑制剂的研究进展.中国病原生物学杂志,2006,1:229-231.
[10]Ryser HJ.Inhibition of human immunodeficiency virus infection by agents that interfere with thiol-disulfide interchange upon virus-receptor interaction.Proc.Natl.Acad.Sci.U.S.A,1994,91:4559-4563.
[11]Fenouillet E.The catalytic activity of protein disulfide isomerase is involved in human immunodeficiency virus envelopemediated membrane fusion after CD4 cell binding.Infect.Dis,2001,183:744-752.
[12]Gallina A.Inhibitors of protein disulfide isomerase prevent cleavage of disulfide bonds in receptor-bound glycoprotein 120 and prevent HIV-l entry. Biol. Chem, 2002, 277: 50579-50588.
[13] Barbouche R. Protein-disulfide isomerase-mediated reduction of two disulfide bonds of HIV envelope glycoprotein 120 occurs post-CXCR4 binding and is required for fusion. Biol.Chem, 2003, 278: 3131-3136.
[14] Markovic I. Thiol/disulfide exchange is a prerequisite for CXCR4-tropic HIV-l envelope-mediated T-cell fusion during viral entry. Blood, 2004, 103: 1586-1594.
[15] Inga Sliskovic, Arun Raturi, Bulent Mutus. Characterization of the S-Denitrosation activity of protein disulfide Isomerase. Bio.Chem, 2005, 10: 8733-8741.
[16] Ryser HJ. Plasma membrane protein disulfide isomerase: its role in the translocation of diphtheria toxin and HIV virus across endosomal and cell membranes.In:Plasma membrane redox systems and their role in biological stress and disease (Azard,H.et al.eds): Kluwer Academic Publishers, 1999.
[17] Reeves JD. Sensitivity of HIV-l to entry inhibitors correlates with envelope/coreceptor affinity, receptor density,and fusion kinetics. Proc. Natl. Acad. Sci. U.S.A, 2002, 99: 16249-16254.
[18] Kwong PD. Structure of an HIV gpl20 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature, 1998, 393: 648-659.
[19] Chan DC. Core structure of gp41 from the HIV envelope glycoprotein.Cell, 1997, 89: 263-273.
[20] Weissenhorn W. Atomic structure of the ectodomain from HIV-l gp41. Nature,1997, 387: 426-430.
[21] Kwong PD. Structures of HIV-l gpl20 envelope glycoproteins from laboratoryadapted and primary isolates. Structure Fold.Des, 2000, 8: 1329-1339.
[22] Chen B. Structure of an unliganded simian immunodeficiency virus gpl20 core. Nature, 2005, 433: 834-841.
[23] Madani N. Localized changes in gpl20 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitor BMS-806 and #155. Virol, 2004, 78: 3742-3752.
[24] Hugues JP, Ryser and Rudolf Fluckiger. Progress in targeting HIV-1 entry. DDT, 2005, 10: 1085-1094.
[25] Bar S, Alizon, M. Role of the ectodomain of the gp41 transmembraneenvelope protein of human immunodeficiency virus type 1 in late steps of the membranefusion process. Virol, 2004, 78: 811-820.
[26] Markosyan RM. HIV-1 envelope proteins complete their folding into six-helix bundles immediately after fusion pore formation. Mol. Biol.Cell, 2003, 14: 926-938.
[27] Shnaper S. The C- and the Nterminal regions of glycoprotein 41 ectodomain fuse membranes enriched and not enriched with cholesterol, respectively. Biol. Chem, 2004, 279: 18526-18534.
[28] Gallo SA. The HIV Env-mediated fusion reaction. Biochim. Biophys. Acta, 2003, 16(14): 36-50.
[29] S1 Z. Small-molecule inhibitors of HIV-1 entry block receptor r-in duced conformational changes in the viral envelope glycoproteins. Proc. Natl. Acad. Sci. U.S.A, 2004, 101: 5036-5041.
[30] Lin PF, Blair W, Wang T et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding. Proc Natl Acad Sci USA, 2003, 100(19): 11013-11018.
[31] Dezube BJ, Dahl TA, Wong TK et al. A fusion inhibitor(FP-21399)for the treatment of human immunodeficiency virus infections phase I study. J Infect Dis, 2000, 182(2): 607-610.
[32] De Clercq E. Antiviral drugs in current clinical use. J Clin Virol, 2004,30(2): 115-133.
[33] Mosier DE, Picchio GR, Gulizia ftj et al. Hiighly potent RANTES an alogues either prevent CCR5-using human immunodeficiency virus type 1 infection in vivo or rapidly select for CXCR4 using variants. J Virol, 1999, 73(5): 3544-3550.
[34] Masuda M, Nakashima H, Ueda T et al. A novel anti-HIV synthetic peptide,T-22(Try55,12,Lys7]-polyphemusin II).Biochem Biophys Res Commun,1992,189(2):845-850.
[35]Trkola A,Ketas TJ,Nagashima KA et al.Potent,broad,spectrum inhibition of human immunodeficiency virus type 1 by the CCR5monoclonal antibody PRO140.J Viro,2001,75(2):579-588.
[36]Hendfix CW,Flexner C,Macfarland RT et al.Pharmacokinetics and safety of AMD-3100,a novel an tagonist of the CXCR-4 chemokine receptor in human volunteer.Antimicrob Agents Chemother,2000,44(6):1667-1673.
[37]Baba M,Nishimuro O,Kanzaki Net al.A small-molecule,non-peptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity.Proc Natl Acad Sci USA,1999,96(10):5698-5703.
[38]Chan DC,Fass D,Berger JM,et al.Core structure of goal from the HIV envelope glycoprotein.Cell,1997,89:263-273.
[39]刘叔文,吴曙光,姜世勃.作用于HIV包膜蛋白亚基gp41的多肽类融合抑制剂.中国药理学通报,2003,19(11):1201-1208.
[40]Jiang S,Lin K,Stfick N et al.HIV-1 inhibition by a peptide.Nature,1993,365(6442):113.
[41]Wild CT,Shugars DC,Greenwell TK et al.Peptides coresponding to a predictive alpha-helical domain of human immunod eficiency virus type 1 gp41 are potent inhibitors of virus infection.Proc Natl Acad Sci USA,1994,91(21):9770-9774.
[42]Lu M,Blacklow SC,Kim PS.A trimeric structural domain of the HIV-1 transmembrane glycopmtein.Nat Struct Biol,1995,2(12):1075-1082.
[43]Jiang S,Zhang Q,Debnath AK.Peptide and Non-peptide HIV Fusion inhibitor.Curr Pharm Des,2002,8(8):563-568.
[44]Liu S,Lu H,Niu J et al.Different from the HIV fusion Inhibitor C34,the anti-HIV drug Fuzeon(T-20)inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120.J Biol Chem,2005,260(12):11259-11273.
[45]Root MJ,Kay MS,Kim PS.Protein design of an HIV-1 entry inhibitor. Science,2001,291(5505):884-888.
[46]Debnath AK,Radigan L,Jiang S.Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1.J Med Chem,1999,42(17):3203-3209.
[47]Liu S,Boyer Chatenet L,Lu H et al.Rapid and automated fluorescence-linked immunosorbent as say for high throughput screening of HIV-1 fusion inhibitors targeting gp41.J Biomol Screen,2003,8(6):685-689.
[48]刘叔文,姜世勃,刘北一等.作用于gp41的HIV融合抑制剂高通量筛选方法的研究.中国药理学通报,2002,18(5):507-511.
[49]Jiang S,Lu H,Liu S et al.N-Substituted pyrrole derivatives as novel human immunodeficiency virus type 1 inhibitors that interfere with the gp41 six-helix bundle formation an block virus fusion.Antimicrob Agents Chemother,2004,48(11):4349-4359.
[50]Ferrer M,Kapor TM,Strassmaier T et al.Selection of gp41-mediated HIV-1 cell entry inhibitors from biased combinatorial libraries of non-natural binding elements.Nat Struct Biol,1999,6(10):953-956.
[51]Liu S,Jiang S,Wu Z et al.Identification of all inhibitor of the HIV-1gp41 six-helix bundle formation from extracts of Chinesemedical herbs.Prunella Vulgaris and Rh&oma Cibotte.life sci,2002,71:1779-1779.
[52]Lv L,Liu S,Jiang S et al.Tannin inhibits HIV-1 entry by targeting gp41.Acta Pharmacol Sin,2004,25(2):213-218.
[53]Liu S,Lu H,Zhao Q et al.Theaflavin derivatives in black tea and catechin derivatives in green tea inhibit HIV-1 entry by targeting gp41.Biochim Biophy Acta,2005,1723((1-3)):270-278.
[54]Lam T L,Lan ML,Au T K,et al.A comparison of human immunodeficiency virus type-1 protease inhibition activities by the aqueous and methanol extracts of Chinese medicine herbs.Life Sci,2000,67(23):2889.
[55]Au T K,Lam TL,Ng T B,et al.A comparison of H IV-1 integrase inhibition by aqueous and methanol extracts of Chinese medicinal herbs.Life Sci,2001,681-687.
[56]Kobayashi Y,Watanabe M,Ogihara J,et al.Inhibition of H IV-1reverse transcriptase by methanol extracts of commercial herbs and spices.J Jap Society Food Sci Technol(nippon shokuhin kagaku kogaku kaishi),2000,47(8):642.
[57]Schaeffer DJ,Krylov VS.Anti-H IV activity of extracts and compounds from algae and cyanobacteria Ecotoxicol Environ Safe,2000,45(3):208.
[58]Taher MM,Lammering G,Hershey C,et al.Curcumin inhibits ultraviolet light induced human immunodeficiency virus gene expression.Mol Cell Biochem,2003,254(122):289.
[59]Chen X,YangL,ZhangN,et al.Shikonin a component of Chinese herbal medicine,inhibits chemokine receptor function and suppresses human immunodeficienct virus type 1 Antimicrob Agents Chemother,2003,47(9):2810.
[60]Asres K,Bucar F,Kartnig T,et al.Antiviral activity against human immunodeficiency virus type 1(H IV-l)and type2(H IV-2)of ethnobotanically selected Ethiopian medicinal plants.Phytotherapy Research,2001,15(1):62.
[61]赵芬琴,朴惠善.桦褐孔菌的研究进展.中国中医药信息杂志,2005,12(2):96.
[62]Lee-Huang S,ZhangL,Huang P L,et al.Anti-H IV activity of olive leaf extract(OLE)and modulation of host cell gene expression by H IV-1 infection and OLE treatment.Biochem Biophy Res Commun,2003,307(4):1029.
[63]吕红,方岩雄.a—,β—,γ—倒捻子素药理研究进展.中药材,2005,28(6):519.
[64]Bedoya L M,Sanchezpakmino S,Abad M J,et al.Anti-HIV activity of medicinal plant extracts.J Ethnopharmacol,2001,77(1):113.
[65]Hsiao A - F,Wong MD,Kanouse DE,et al.Complementary and alternative medicine use and substitution for conventional therapy by HIV - infected patients.JAIDS,2003,33(2):157.
[66]曾庆平,冯丽玲.重组人细胞因子基因在转基因中药细胞中的瞬时表达.中草药,2003,34(1):63.
[67]Zinkernagel RM The challenges of an HIV vaccine enterprise.Science,2004,303:1294-1295.
[68]Turpin JA.Considerations and development of topical microbicides to inhibit the sexual transmission of HIV.Expert Opin Investig Drugs,2002,11:1077-1097.
[69]Shattock RJ.Moore JP.Inhibiting sexual transmission of HIV-1infection.Nature Review Microbiology,2003,125-134.
[70]Wilson DP.Blower SM,Stein Z,et al.Microbicides:Anti-HIV efficacy and ethics.Science,2004,306:1890.
[71]Stone A.Microbicides:A new approach to preventing HIV and other sexually transmitted infections.Nature Reviews Drug Discovery,2002,977-985.
[72]Damme LV.Wright A.A phase Ⅰ study of a novel potential intravaginal microbicide,PRO 2000,in healthy sexually inactive women.Sex Transm Inf.,2000,76:126-130.
[73]Mori T.,Body MR.Cyanovirin-N,a potent human immunodeficiency virus -inactivating protein,blocks both CD4-dependent and CD4-independent binding of soluble gp120(sgp120)to target cells,inhibits sCD4-induced binding of sgp120 to cell-associated CXCR4,and dissociates bound sgp120 from target cell.Antimicrob Agents Chemother,2001,45:664-672.
[74]UNAIDS,International Working Group on Vaginal Microbicides.Recommendations for the development of microbicides.AIDS,1996,10:1-6.
[75]Van de Wijgert J.,Coggins C.Microbicides to prevent heterosexual transmission of HIV:ten years down the road.EBTA,2002,223-228.
[76]Mayer KH.,Peipert J,Fleming T,et al.Safety and tolerability of BufferGel,a novel vaginal microbicide,in women in the United States.Clin Infect Dis.,2001,32:476-482.
[77]Sanjay G.,Rober A,Calvin J.et al.Properties of a new acid-buffering bioadhesive vaginal formulation(ACIDFORM).Contraception,2001,64:67-75.
[78]Lagenaur LA.,Liu X,Wells K.et al.Vaginal lactobacilli for mucosal delivery of the anti-HIV microbicide,Cyanovirin-N.Microbicides Conference,Cape Town,South Africa,April 2006,23-26.
[79]Xu Q.,Lagenaur LA,Liu X.et al.Vaginal lactobacilli for mucosal delivery of the anti-HIV microbicide,Cyanovirin-N(CV-N).International Meeting of the IHV,Baltimore,August 29-September 2,2005.
[80]Stafford MK.,Ward AH.Safety study of nonoxynol-9 as a vaginal microbicide" evidence of adverse effects.J.Acquir.Immune Defic.Syndr.Hum.Retrovirol.,1998,17:327-331.
[81]Boonatra H.Condom,contraceptives and nonoxynol-9:complex issues obscure by ideology.The Guttmacher Report on Public Policy,May 2005,,20054-7.
[82]Robin Maguire.Lesson from CarragurdTM Microbicide 2002 conference report see http://www.microbicide.org.,2002.
[83]Alliance for Microbicide Development.Microbicide reseach and development progress report 2006.see http://www.microbicide.org.,2006.
[84]Stoneburner RL.Low-BeerD.Population-level HIV declines and behavioral risk avoidance in Uganda.Science,2004,304:714-718.
[85]国务院防治艾滋病工作委员会办公室、联合国艾滋病中国专题组.中国艾滋病防治联合报告.2005.
[86]贲昆龙,赵声兰.艾滋病毒性传播的分子细胞机理与性传播的预防策略.中国性病与艾滋病,2005,11(增刊)3-10.
[87]Vlietinck AJ,DeBruyne T,Apers S,et al.Plant-derived leading compounds for chemotherapy of human immunodeficiency virus(HIV)infection.Planta Med.,1998,64:97-109.
[88]Matthee G.,Wright AD,Konig GM.HIV reverse transcriptase inhibitors of natural origin.Planta Med.,1999,65:493-506.
[89]Cos P.,Maes L,vanden Berghe D.et al.Plant substances as anti-HIV agents selected according to their putative mechanism of action..J Nat.Prod.,2004,67284-293.
[90]Yu D.,Wild CT,Martin DE.et al.The discovery of a class of novel HIV-1 maturation inhibitors and their potential in the therapy of HIV.Expert Opin.Investig.Drugs.,2005,14:681-693.
[91]Gartner S.PM.Virus isolation and production;in(?)Techniques in HIV research.(?)(Aldovini A and Walker B D,et al.)..Stockton Press.New York,USA,1990.
[92]李秀义.几种植物多糖和镧系化合物体外抗艾滋病毒和其它性传播疾病原体活性的研究.硕士学位论文,2007.
[93]陶剑.预防艾滋病毒性传播的新型杀微生物剂的研究.博士学位论文,2007.
[94]Cabrera C.,Gutierrez A,Barretina J.Anti-HIV activity of a novel aminoglycoside-arginine conjugate.Antiviral Res.,2002,53(1):1-8.
[95]Zheng YT.,Ben KL.Anti-HIV-1 activity of trichobitacin,a novel ribosome-inactivating protein..Acta Pharmacol Sin.,2000,21:179-182.
[96]郑永唐,贲昆龙.测定细胞存活和增殖MTT方法的建立.免疫学杂志,1992,8(4):266-269.
[97]杨静.四种杀微生物剂候选物体外抗HIV-1及其它性传播疾病病原体活性的初步评价.硕士学位论文,2004.
[98]李伟,熊川男,王建华等.贻贝凝集素抗HIV活性研究.沈阳农业大学学报,2007,38(2):207-210.
[99]Bedoya LM.,Sanchez-Palomino S,Abad MJ.Anti-HIV activity of medicinal plant extracts.Journal of Ethnopharmacology,2001,77(1):113-116.
[100]Pereira CF.,Paridaen JT,Rutten K.Aspirin-like molecules that inhibit human immunodeficiency virus-1 replication.Antiviral Res.,2003,58(3):253-263.
[101]Pinto LA.,Sharpe S,Cohen SS.Alloantigen-stimulated anti-HIV activity.Blood,1998,92(9):3346-3354.
[102]Pluymers W.,Neamati N,Pannecouque C.Viral entry as the primary target for the anti-HIV activity of chicoric acid and its tetra-acetyl esters.Mol Pharmacol.,2000,58(3):641-648.
[103]Kanamoto T.,Kashiwada Y,Kanbara K.Anti-human immunodeficiency virus activity of YK-FH312(a betulinic acid derivative),a novel compound blocking viral maturation.Antimicrob Agents Chemother.,2001,45:1225-1230.
[104]De Clercq E.,Yamanoto N,Pauwels R.et al.Potent and selective inhibition of human immunodeficiency virus(HIV)-1 and HIV-2replication by a class of bicyclams interacting with a viral uncoating event..Proc.Natl.Acad.Sci.USA.,1992,89:5286-5290.
[105]Baba M.,Snoeck R,Pauwels R.ulfated polysaccharides are potent and selective inhibitors of various enveloped viruses,including herpes simplex virus,cytomegalovirus,vesicular stomatitis virus,and human immunodeficiency virus.Antimicrob Agents Chemother,1988,32:1742-1745.
[106]Dimitrios M.,Michael A,Parniak.A tight-binding mode of inhibition is essential for anti-human immunodeficiency virus type 1 virucidal activity of nonnucleoside reverse transcriptase inhibitors.Antimicrob Agents Chemother,2002,46:1851-1856.
[107]国家食品药品监督管理局.化学药物稳定性研究技术指导原则.2005.