摘要
获得性免疫缺陷综合症(AIDS)在1981年首次被发现,两年之后得到了第一个HIV分离株,标志着人类与病原体的斗争进入了一个新的时代。从那以后,HIV感染成为世界范围内影响人类健康的重大问题之一。高效的抗逆转录病毒治疗(HAART)的展开,极大地降低了HIV感染者的发病率和死亡率。然而,耐药突变株和药物的毒性极大地限制了当前的治疗手段,这一情况促使人们不断地寻求新的治疗策略。HIV的进入过程成为当前新药研发中最具有吸引力的靶点。HIV进入抑制剂是抗逆转录病毒治疗方案中的一种合理选择,因为它们可以阻止病毒感染新的细胞,从而有可能阻止或者在很大程度上限制病毒的传播。
七肽重复序列重组蛋白HR212是一种人工设计的Ⅰ型人类免疫缺陷病毒(HIV-1)融合抑制剂,它可以通过大肠杆菌系统以较低的成本进行制备。前期的研究工作表明HR212可以有效地抑制不同HIV-1株系对宿主细胞的侵入和复制,而且与T20相比,它的稳定性更好,对蛋白酶消化的耐受性更强。但是HR212具体的作用机制目前尚不清楚。
HIV-1侵入宿主细胞的过程大致可以分为以下三个阶段:(1)病毒包膜糖蛋白gp120与宿主细胞表面受体CD4的结合;(2)gp120与辅助受体CCR5或CXCR5的结合;(3)gp41的构象发生改变,N端七肽重复区(NHR)形成三聚体,紧接着C端七肽重复区(CHR)折叠与NHR三聚体形成六聚体螺旋束结构,病毒与细胞发生膜融合。研究发现HR212对gp120与CD4的相互作用以及gp120与辅助受体的结合均没有影响,但是ELISA,非变性凝胶电泳和圆二色谱实验结果指出HR212可以有效抑制gp41的NHR和CHR形成六螺旋束。而且荧光非变性凝胶电泳的结果进一步阐明HR212可以与gp41的N端肽N36相互作用形成复合物从而达到阻断六螺旋束形成的目的。这些结果表明HR212通过作用于gp41的NHR区域来达到阻断病毒进入的目的。因此,HR212有望可以开发成一种新型有效的HIV-1进入抑制剂。
棉酚是从棉属植物中提取的一种多酚型化合物。为了探索棉酚的抗病毒效果,我们从提高亲水性和降低毒性两个方面采用多种氨基酸,氨基糖以及寡肽对棉酚的结构进行修饰,合成了一系列的新型棉酚衍生物,并通过体外实验筛选其抗HIV-1活性。我们发现把棉酚的甲酰基用部分氨基酸取代后不仅有效的降低了棉酚的细胞毒性,而且可以增强其抗HIV-1活性。进一步研究指出,左旋棉酚的脂肪族氨基酸衍生物具有最好的抗病毒效果和最低的细胞毒性,其选择性指数与棉酚相比提高了100倍左右。接下来我们进一步检测了(-)-棉酚-L-丙氨酸钠希夫碱(50#)对原代病毒感染PBMC的抑制效果,结果显示该化合物具有针对不同基因型HIV-1病毒的广谱的抑制活性。
传统观点认为棉酚及其衍生物主要通过作用于逆转录酶达到抑制HIV-1复制的目的。但我们通过加药时间梯度实验,假病毒抑制实验以及HIV-1介导的细胞融合实验证明(-)-棉酚-L-丙氨酸钠希夫碱(50#)是一种有效的HIV-1进入抑制剂。因此,它可以作为一种新型HIV-1进入抑制剂的先导化合物进一步研究。
Acquired immunodeficiency syndrome (AIDS) was recognized in1981, and the first human immunodeficiency virus (HIV) was isolated2years later, heralding a new era in the fight against pathogenic viruses. Since then, HIV infection has become a major public health problem worldwide. The introduction of highly active antiretroviral therapy (HAART) has markedly decreased mortality and morbidity. However, drug resistance and high toxicity are serious limitations to current treatments that justify the continuation of research efforts for new strategies and interventions. Viral entry currently represents one of the most attractive targets in the search for new drugs to treat HIV infection. HIV entry inhibitors appear to be a rational step forward in ARV therapy, because they prevent the virus from infecting new host cells, and may potentially stop or significantly limit HIV transmission.
HR212, a recombinant protein composed of the heptad repeat, is a rationally designed human immunodeficiency virus type1(HIV-1) fusion inhibitor. This protein can be easily produced by E. coli at a low cost. Previously, studies indicated that HR212can efficiently inhibit the entry and replication of both laboratory and clinical HIV-1strains, and this protein is more stable and less sensitive to proteinases than the T20. However, the potential mechanism of action of HR212is still not clear.
The procedure of HIV-1entry into the host cells can be divided into three main steps:(Ⅰ) attachment of the viral gp120to the CD4T cell receptor,(Ⅱ) binding of the gp120to CCR5or CXCR4co-receptors and (Ⅲ) gp41changes its conformation by forming N-helix trimer between N-heptad repeats (NHRs) and then six-helix bundle between the N-trimer and the C-heptad repeats (CHRs), the viral and cellular membranes fusion. In the present study, we demonstrated that HR212does not block gp120-CD4binding or interfere with the HIV-1coreceptor CXCR4. However, HR212inhibited the fusion-active gp41core formation mimicked by peptides derived from the viral gp41N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), as determined by ELISA, native polyacrylamide gel electrophoresis, and circular dichroism analysis. Moreover, the fluorescence native polyacrylamide gel electrophoresis (FN-PAGE) indicated that HR212could form a complex with peptide N36to block the gp41fusogenic core formation. These results suggest that HR212inhibits HIV-1entry by targeting the NHR region of gp41. Therefore, HR212can be potentially developed as a novel, high-efficiency HIV-1entry inhibitor.
Gossypol is a polyphenolic aldehyde extracted from cotton plants. In order to explore the antiviral effect of gossypol, from the aspects of improving hydrophilicity and lower toxicity, a series of amino acids, amino sugars, and oligopeptides have been used to modify gossypol's structure and a number of novel gossypol derivatives have been synthesized and screened in vitro for their anti-HIV-1activity. We found that replacing the aldehyde groups of gossypol with some amino acids not only reduced the cytotoxicity but also enhanced the activities against HIV-1. Further study indicated that the neutral amino acids with aliphatic group derivatives of (-)-gossypol showed the strongest inhibitory activity and the lowest cytotoxicity in vitro among all the derivatives tested. The selectivity index of the novel (-)-gossypol-neutral amino acid conjugates is increased100fold when compared with gossypol alone. Additionally, the inhibitory activities of the (-)-gossypol bis L-alanine sodium scruff's base (50#) on infection of PBMC by primary HIV-1strains were also determined. This compound had potent inhibitory activity on infection by primary HIV-1strains with distinct genotypes and biotypes. This result suggest that the novel (-)-gossypol derivative has potent antiviral activity against a broad spectrum of HIV-1strains.
It is widely accepted that gossypol and gossypol derivatives inhibit HIV-1replication by targeting reverse transcriptase. However, from the results of our time-of-addition assay, HIV-1-mediated cell fusion assay and pseudotyped virus assay, we demonstrate that the (-)-gossypol bis L-alanine sodium schiff's base (50#) is an effective HIV-1entry inhibitor. Thus it may be used as lead compound of a new type of anti-HIV entry inhibitors for further study.
引文
[1]BARBARO G, SCOZZAFAVA A, MASTROLORENZO A, et al. Highly active antiretroviral therapy: current state of the art, new agents and their pharmacological interactions useful for improving therapeutic outcome [J]. Curr Pharm Des,2005,11(14):1805-43.
[2]FINZI D, HERMANKOVA M, PIERSON T, et al. Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy [J]. Science,1997,278(5341):1295-300.
[3]PISCITELLI S C, FLEXNER C, MINOR J R, et al. Drug interactions in patients infected with human immunodeficiency virus [J]. Clin Infect Dis,1996,23(4):685-93.
[4]BODEN D, HURLEY A, ZHANG L, et al. HIV-1 drug resistance in newly infected individuals [J]. JAMA, 1999,282(12):1135-41.
[5]WEGNER S A, BRODINE S K, MASCOLA J R, et al. Prevalence of genotypic and phenotypic resistance to anti-retroviral drugs in a cohort of therapy-naive HIV-1 infected US military personnel [J]. AIDS,2000,14(8):1009-15.
[6]POPOVIC M, SARNGADHARAN M G, READ E, et al. Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-Ⅲ) from patients with AIDS and pre-AIDS [J]. Science, 1984,224(4648):497-500.
[7]LEVY J A, HOFFMAN A D, KRAMER S M, et al. Isolation of lymphocytopathic retroviruses from San Francisco patients with AIDS [J]. Science,1984,225(4664):840-2.
[8]COFFIN J, HAASE A, LEVY J A, et al. Human immunodeficiency viruses[J]. Science,1986, 232(4751):697.
[9]CLAVEL F, GUETARD D, BRUN-VEZINET F, et al. Isolation of a new human retrovirus from West African patients with AIDS [J]. Science,1986,233(4761):343-6.
[10]HIRSCH V M, OLMSTED R A, MURPHEY-CORB M, et al. An African primate lentivirus (SIVsm) closely related to HIV-2 [J]. Nature,1989,339(6223):389-92.
[11]GAO K, GORELICK R J, JOHNSON D G, et al. Cofactors for human immunodeficiency virus type 1 cDNA integration in vitro [J]. J Virol,2003,77(2):1598-603.
[12]GREEN K, CHEN I, KNIPE D, et al. Fields virology [J]. Fields Virology,2007,
[13]MCCUTCHAN F E. Understanding the genetic diversity of HIV-1 [J]. AIDS,2000,14 Suppl 3(S31-44.
[14]TAKEHISA J, ZEKENG L, IDO E, et al. Human immunodeficiency virus type 1 intergroup (M/O) recombination in cameroon[J]. J Virol,1999,73(8):6810-20.
[15]KUIKEN C L, LUKASHOV V V, BAAN E, et al. Evidence for limited within-person evolution of the V3 domain of the HIV-1 envelope in the amsterdam population[J]. AIDS,1996,10(1):31-7.
[16]ZOLLA-PAZNER S, GORNY M K, NYAMBI P N, et al. Immunotyping of human immunodeficiency virus type 1 (HIV):an approach to immunologic classification of HIV [J]. J Virol,1999,73(5):4042-51.
[17]OSMANOV S, PATTOU C, WALKER N, et al. Estimated global distribution and regional spread of HIV-1 genetic subtypes in the year 2000 [J]. J Acquir Immune Defic Syndr,2002,29(2):184-90.
[18]GREZ M, DIETRICH U, BALFE P, et al. Genetic analysis of human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2) mixed infections in India reveals a recent spread of HIV-1 and HIV-2 from a single ancestor for each of these viruses [J]. J Virol,1994,68(4):2161-8.
[19]HASELTINE W A, SODROSKI J, PATARCA R, et al. Structure of 3'terminal region of type Ⅱ human T lymphotropic virus:evidence for new coding region [J]. Science,1984,225(4660):419-21.
[20]BEERENS N, GROOT F, BERKHOUT B. Initiation of HIV-1 reverse transcription is regulated by a primer activation signal [J]. J Biol Chem,2001,276(33):31247-56.
[21]FENG Y X, CAMPBELL S, HARVIN D, et al. The human immunodeficiency virus type 1 Gag polyprotein has nucleic acid chaperone activity:possible role in dimerization of genomic RNA and placement of tRNA on the primer binding site [J]. J Virol,1999,73(5):4251-6.
[22]MCBRIDE M S, PANGANIBAN A T. The human immunodeficiency virus type 1 encapsidation site is a multipartite RNA element composed of functional hairpin structures [J]. J Virol,1996,70(5): 2963-73.
[23]PAILLART J C, SKRIPKIN E, EHRESMANN B, et al. A loop-loop "kissing" complex is the essential part of the dimer linkage of genomic HIV-1 RNA [J]. Proc Natl Acad Sci U S A,1996,93(11):5572-7.
[24]DAS A T, KLAVER B, BERKHOUT B. A hairpin structure in the R region of the human immunodeficiency virus type 1 RNA genome is instrumental in polyadenylation site selection [J]. J Virol,1999,73(1):81-91.
[25]BERNACCHI S, STOYLOV S, PIEMONT E, et al. HIV-1 nucleocapsid protein activates transient melting of least stable parts of the secondary structure of TAR and its complementary sequence [J]. J Mol Biol,2002,317(3):385-99.
[26]CHARNEAU P, ALIZON M, CLAVEL F. A second origin of DNA plus-strand synthesis is required for optimal human immunodeficiency virus replication [J]. J Virol,1992,66(5):2814-20.
[27]JACKS T, POWER M D, MASIARZ F R, et al. Characterization of ribosomal frameshifting in HIV-1 gag-pol expression [J]. Nature,1988,331(6153):280-3.
[28]MALDARELLI F, MARTIN M A, STREBEL K. Identification of posttranscriptionally active inhibitory sequences in human immunodeficiency virus type 1 RNA:novel level of gene regulation [J]. J Virol, 1991,65(11):5732-43.
[29]BERKHOUT B, VAN HEMERT F J. The unusual nucleotide content of the HIV RNA genome results in a biased amino acid composition of HIV proteins [J]. Nucleic Acids Res,1994,22(9):1705-11.
[30]FREED E O. HIV-1 gag proteins:diverse functions in the virus life cycle [J]. Virology,1998,251(1): 1-15.
[31]FREED E O, ORENSTEIN J M, BUCKLER-WHITE A J, et al. Single amino acid changes in the human immunodeficiency virus type 1 matrix protein block virus particle production [J]. J Virol,1994,68(8): 5311-20.
[32]GAMBLE T R, VAJDOS F F, YOO S, et al. Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid [J]. Cell,1996,87(7):1285-94.
[33]MORELLET N, DRUILLENNEC S, LENOIR C, et al. Helical structure determined by NMR of the HIV-1 (345-392)Gag sequence, surrounding p2:implications for particle assembly and RNA packaging [J]. Protein Sci,2005,14(2):375-86.
[34]BESS J W, JR., POWELL P J, ISSAQ H J, et al. Tightly bound zinc in human immunodeficiency virus type 1, human T-cell leukemia virus type I, and other retroviruses [J]. J Virol,1992,66(2):840-7.
[35]HARILA K, PRIOR I, SJOBERG M, et al. Vpu and Tsg101 regulate intracellular targeting of the human immunodeficiency virus type 1 core protein precursor Pr55gag [J]. J Virol,2006,80(8): 3765-72.
[36]HUANG M, ORENSTEIN J M, MARTIN M A, et al. p6Gag is required for particle production from full-length human immunodeficiency virus type 1 molecular clones expressing protease [J]. J Virol, 1995,69(11):6810-8.
[37]CRAWFORD S, GOFF S P. A deletion mutation in the 5'part of the pol gene of Moloney murine leukemia virus blocks proteolytic processing of the gag and pol polyproteins [J]. J Virol,1985,53(3): 899-907.
[38]JACOBO-MOLINA A, DING J, NANNI R G, et al. Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 A resolution shows bent DNA [J]. Proc Natl Acad Sci U S A,1993,90(13):6320-4.
[39]ENGELMAN A, HICKMAN A B, CRAIGIE R. The core and carboxyl-terminal domains of the integrase protein of human immunodeficiency virus type 1 each contribute to nonspecific DNA binding [J]. J Virol,1994,68(9):5911-7.
[40]ROSEN C A, SODROSKI J G, HASELTINE W A. The location of cis-acting regulatory sequences in the human T cell lymphotropic virus type III (HTLV-III/LAV) long terminal repeat [J]. Cell,1985,41(3): 813-23.
[41]FENG S, HOLLAND E C. HIV-1 tat trans-activation requires the loop sequence within tar [J]. Nature, 1988,334(6178):165-7.
[42]FELBER B K, HADZOPOULOU-CLADARAS M, CLADARAS C, et al. rev protein of human immunodeficiency virus type 1 affects the stability and transport of the viral mRNA [J]. Proc Natl Acad Sci U S A,1989,86(5):1495-9.
[43]MANN D A, MIKAELIAN I, ZEMMEL R W, et al. A molecular rheostat. Co-operative rev binding to stem I of the rev-response element modulates human immunodeficiency virus type-1 late gene expression [J]. J Mol Biol,1994,241(2):193-207.
[44]WILLEY R L, MALDARELLI F, MARTIN M A, et al. Human immunodeficiency virus type 1 Vpu protein induces rapid degradation of CD4 [J]. J Virol,1992,66(12):7193-200.
[45]HARRIS R S, BISHOP K N, SHEEHY A M, et al. DNA deamination mediates innate immunity to retroviral infection [J]. Cell,2003,113(6):803-9.
[46]MANGEAT B, TURELLI P, CARON G, et al. Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcripts [J]. Nature,2003,424(6944):99-103.
[47]COHEN E A, SUBBRAMANIAN R A, GOTTLINGER H G. Role of auxiliary proteins in retroviral morphogenesis [J]. Curr Top Microbiol Immunol,1996,214(219-35.
[48]MCDONALD D, VODICKA M A, LUCERO G, et al. Visualization of the intracellular behavior of HIV in living cells [J]. J Cell Biol,2002,159(3):441-52.
[49]SCHWARTZBERG P, COLICELLI J, GOFF S P. Construction and analysis of deletion mutations in the pol gene of Moloney murine leukemia virus:a new viral function required for productive infection [J]. Cell,1984,37(3):1043-52.
[50]DETELS R, MUNOZ A, MCFARLANE G, et al. Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators [J]. JAMA,1998,280(17):1497-503.
[51]GULICK R M, MEIBOHM A, HAVLIR D, et al. Six-year follow-up of HIV-1-infected adults in a clinical trial of antiretroviral therapy with indinavir, zidovudine, and lamivudine [J]. AIDS,2003,17(16): 2345-9.
[52]KITAHATA M M, GANGE S J, ABRAHAM A G, et al. Effect of early versus deferred antiretroviral therapy for HIV on survival [J]. N Engl J Med,2009,360(18):1815-26.
[53]CHUN T W, CARRUTH L, FINZI D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection [J]. Nature,1997,387(6629):183-8.
[54]CHUN T W, DAVEY R T, JR., ENGEL D, et al. Re-emergence of HIV after stopping therapy [J]. Nature, 1999,401(6756):874-5.
[55]LUCAS G M, CHAISSON R E, MOORE R D. Highly active antiretroviral therapy in a large urban clinic: risk factors for virologic failure and adverse drug reactions [J]. Ann Intern Med,1999,131(2):81-7.
[56]ZHU P, CHERTOVA E, BESS J, JR., et al. Electron tomography analysis of envelope glycoprotein trimers on HIV and simian immunodeficiency virus virions [J]. Proc Natl Acad Sci U S A,2003,100(26): 15812-7.
[57]ZHU P, LIU J, BESS J, JR., et al. Distribution and three-dimensional structure of AIDS virus envelope spikes [J]. Nature,2006,441(7095):847-52.
[58]ZHU P, WINKLER H, CHERTOVA E, et al. Cryoelectron tomography of HIV-1 envelope spikes: further evidence for tripod-like legs [J]. PLoS Pathog,2008,4(11):e1000203.
[59]MAGNUS C, RUSERT P, BONHOEFFER S, et al. Estimating the stoichiometry of human immunodeficiency virus entry [J]. J Virol,2009,83(3):1523-31.
[60]STARCICH B R, HAHN B H, SHAW G M, et al. Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS [J]. Cell,1986,45(5): 637-48.
[61]LEONARD C K, SPELLMAN M W, RIDDLE L, et al. Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells [J]. J Biol Chem,1990, 265(18):10373-82.
[62]DUBAY J W, ROBERTS S J, BRODY B, et al. Mutations in the leucine zipper of the human immunodeficiency virus type 1 transmembrane glycoprotein affect fusion and infectivity [J]. J Virol, 1992,66(8):4748-56.
[63]WILD C, DUBAY J W, GREENWELL T, et al. Propensity for a leucine zipper-like domain of human immunodeficiency virus type 1 gp41 to form oligomers correlates with a role in virus-induced fusion rather than assembly of the glycoprotein complex [J]. Proc Natl Acad Sci U S A,1994,91(26): 12676-80.
[64]TILTON J C, DOMS R W. Entry inhibitors in the treatment of HIV-1 infection [J]. Antiviral Res,2010, 85(1):91-100.
[65]MONDOR I, UGOLINI S, SATTENTAU Q J. Human immunodeficiency virus type 1 attachment to HeLa CD4 cells is CD4 independent and gp120 dependent and requires cell surface heparans [J]. J Virol, 1998,72(5):3623-34.
[66]MOULARD M, LORTAT-JACOB H, MONDOR I, et al. Selective interactions of polyanions with basic surfaces on human immunodeficiency virus type 1 gp120 [J]. J Virol,2000,74(4):1948-60.
[67]GEIJTENBEEK T B, KWON D S, TORENSMA R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells [J]. Cell,2000,100(5):587-97.
[68]KWONG P D, WYATT R, ROBINSON J, et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody [J]. Nature,1998,393(6686): 648-59.
[69]CHEN B, VOGAN E M, GONG H, et al. Structure of an unliganded simian immunodeficiency virus gp120 core [J]. Nature,2005,433(7028):834-41.
[70]HUANG C C, TANG M, ZHANG M Y, et al. Structure of a V3-containing HIV-1 gp120 core [J]. Science,2005,310(5750):1025-8.
[71]ALKHATIB G, COMBADIERE C, BRODER C C, et al. CC CKR5:a RANTES, MIP-lalpha, MIP-lbeta receptor as a fusion cofactor for macrophage-tropic HIV-1[J]. Science,1996,272(5270):1955-8.
[72]ZHANG L, HE T, TALAL A, et al. In vivo distribution of the human immunodeficiency virus/simian immunodeficiency virus coreceptors:CXCR4, CCR3, and CCR5 [J]. J Virol,1998,72(6):5035-45.
[73]ATCHISON R E, GOSLING J, MONTECLARO F S, et al. Multiple extracellular elements of CCR5 and HIV-1 entry:dissociation from response to chemokines [J]. Science,1996,274(5294):1924-6.
[74]BERGER E A, DOMS R W, FENYO E M, et al. A new classification for HIV-1[J]. Nature,1998, 391(6664):240.
[75]HUANG C C, LAM S N, ACHARYA P, et al. Structures of the CCR5 N terminus and of a tyrosine-sulfated antibody with HIV-1 gp120 and CD4 [J]. Science,2007,317(5846):1930-4.
[76]BASMACIOGULLARI S, BABCOCK G J, VAN RYK D, et al. Identification of conserved and variable structures in the human immunodeficiency virus gp120 glycoprotein of importance for CXCR4 binding [J]. J Virol,2002,76(21):10791-800.
[77]LEE B, SHARRON M, BLANPAIN C, et al. Epitope mapping of CCR5 reveals multiple conformational states and distinct but overlapping structures involved in chemokine and coreceptor function [J]. J Biol Chem,1999,274(14):9617-26.
[78]PLATT E J, KUHMANN S E, ROSE P P, et al. Adaptive mutations in the V3 loop of gp120 enhance fusogenicity of human immunodeficiency virus type 1 and enable use of a CCR5 coreceptor that lacks the amino-terminal sulfated region [J]. J Virol,2001,75(24):12266-78.
[79]LIN G, BARIBAUD F, ROMANO J, et al. Identification of gp120 binding sites on CXCR4 by using CD4-independent human immunodeficiency virus type 2 Env proteins [J]. J Virol,2003,77(2):931-42.
[80]DE JONG J J, DE RONDE A, KEULEN W, et al. Minimal requirements for the human immunodeficiency virus type 1 V3 domain to support the syncytium-inducing phenotype:analysis by single amino acid substitution [J]. J Virol,1992,66(11):6777-80.
[81]XIAO L, OWEN S M, GOLDMAN I, et al. CCR5 coreceptor usage of non-syncytium-inducing primary HIV-1 is independent of phylogenetically distinct global HIV-1 isolates:delineation of consensus motif in the V3 domain that predicts CCR-5 usage [J]. Virology,1998,240(1):83-92.
[82]ESTE J A, TELENTI A. HIV entry inhibitors [J]. Lancet,2007,370(9581):81-8.
[83]CHAN D C, FASS D, BERGER J M, et al. Core structure of gp41 from the HIV envelope glycoprotein [J]. Cell,1997,89(2):263-73.
[84]WEISSENHORN W, DESSEN A, HARRISON S C, et al. Atomic structure of the ectodomain from HIV-1 gp41 [J]. Nature,1997,387(6631):426-30.
[85]MIYAUCHI K, KIM Y, LATINOVIC O, et al. HIV enters cells via endocytosis and dynamin-dependent fusion with endosomes[J]. Cell,2009,137(3):433-44.
[86]CALLAHAN L N, PHELAN M, MALLINSON M, et al. Dextran sulfate blocks antibody binding to the principal neutralizing domain of human immunodeficiency virus type 1 without interfering with gp120-CD4 interactions [J]. J Virol,1991,65(3):1543-50.
[87]QIAN K, MORRIS-NATSCHKE S L, LEE K H. HIV entry inhibitors and their potential in HIV therapy [J]. Med Res Rev,2009,29(2):369-93.
[88]BOYD M R, GUSTAFSON K R, MCMAHON J B, et al. Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development [J]. Antimicrob Agents Chemother,1997,41(7): 1521-30.
[89]DEY B, LERNER D L, LUSSO P, et al. Multiple antiviral activities of cyanovirin-N:blocking of human immunodeficiency virus type 1 gp120 interaction with CD4 and coreceptor and inhibition of diverse enveloped viruses [J]. J Virol,2000,74(10):4562-9.
[90]BOTOS I, O'KEEFE B R, SHENOY S R, et al. Structures of the complexes of a potent anti-HIV protein cyanovirin-N and high mannose oligosaccharides[J]. J Biol Chem,2002,277(37):34336-42.
[91]RUSCONI S, MOONIS M, MERRILL D P, et al. Naphthalene sulfonate polymers with CD4-blocking and anti-human immunodeficiency virus type 1 activities [J]. Antimicrob Agents Chemother,1996, 40(1):234-6.
[92]VAN DAMME L, WRIGHT A, DEPRAETERE K, et al. A phase Ⅰ study of a novel potential intravaginal microbicide, PRO 2000, in healthy sexually inactive women [J]. Sex Transm Infect,2000,76(2):126-30.
[93]SMITA J, SOMA D, BEVERLY B, et al. Phase Ⅰ safety study of 0.5% PRO 2000 vaginal Gel among HIV un-infected women in Pune, India [J]. AIDS Res Ther,2006,3(4.
[94]HUANG L, CHEN C H. Molecular targets of anti-HIV-1 triterpenes [J]. Curr Drug Targets Infect Disord,2002,2(1):33-6.
[95]ALLAWAY G P, DAVIS-BRUNO K L, BEAUDRY G A, et al. Expression and characterization of CD4-IgG2, a novel heterotetramer that neutralizes primary HIV type 1 isolates [J]. AIDS Res Hum Retroviruses,1995,11(5):533-9.
[96]JACOBSON J M, ISRAEL R J, LOWY I, et al. Treatment of advanced human immunodeficiency virus type 1 disease with the viral entry inhibitor PRO 542 [J]. Antimicrob Agents Chemother,2004,48(2): 423-9.
[97]JACOBSON J M, LOWY I, FLETCHER C V, et al. Single-dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults [J]. J Infect Dis,2000,182(1):326-9.
[98]MOORE J P, SATTENTAU Q J, KLASSE P J, et al. A monoclonal antibody to CD4 domain 2 blocks soluble CD4-induced conformational changes in the envelope glycoproteins of human immunodeficiency virus type 1 (HIV-1) and HIV-1 infection of CD4+cells [J]. J Virol,1992,66(8): 4784-93.
[99]KURITZKES D R, JACOBSON J, POWDERLY W G, et al. Antiretroviral activity of the anti-CD4 monoclonal antibody TNX-355 in patients infected with HIV type 1 [J]. J Infect Dis,2004,189(2): 286-91.
[100]LIN P F, BLAIR W, WANG T, et al. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding [J]. Proc Natl Acad Sci U S A,2003,100(19):11013-8.
[101]GUO Q, HO H T, DICKER I, et al. Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions [J]. J Virol,2003,77(19): 10528-36.
[102]HO H T, FAN L, NOWICKA-SANS B, et al. Envelope conformational changes induced by human immunodeficiency virus type 1 attachment inhibitors prevent CD4 binding and downstream entry events [J]. J Virol,2006,80(8):4017-25.
[103]SI Z, MADANI N, COX J M, et al. Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins [J]. Proc Natl Acad Sci U S A,2004,101(14):5036-41.
[104]KADOW J, WANG H G, LIN P F. Small-molecule HIV-1 gp120 inhibitors to prevent HIV-1 entry: an emerging opportunity for drug development [J]. Curr Opin Investig Drugs,2006,7(8):721-6.
[105]ZHAO Q, MA L, JIANG S, et al. Identification of N-phenyl-N'-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4 [J]. Virology,2005,339(2):213-25.
[106]OJWANG J O, BUCKHEIT R W, POMMIER Y, et al. T30177, an oligonucleotide stabilized by an intramolecular guanosine octet, is a potent inhibitor of laboratory strains and clinical isolates of human immunodeficiency virus type 1 [J]. Antimicrob Agents Chemother,1995,39(11):2426-35.
[107]ESTE J A, CABRERA C, SCHOLS D, et al. Human immunodeficiency virus glycoprotein gp120 as the primary target for the antiviral action of AR177 (Zintevir) [J]. Mol Pharmacol,1998,53(2): 340-5.
[108]WALLACE T L, GAMBA-VITALO C, LOVEDAY K S, et al. Acute, multiple-dose, and genetic toxicology of AR177, an anti-HIV oligonucleotide [J]. Toxicol Sci,2000,53(1):63-70.
[109]WALLACE T L, BAZEMORE S A, KORNBRUST D J, et al. Single-dose hemodynamic toxicity and pharmacokinetics of a partial phosphorothioate anti-HIV oligonucleotide (AR177) after intravenous infusion to cynomolgus monkeys [J]. J Pharmacol Exp Ther,1996,278(3):1306-12.
[110]WEBER J, PIONTKIVSKA H, QUINONES-MATEU M E. HIV type 1 tropism and inhibitors of viral entry:clinical implications [J]. AIDS Rev,2006,8(2):60-77.
[111]VERMEIRE K, ZHANG Y, PRINCEN K, et al. CADA inhibits human immunodeficiency virus and human herpesvirus 7 replication by down-modulation of the cellular CD4 receptor [J]. Virology,2002, 302(2):342-53.
[112]VERMEIRE K, SCHOLS D. Specific CD4 down-modulating compounds with potent anti-HIV activity [J]. J Leukoc Biol,2003,74(5):667-75.
[113]VERMEIRE K, BELL T W, CHOI H J, et al. The Anti-HIV potency of cyclotriazadisulfonamide analogs is directly correlated with their ability to down-modulate the CD4 receptor [J]. Mol Pharmacol, 2003,63(1):203-10.
[114]VERMEIRE K, SCHOLS D, BELL T W. CD4 down-modulating compounds with potent anti-HIV activity[J]. Curr Pharm Des,2004,10(15):1795-803.
[115]BELL T W, ANUGU S, BAILEY P, et al. Synthesis and structure-activity relationship studies of CD4 down-modulating cyclotriazadisulfonamide (CADA) analogues [J]. J Med Chem,2006,49(4): 1291-312.
[116]VERMEIRE K, LISCO A, GRIVEL J C, et al. Design and cellular kinetics of dansyl-labeled CADA derivatives with anti-HIV and CD4 receptor down-modulating activity [J]. Biochem Pharmacol,2007, 74(4):566-78.
[117]LIU R, PAXTON W A, CHOE S, et al. Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection [J]. Cell,1996,86(3):367-77.
[118]SAMSON M, LIBERT F, DORANZ B J, et al. Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene [J]. Nature,1996,382(6593): 722-5.
[119]COCCHI F, DEVICO A L, GARZINO-DEMO A, et al. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+T cells[J]. Science,1995, 270(5243):1811-5.
[120]SIMMONS G, CLAPHAM P R, PICARD L, et al. Potent inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist [J]. Science,1997,276(5310):276-9.
[121]POLO S, NARDESE V, DE SANTIS C, et al. Enhancement of the HIV-1 inhibitory activity of RANTES by modification of the N-terminal region:dissociation from CCR5 activation [J]. Eur J Immunol, 2000,30(11):3190-8.
[122]LEDERMAN M M, VEAZEY R S, OFFORD R, et al. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5 [J]. Science,2004,306(5695):485-7.
[123]TRKOLA A, KETAS T J, NAGASHIMA K A, et al. Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140 [J]. J Virol,2001,75(2): 579-88.
[124]KONDRU R, ZHANG J, JI C, et al. Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists [J]. Mol Pharmacol,2008,73(3):789-800.
[125]BABA M, NISHIMURA O, KANZAKI N, et al. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity [J]. Proc Natl Acad Sci U S A,1999,96(10): 5698-703.
[126]DRAGIC T, TRKOLA A, THOMPSON D A, et al. A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5 [J]. Proc Natl Acad Sci U S A,2000,97(10): 5639-44.
[127]SETO M, AIKAWA K, MIYAMOTO N, et al. Highly potent and orally active CCR5 antagonists as anti-HIV-1 agents:synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety [J]. J Med Chem,2006,49(6):2037-48.
[128]IMAMURA S, ICHIKAWA T, NISHIKAWA Y, et al. Discovery of a piperidine-4-carboxamide CCR5 antagonist (TAK-220) with highly potent Anti-HIV-1 activity [J]. J Med Chem,2006,49(9): 2784-93.
[129]DORR P, WESTBY M, DOBBS S, et al. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity [J]. Antimicrob Agents Chemother,2005,49(11):4721-32.
[130]WOOD A, ARMOUR D. The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS [J]. Prog Med Chem,2005,43(239-71.
[131]ARMOUR D, DE GROOT M J, EDWARDS M, et al. The discovery of CCR5 receptor antagonists for the treatment of HIV infection:hit-to-lead studies [J]. ChemMedChem,2006,1(7):706-9.
[132]PRICE D A, ARMOUR D, DE GROOT M, et al. Overcoming HERG affinity in the discovery of the CCR5 antagonist maraviroc [J]. Bioorg Med Chem Lett,2006,16(17):4633-7.
[133]CASTONGUAY L A, WENG Y, ADOLFSEN W, et al. Binding of 2-aryl-4-(piperidin-1-yl)butanamines and 1,3,4-trisubstituted pyrrolidines to human CCR5:a molecular modeling-guided mutagenesis study of the binding pocket [J]. Biochemistry,2003,42(6):1544-50.
[134]CARTER N J, KEATING G M. Maraviroc [J]. Drugs,2007,67(15):2277-88; discussion 89-90.
[135]TAGAT J R, MCCOMBIE S W, NAZARENO D, et al. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. IV. Discovery of 1-[(4,6-dimethyl-5-pyrimidinyl)carbonyl]-4-[4-[2-methoxy-1(R)-4-(trifluoromethyl)phenyl]ethyl-3(S)-methyl-l-piperazinyl]- 4-methylpiperidine (Sch-417690/Sch-D), a potent, highly selective, and orally bioavailable CCR5 antagonist [J]. J Med Chem,2004,47(10):2405-8.
[136]STRIZKI J M, TREMBLAY C, XU S, et al. Discovery and characterization of vicriviroc (SCH 417690), a CCR5 antagonist with potent activity against human immunodeficiency virus type 1 [J]. Antimicrob Agents Chemother,2005,49(12):4911-9.
[137]TSAMIS F, GAVRILOV S, KAJUMO F, et al. Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry [J]. J Virol,2003,77(9):5201-8.
[138]SEIBERT C, YING W, GAVRILOV S, et al. Interaction of small molecule inhibitors of HIV-1 entry with CCR5 [J]. Virology,2006,349(1):41-54.
[139]MAEDA K, NAKATA H, KOH Y, et al. Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro [J]. J Virol,2004,78(16):8654-62.
[140]WATSON C, JENKINSON S, KAZMIERSKI W, et al. The CCR5 receptor-based mechanism of action of 873140, a potent allosteric noncompetitive HIV entry inhibitor [J]. Mol Pharmacol,2005, 67(4):1268-82.
[141]HOWARD O M, KORTE T, TARASOVA N I, et al. Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function [J]. J Leukoc Biol,1998,64(1):6-13.
[142]CHEN X, YANG L, ZHANG N, et al. Shikonin, a component of chinese herbal medicine, inhibits chemokine receptor function and suppresses human immunodeficiency virus type 1 [J]. Antimicrob Agents Chemother,2003,47(9):2810-6.
[143]DORN C P, FINKE P E, OATES B, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. part 1:discovery and initial structure-activity relationships for 1-amino-2-phenyl-4-(piperidin-1-yl)butanes [J]. Bioorg Med Chem Lett,2001,11(2):259-64.
[144]FINKE P E, MEURER L C, OATES B, et al. Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 3:a proposed pharmacophore model for 1-[N-(methyl)-N-(phenylsulfonyl)amino]-2-(phenyl)-4-[4-(substituted)piperidin-1-y 1]butanes [J]. Bioorg Med Chem Lett,2001,11(18):2469-73.
[145]HALE J J, BUDHU R J, HOLSON E B, et al.1,3,4-Trisubstituted pyrrolidine CCR5 receptor antagonists. Part 2:lead optimization affording selective, orally bioavailable compounds with potent anti-HIV activity [J]. Bioorg Med Chem Lett,2001,11(20):2741-5.
[146]KIM D, WANG L, CALDWELL C G, et al. Discovery of human CCR5 antagonists containing hydantoins for the treatment of HIV-1 infection [J]. Bioorg Med Chem Lett,2001,11(24):3099-102.
[147]TACHIBANA K, HIROTA S, IIZASA H, et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract [J]. Nature,1998,393(6685):591-4.
[148]ZOU Y R, KOTTMANN A H, KURODA M, et al. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development [J]. Nature,1998,393(6685):595-9.
[149]MA Q, JONES D, BORGHESANI P R, et al. Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice [J]. Proc Natl Acad Sci U S A, 1998,95(16):9448-53.
[150]MOYLE G J, WILDFIRE A, MANDALIA S, et al. Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection [J]. J Infect Dis,2005,191(6):866-72.
[151]TAMAMURA H, MURAKAMI T, MASUDA M, et al. Structure-activity relationships of an anti-HIV peptide, T22 [J]. Biochem Biophys Res Commun,1994,205(3):1729-35.
[152]TAMAMURA H, XU Y, HATTORI T, et al. A low-molecular-weight inhibitor against the chemokine receptor CXCR4:a strong anti-HIV peptide T140 [J]. Biochem Biophys Res Commun,1998, 253(3):877-82.
[153]ARAKAKI R, TAMAMURA H, PREMANATHAN M, et al. T134, a small-molecule CXCR4 inhibitor, has no cross-drug resistance with AMD3100, a CXCR4 antagonist with a different structure [J]. J Virol, 1999,73(2):1719-23.
[154]TAMAMURA H, OMAGARI A, OISHI S, et al. Pharmacophore identification of a specific CXCR4 inhibitor, T140, leads to development of effective anti-HIV agents with very high selectivity indexes [J]. Bioorg Med Chem Lett,2000,10(23):2633-7.
[155]FUJII N, OISHI S, HIRAMATSU K, et al. Molecular-size reduction of a potent CXCR4-chemokine antagonist using orthogonal combination of conformation-and sequence-based libraries [J]. Angew Chem Int Ed Engl,2003,42(28):3251-3.
[156]DORANZ B J, FILION L G, DIAZ-MITOMA F, et al. Safe use of the CXCR4 inhibitor ALX40-4C in humans[J]. AIDS Res Hum Retroviruses,2001,17(6):475-86.
[157]DAELEMANS D, SCHOLS D, WITVROUW M, et al. A second target for the peptoid Tat/transactivation response element inhibitor CGP64222:inhibition of human immunodeficiency virus replication by blocking CXC-chemokine receptor 4-mediated virus entry [J]. Mol Pharmacol,2000, 57(1):116-24.
[158]HAMY F, FELDER E R, HEIZMANN G, et al. An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication[J]. Proc Natl Acad Sci U S A,1997,94(8):3548-53.
[159]BLANCO J, BARRETINA J, HENSON G, et al. The CXCR4 antagonist AMD3100 efficiently inhibits cell-surface-expressed human immunodeficiency virus type 1 envelope-induced apoptosis [J]. Antimicrob Agents Chemother,2000,44(1):51-6.
[160]HATSE S, PRINCEN K, DE CLERCQ E, et al. AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor [J]. Biochem Pharmacol,2005,70(5):752-61.
[161]SEIBERT C, SAKMAR T P. Small-molecule antagonists of CCR5 and CXCR4:a promising new class of anti-HIV-1 drugs [J]. Curr Pharm Des,2004,10(17):2041-62.
[162]STONE N D, DUNAWAY S B, FLEXNER C, et al. Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects [J]. Antimicrob Agents Chemother,2007,51(7):2351-8.
[163]ICHIYAMA K, YOKOYAMA-KUMAKURA S, TANAKA Y, et al. A duodenally absorbable CXC chemokine receptor 4 antagonist, KRH-1636, exhibits a potent and selective anti-HIV-1 activity [J]. Proc Natl Acad Sci U S A,2003,100(7):4185-90.
[164]BRIZ V, POVEDA E, SORIANO V. HIV entry inhibitors:mechanisms of action and resistance pathways [J]. J Antimicrob Chemother,2006,57(4):619-27.
[165]CHEN C H, MATTHEWS T J, MCDANAL C B, et al. A molecular clasp in the human immunodeficiency virus (HIV) type 1 TM protein determines the anti-HIV activity of gp41 derivatives: implication for viral fusion [J]. J Virol,1995,69(6):3771-7.
[166]MELIKYAN G B, MARKOSYAN R M, HEMMATI H, et al. Evidence that the transition of HIV-1 gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion [J]. J Cell Biol, 2000,151(2):413-23.
[167]WILD C, OAS T, MCDANAL C, et al. A synthetic peptide inhibitor of human immunodeficiency virus replication:correlation between solution structure and viral inhibition [J]. Proc Natl Acad Sci U S A,1992,89(21):10537-41.
[168]WILD C T, SHUGARS D C, GREENWELL T K, et al. Peptides corresponding to a predictive alpha-helical domain of human immunodeficiency virus type 1 gp41 are potent inhibitors of virus infection [J]. Proc Natl Acad Sci U S A,1994,91(21):9770-4.
[169]KILBY J M, HOPKINS S, VENETTA T M, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry [J]. Nat Med,1998,4(11):1302-7.
[170]ARMAND-UGON M, GUTIERREZ A, CLOTET B, et al. HIV-1 resistance to the gp41-dependent fusion inhibitor C-34 [J]. Antiviral Res,2003,59(2):137-42.
[171]JIANG S, LIN K, STRICK N, et al. HIV-1 inhibition by a peptide [J]. Nature,1993,365(6442): 113.
[172]LU M, BLACKLOW S C, KIM P S. A trimeric structural domain of the HIV-1 transmembrane glycoprotein [J]. Nat Struct Biol,1995,2(12):1075-82.
[173]GALLO S A, PURI A, BLUMENTHAL R. HIV-1 gp41 six-helix bundle formation occurs rapidly after the engagement of gp120 by CXCR4 in the HIV-1 Env-mediated fusion process [J]. Biochemistry, 2001,40(41):12231-6.
[174]MUNOZ-BARROSO I, DURELL S, SAKAGUCHI K, et al. Dilation of the human immunodeficiency virus-1 envelope glycoprotein fusion pore revealed by the inhibitory action of a synthetic peptide from gp41 [J]. J Cell Biol,1998,140(2):315-23.
[175]MARTIN N, WELSCH S, JOLLY C, et al. Virological synapse-mediated spread of human immunodeficiency virus type 1 between T cells is sensitive to entry inhibition [J]. J Virol,2010,84(7): 3516-27.
[176]KILBY J M, LALEZARI J P, ERON J J, et al. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults [J]. AIDS Res Hum Retroviruses,2002,18(10):685-93.
[177]LALEZARI J P, ERON J J, CARLSON M, et al. A phase Ⅱ clinical study of the long-term safety and antiviral activity of enfuvirtide-based antiretroviral therapy [J]. AIDS,2003,17(5):691-8.
[178]LALEZARI J P, DEJESUS E, NORTHFELT D W, et al. A controlled Phase Ⅱ trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in non-nucleoside reverse transcriptase inhibitor-naive HIV-infected adults [J]. Antivir Ther,2003,8(4): 279-87.
[179]REYNES J, ARASTEH K, CLOTET B, et al. TORO:ninety-six-week virologic and immunologic response and safety evaluation of enfuvirtide with an optimized background of antiretrovirals [J]. AIDS Patient Care STDS,2007,21(8):533-43.
[180]TROTTIER B, WALMSLEY S, REYNES J, et al. Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks [J]. J Acquir Immune Defic Syndr,2005,40(4):413-21.
[181]RAFFI F, KATLAMA C, SAAG M, et al. Week-12 response to therapy as a predictor of week 24, 48, and 96 outcome in patients receiving the HIV fusion inhibitor enfuvirtide in the T-20 versus Optimized Regimen Only (TORO) trials [J]. Clin Infect Dis,2006,42(6):870-7.
[182]NI L, GAO G F, TIEN P. Rational design of highly potent HIV-1 fusion inhibitory proteins: implication for developing antiviral therapeutics [J]. Biochem Biophys Res Commun,2005,332(3): 831-6.
[183]QI Z, SHI W, XUE N, et al. Rationally designed anti-HIV peptides containing multifunctional domains as molecule probes for studying the mechanisms of action of the first and second generation HIV fusion inhibitors [J]. J Biol Chem,2008,283(44):30376-84.
[184]LIU S, JING W, CHEUNG B, et al. HIV gp41 C-terminal heptad repeat contains multifunctional domains. Relation to mechanisms of action of anti-HIV peptides [J]. J Biol Chem,2007,282(13): 9612-20.
[185]ERON J J, GULICK R M, BARTLETT J A, et al. Short-term safety and antiretroviral activity of T-1249, a second-generation fusion inhibitor of HIV [J]. J Infect Dis,2004,189(6):1075-83.
[186]LALEZARI J P, BELLOS N C, SATHASIVAM K, et al. T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen [J]. J Infect Dis,2005,191(7):1155-63.
[187]LOUIE M, HOGAN C, DI MASCIO M, et al. Determining the relative efficacy of highly active antiretroviral therapy [J]. J Infect Dis,2003,187(6):896-900.
[188]MARTINS DO CANTO A M, PALACE CARVALHO A J, PRATES RAMALHO J P, et al. T-20 and T-1249 HIV fusion inhibitors' structure and conformation in solution:a molecular dynamics study [J]. J Pept Sci,2008,14(4):442-7.
[189]HUET T, KERBARH O, SCHOLS D, et al. Long-lasting enfuvirtide carrier pentasaccharide conjugates with potent anti-human immunodeficiency virus type 1 activity [J]. Antimicrob Agents Chemother,2010,54(1):134-42.
[190]STODDART C A, NAULT G, GALKINA S A, et al. Albumin-conjugated C34 peptide HIV-1 fusion inhibitor:equipotent to C34 and T-20 in vitro with sustained activity in SCID-hu Thy/Liv mice [J]. J Biol Chem,2008,283(49):34045-52.
[191]ECKERT D M, MALASHKEVICH V N, HONG L H, et al. Inhibiting HIV-1 entry:discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket [J]. Cell,1999,99(1):103-15.
[192]JIN B S, RYU J R, AHN K, et al. Design of a peptide inhibitor that blocks the cell fusion mediated by glycoprotein 41 of human immunodeficiency virus type 1 [J]. AIDS Res Hum Retroviruses, 2000,16(17):1797-804.
[193]CHAN D C, CHUTKOWSKI C T, KIM P S. Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target [J]. Proc Natl Acad Sci U S A,1998,95(26):15613-7.
[194]DWYER J J, WILSON K L, DAVISON D K, et al. Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus [J]. Proc Natl Acad Sci U S A, 2007,104(31):17712-1.
[195]EGGINK D, BALDWIN C E, DENG Y, et al. Selection of T1249-resistant human immunodeficiency virus type 1 variants [J]. J Virol,2008,82(13):6678-88.
[196]HE Y, CHENG J, LU H, et al. Potent HIV fusion inhibitors against Enfuvirtide-resistant HIV-1 strains [J]. Proc Natl Acad Sci U S A,2008,105(42):16332-7.
[197]DAI S J, DOU G F, QIANG X H, et al. Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro [J]. Acta Pharmacol Sin,2005,26(10): 1274-80.
[198]HE Y, XIAO Y, SONG H, et al. Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor [J]. J Biol Chem,2008,283(17):11126-34.
[199]OISHI S, ITO S, NISHIKAWA H, et al. Design of a novel HIV-1 fusion inhibitor that displays a minimal interface for binding affinity [J]. J Med Chem,2008,51(3):388-91.
[200]OISHI S, ITO S, NISHIKAWA H, et al. Development of a novel fusion inhibitor against T-20-resistant HIV-1 [J]. Adv Exp Med Biol,2009,611(389-91.
[201]NAITO T, IZUMI K, KODAMA E, et al. SC29EK, a peptide fusion inhibitor with enhanced alpha-helicity, inhibits replication of human immunodeficiency virus type 1 mutants resistant to enfuvirtide [J]. Antimicrob Agents Chemother,2009,53(3):1013-8.
[202]NISHIKAWA H, NAKAMURA S, KODAMA E, et al. Electrostatically constrained alpha-helical peptide inhibits replication of HIV-1 resistant to enfuvirtide [J]. Int J Biochem Cell Biol,2009,41(4): 891-9.
[203]KAJIWARA K, WATANABE K, TOKIWA R, et al. Bioorganic synthesis of a recombinant HIV-1 fusion inhibitor, SC35EK, with an N-terminal pyroglutamate capping group [J]. Bioorg Med Chem,2009, 17(23):7964-70.
[204]SIA S K, CARR P A, COCHRAN A G, et al. Short constrained peptides that inhibit HIV-1 entry [J]. Proc Natl Acad Sci U S A,2002,99(23):14664-9.
[205]WALENSKY L D, KUNG A L, ESCHER I, et al. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix [J]. Science,2004,305(5689):1466-70.
[206]EGGINK D, BERKHOUT B, SANDERS R W. Inhibition of HIV-1 by fusion inhibitors [J]. Curr Pharm Des,2010,16(33):3716-28.
[207]RIMSKY L T, SHUGARS D C, MATTHEWS T J. Determinants of human immunodeficiency virus type 1 resistance to gp41-derived inhibitory peptides [J]. J Virol,1998,72(2):986-93.
[208]JIANG S, LIN K, STRICK N, et al. Inhibition of HIV-1 infection by a fusion domain binding peptide from the HIV-1 envelope glycoprotein GP41 [J]. Biochem Biophys Res Commun,1993,195(2): 533-8.
[209]EGGINK D, LANGEDIJK J P, BONVIN A M, et al. Detailed mechanistic insights into HIV-1 sensitivity to three generations of fusion inhibitors [J]. J Biol Chem,2009,284(39):26941-50.
[210]IZUMI K, KODAMA E, SHIMURA K, et al. Design of peptide-based inhibitors for human immunodeficiency virus type 1 strains resistant to T-20 [J]. J Biol Chem,2009,284(8):4914-20.
[211]DENG Y, ZHENG Q, KETAS T J, et al. Protein design of a bacterially expressed HIV-1 gp41 fusion inhibitor [J]. Biochemistry,2007,46(14):4360-9.
[212]BEWLEY C A, LOUIS J M, GHIRLANDO R, et al. Design of a novel peptide inhibitor of HIV fusion that disrupts the internal trimeric coiled-coil of gp41 [J]. J Biol Chem,2002,277(16):14238-45.
[213]ECKERT D M, KIM P S. Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region [J]. Proc Natl Acad Sci U S A,2001,98(20):11187-92.
[214]LOUIS J M, BEWLEY C A, CLORE G M. Design and properties of N(CCG)-gp41, a chimeric gp41 molecule with nanomolar HIV fusion inhibitory activity [J]. J Biol Chem,2001,276(31):29485-9.
[215]OWEN S M, RUDOLPH D L, WANG W, et al. RC-101, a retrocyclin-1 analogue with enhanced activity against primary HIV type 1 isolates [J]. AIDS Res Hum Retroviruses,2004,20(11):1157-65.
[216]MUNCH J, STANDKER L, ADERMANN K, et al. Discovery and optimization of a natural HIV-1 entry inhibitor targeting the gp41 fusion peptide [J]. Cell,2007,129(2):263-75.
[217]BALDWIN C E, SANDERS R W, DENG Y, et al. Emergence of a drug-dependent human immunodeficiency virus type 1 variant during therapy with the T20 fusion inhibitor [J]. J Virol,2004, 78(22):12428-37.
[218]RAY N, BLACKBURN L A, DOMS R W. HR-2 mutations in human immunodeficiency virus type 1 gp41 restore fusion kinetics delayed by HR-1 mutations that cause clinical resistance to enfuvirtide [J]. J Virol,2009,83(7):2989-95.
[219]XU L, POZNIAK A, WILDFIRE A, et al. Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41 [J]. Antimicrob Agents Chemother,2005,49(3):1113-9.
[220]TOLSTRUP M, SELZER-PLON J, LAURSEN A L, et al. Full fusion competence rescue of the enfuvirtide resistant HIV-1 gp41 genotype (43D) by a prevalent polymorphism (137K) [J]. AIDS,2007, 21(4):519-21.
[221]WANG W, OWEN S M, RUDOLPH D L, et al. Activity of alpha- and theta-defensins against primary isolates of HIV-1 [J]. J Immunol,2004,173(1):515-20.
[222]WANG G, WATSON K M, BUCKHEIT R W, JR. Anti-human immunodeficiency virus type 1 activities of antimicrobial peptides derived from human and bovine cathelicidins [J]. Antimicrob Agents Chemother,2008,52(9):3438-40.
[223]PLAZA A, GUSTCHINA E, BAKER H L, et al. Mirabamides A-D, depsipeptides from the sponge Siliquariaspongia mirabilis that inhibit HIV-1 fusion [J]. J Nat Prod,2007,70(11):1753-60.
[224]ROOT M J, KAY M S, KIM P S. Protein design of an HIV-1 entry inhibitor [J]. Science,2001, 291(5505):884-8.
[225]BIANCHI E, FINOTTO M, INGALLINELLA P, et al. Covalent stabilization of coiled coils of the HIV gp41 N region yields extremely potent and broad inhibitors of viral infection [J]. Proc Natl Acad Sci USA,2005,102(36):12903-8.
[226]STOLLER J K, ABOUSSOUAN L S. Alphal-antitrypsin deficiency [J]. Lancet,2005,365(9478): 2225-36.
[227]STOCKER H, KLOFT C, PLOCK N, et al. Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings [J]. Antimicrob Agents Chemother,2006,50(2):667-73.
[228]ZHANG X, NIEFORTH K, LANG J M, et al. Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus:Inverse Gaussian density absorption and 2-compartment disposition [J]. Clin Pharmacol Ther,2002,72(1):10-9.
[229]VERONESE F M, PASUT G. PEGylation, successful approach to drug delivery [J]. Drug Discov Today,2005,10(21):1451-8.
[230]GARBER A J. Pharmacologic modifications of hormones to improve their therapeutic potential for diabetes management [J]. Diabetes Obes Metab,2005,7(6):666-74.
[231]SINCLAIR A M, ELLIOTT S. Glycoengineering:the effect of glycosylation on the properties of therapeutic proteins [J]. J Pharm Sci,2005,94(8):1626-35.
[232]HUANG W, GROOTHUYS S, HEREDIA A, et al. Enzymatic glycosylation of triazole-linked GIcNAc/GIc-peptides:synthesis, stability and anti-HIV activity of triazole-linked HIV-1 gp41 glycopeptide C34 analogues [J]. Chembiochem,2009,10(7):1234-42.
[233]INGALLINELLA P, BIANCHI E, LADWA N A, et al. Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency [J]. Proc Natl Acad Sci U S A,2009, 106(14):5801-6.
[234]JI H, SHU W, BURLING F T, et al. Inhibition of human immunodeficiency virus type 1 infectivity by the gp41 core:role of a conserved hydrophobic cavity in membrane fusion [J]. J Virol, 1999,73(10):8578-86.
[235]DWYER J J, HASAN A, WILSON K L, et al. The hydrophobic pocket contributes to the structural stability of the N-terminal coiled coil of HIV gp41 but is not required for six-helix bundle formation [J]. Biochemistry,2003,42(17):4945-53.
[236]LIU S, WU S, JIANG S. HIV entry inhibitors targeting gp41:from polypeptides to small-molecule compounds [J]. Curr Pharm Des,2007,13(2):143-62.
[237]FERRER M, KAPOOR T M, STRASSMAIER T, et al. Selection of gp41-mediated HIV-1 cell entry inhibitors from biased combinatorial libraries of non-natural binding elements [J]. Nat Struct Biol, 1999,6(10):953-60.
[238]ZHOU G, FERRER M, CHOPRA R, et al. The structure of an HIV-1 specific cell entry inhibitor in complex with the HIV-1 gp41 trimeric core [J]. Bioorg Med Chem,2000,8(9):2219-27.
[239]GONZALEZ-ORTEGA E, MENA M P, PERMANYER M, et al. ADS-J1 inhibits HIV-1 entry by interacting with gp120 and does not block fusion-active gp41 core formation [J]. Antimicrob Agents Chemother,2010,54(10):4487-92.
[240]TAN K, LIU J, WANG J, et al. Atomic structure of a thermostable subdomain of HIV-1 gp41 [J]. Proc Natl Acad Sci U S A,1997,94(23):12303-8.
[241]ZHAO Q, ERNST J T, HAMILTON A D, et al. XTT formazan widely used to detect cell viability inhibits HIV type 1 infection in vitro by targeting gp41 [J]. AIDS Res Hum Retroviruses,2002,18(14): 989-97.
[242]LIU S, LU H, ZHAO Q, et al. Serva blue derivatives inhibit HIV entry.; proceedings of the XV International AIDS Conference, F,2004 [C].
[243]SMALL E J, MEYER M, MARSHALL M E, et al. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer:results of a randomized phase Ⅲ trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone [J]. J Clin Oncol,2000,18(7):1440-50.
[244]DEZUBE B J, DAHL T A, WONG T K, et al. A fusion inhibitor (FP-21399) for the treatment of human immunodeficiency virus infection:a phase I study [J]. J Infect Dis,2000,182(2):607-10.
[245]JIANG S, LU H, LIU S, et al. N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion [J]. Antimicrob Agents Chemother,2004,48(11):4349-59.
[246]TAN W C, KOH T H. Evaluation of obstructive sleep apnoea in Singapore using computerised polygraphic monitoring [J]. Ann Acad Med Singapore,1991,20(2):196-200.
[247]XU H X, WAN M, DONG H, et al. Inhibitory activity of flavonoids and tannins against HIV-1 protease[J]. Biol Pharm Bull,2000,23(9):1072-6.
[248]AU T K, LAM T L, NG T B, et al. A comparison of HIV-1 integrase inhibition by aqueous and methanol extracts of Chinese medicinal herbs [J]. Life Sci,2001,68(14):1687-94.
[249]WEAVER J L, PINE P S, DUTSCHMAN G, et al. Prevention of binding of rgp120 by anti-HIV active tannins [J]. Biochem Pharmacol,1992,43(11):2479-80.
[250]KIM H J, YU Y G, PARK H, et al. HIV gp41 binding phenolic components from Fraxinus sieboldiana var. angustata [J]. Planta Med,2002,68(11):1034-6.
[251]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 [J]. Biochim Biophys Acta,2005,1723(1-3):270-81.
[252]KAWAI K, TSUNO N H, KITAYAMA J, et al. Epigallocatechin gallate, the main component of tea polyphenol, binds to CD4 and interferes with gp120 binding [J]. J Allergy Clin Immunol,2003, 112(5):951-7.
[253]IKIGAI H, NAKAE T, HARA Y, et al. Bactericidal catechins damage the lipid bilayer [J]. Biochim Biophys Acta,1993,1147(1):132-6.
[254]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]. J Biol Chem,2005, 280(12):11259-73.
[255]SIGAL A, KIM J T, BALAZS A B, et al. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy [J]. Nature,2011,477(7362):95-8.
[256]LIU J J, REID G, JIANG Y, et al. Activity of HIV entry and fusion inhibitors expressed by the human vaginal colonizing probiotic Lactobacillus reuteri RC-14 [J]. Cell Microbiol,2007,9(1):120-30.
[257]VEAZEY R S, KLASSE P J, SCHADER S M, et al. Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion [J].Nature,2005,438(7064):99-102.
[258]PANG W, WANG R R, YANG L M, et al. Recombinant protein of heptad-repeat HR212, a stable fusion inhibitor with potent anti-HIV action in vitro [J]. Virology,2008,377(1):80-7.
[259]LIN T S, SCHINAZI R, GRIFFITH B P, et al. Selective inhibition of human immunodeficiency virus type 1 replication by the (-) but not the (+) enantiomer of gossypol [J]. Antimicrob Agents Chemother,1989,33(12):2149-51.
[260]SHELLEY M D, HARTLEY L, FISH R G, et al. Stereo-specific cytotoxic effects of gossypol enantiomers and gossypolone in tumour cell lines [J]. Cancer Lett,1999,135(2):171-80.
[261]KELLER P A, BIRCH C, LEACH S P, et al. Novel pharmacophore-based methods reveal gossypol as a reverse transcriptase inhibitor [J]. J Mol Graph Model,2003,21(5):365-73.
[262]ROYER R E, DECK L M, VANDER JAGT T J, et al. Synthesis and anti-HIV activity of 1,1'-dideoxygossypol and related compounds [J]. J Med Chem,1995,38(13):2427-32.
[263]LIN T S, SCHINAZI R F, ZHU J, et al. Anti-HIV-1 activity and cellular pharmacology of various analogs of gossypol [J]. Biochem Pharmacol,1993,46(2):251-5.