单克隆抗体HIV进入抑制剂PRO140

HIV病毒株可分为R5嗜性和X4嗜性,它们分别通过趋化因子CCR5和CXCR4辅助受体进入CD4细胞。在HIV的整个发展进程中,可常发生其病毒株由R5嗜性转型为X4嗜性,且也有可能某个体同时被R5嗜性和X4嗜性病毒感染,而CCR5拮抗剂则对x4嗜性病毒无效。由Progenics制药公司开发的用于治疗HIV感染的人源化单克隆抗体CCR5拮抗剂PRO140为一种新型HIV进人抑制剂,可与CCR5受体的特殊区段紧密结合,对CCR5产生拮抗作用,从而抑制HIV通过这一辅助受体进入靶细胞;     

作用于HIV gp120的进入抑制剂研究进展

HIV-1病毒为包膜病毒,其感染靶细胞的第一步是由HIV包膜蛋白表面亚基gp120与靶细胞上的CD4分子和辅助受体（趋化因子受体CCR5或CXCR4等）结合,导致gp41的构型发生改变,启动病毒包膜与靶细胞膜的融合。与gp120相结合的一些抗体、蛋白、多糖、多肽和小分子化合物,都可能影响HIV-1病毒包膜和靶细胞膜融合的过程,从而起到抗HIV-1病毒的作用。该文对近年来以HIV gp120为靶点的HIV进入抑制剂的研究进展进行综述。     

抗HIV药物靶点CCR5及HIV对CCR5抑制剂的抗性

趋化因子受体CCR5是细胞膜表面G蛋白偶联受体中的一员.HIV-1在体内与细胞融合时需要CCR5作为辅助受体介导.因此,CCR5可作为抗HIV-1药物的筛选靶点,目前已筛选出多种CCR5抑制剂.但随着CCR5抑制剂的使用,HIV-1对于这些抑制剂的抗性也逐渐产生,而抗性的产生机制还不明确.本文主要介绍CCR5介导HIV-1与细胞融合的机制及HIV-1对CCR5抑制剂的抗性产生机制.     

HIV-1侵入抑制剂的研究进展

人类免疫缺陷病毒(HIV)-1侵入抑制剂能抑制HIV进入靶细胞,在最初环节抑制病毒的传播。具有高活性、较好药物代谢性质的肽及肽类似物不断被发现,并成为抗HIV药物研究的热点。根据HIV-1进入靶细胞的3个步骤可将侵入抑制剂分为黏附抑制剂、辅助受体结合抑制剂和融合抑制剂,并对其研发策略和研究进展进行综述。     

以趋化因子受体为靶点的抗HIV药物研究进展

趋化因子受体是HIV进入宿主细胞的共受体,特别是CCR5和CXCR4在HIV进入免疫细胞过程中起着重要作用。以趋化因子受体为靶点的新型抗艾滋病药物的设计与开发已成为抗艾滋病领域研究的一个热点课题。本文对近期抗HIV-1趋化因子受体(CCR5和CXCR4)拮抗剂的研究进展进行综述。     

CCR5阻滞剂马拉韦罗的药理与临床评价

马拉韦罗是一种选择性、可逆的小分子抑制剂,能与细胞膜表面人化学趋化因子受体-5(CCR5)和HIV-1gp120相互作用,抑制CCR5-tropic HIV-1病毒进入细胞,是一种很有前途的新型抗病毒药.现对其药理作用、药动学、药物相互作用及对仅感染CCR5-tropic HIV-1的成年患者的疗效和安全性进行了综述.     

新型抗艾滋病药马拉韦罗的临床地位及市场潜力

马拉韦罗（maraviroc）是Pfizer公司开发的一个能够抑制艾滋病毒-1（HIV-1）进入细胞的小分子药物,其作用机制是阻滞HIV-1和宿主细胞上的化学因子受体CCR5间的相互作用,2007年8月和9月分别获得美国FDA和欧盟委员会的批准（商品名分别为Selzentry和Celsentri）,用于联用其它抗逆病毒药物治疗CCR5嗜性HIV-1感染患者。马拉韦罗具有全新的作用机制,     

抗艾滋病药Vicriviroc

Vicriviroc是先灵葆雅公司正在开发的抗HIV感染药,属于一种小分子的趋化因子受体CCR5拮抗剂,能显著抑制HIV-1进入宿主细胞,可与其它药物联合使用治疗嗜R5型HIV-1感染的病人。已有临床试验结果表明,在采用优化基础疗法（如利托那韦加另一种蛋白酶抑制剂）的同时使用vicriviroc（10mg,qd）,能明显降低艾滋病患者体内的HIV病毒载量,并增加其CD4＋细胞数量。目前,本品尚处Ⅱ／Ⅲ期临床研究阶段。     

抗H／V逆转录病毒新药MaravJroc近日获得FDA批准

Maraviroc被批准与其他抗逆转录病毒药物联合用药，用于治疗感染CCR5-tropic HIV-1的成年患者。Maraviroc的作用机制为，通过阻断病毒侵入的主要途径-CCR5联合受体，来阻止其侵入健康细胞，而不是在血液白细胞中抵抗HIV。CCR5为某些种类的免疫细胞表面的一种蛋白质。     

新型抗艾滋病药物——HIV进入抑制剂的研究进展

HIV与靶细胞融合的过程是药物干预的重要环节。融合过程主要由H IV包被蛋白表面亚基gp120和跨膜亚基gp41介导。H IV gp120与靶细胞上的CD4分子和辅助受体(趋化因子受体CCR5或CXCR4等)结合,导致gp41的构型发生改变,启动病毒包膜与靶细胞膜的融合。在融合过程中,病毒和靶细胞上的这些蛋白和受体均可作为药物的作用靶点,寻找抑制H IV进入靶细胞的药物用来治疗H IV感染和艾滋病。作用于gp41的肽类药物T-20已被美国FDA批准上市,表明继逆转录酶抑制剂和蛋白酶抑制剂后,H IV进入抑制剂作为第3类抗H IV药物开始在临床上应用。作为一种新机制的抗H IV药物,H IV进入抑制剂单独或与逆转录酶抑制剂和蛋白酶抑制剂联合应用,将有助于提高药物的疗效,降低毒副作用,并可望挽救对现有抗H IV药物耐药的艾滋病病人的生命。该文综述了近年来H IV进入抑制剂的研究进展。     

Inhibition of CCR5-mediated infection by diverse R5 and R5X4 HIV and SIV isolates using novel small molecule inhibitors of CCR5: effects of viral diversity, target cell and receptor density

Highly active anti-retroviral therapy (HAART) has been very effective in reducing viral loads in human immunodeficiency virus (HIV)-1 patients. However, current therapies carry detrimental side effects, require complex drug regimes and are threatened by the emergence of drug-resistant variants. There is an urgent need for new anti-HIV drugs that target different stages of the replication cycle. Several synthetic small organic molecules that inhibit HIV infection by binding to the CCR5 coreceptor without causing cell activation have already been reported. Here, we have exploited a series of CCR5 antagonists to investigate their effects on diverse HIV and the simian counterpart (SIV) isolates for infection of a variety of cell types via different concentrations of cell surface CCR5. These inhibitors show no cross-reactivity against alternative HIV coreceptors including CCR3, CCR8, GPR1, APJ, CXCR4 and CXCR6. They are able to inhibit a diverse range of R5 and R5X4 HIV-1 isolates as well as HIV-2 and SIV strains. Inhibition was observed in cell lines as well as primary PBMCs and macrophages. The extent of inhibition was dependent on cell type and on cell surface CCR5 concentration. Our results underscore the potential of CCR5 inhibitors for clinical development.     

AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor

The chemokine receptors CCR5 and CXCR4 function as coreceptors for human immunodeficiency virus (HIV) and are attractive targets for the development of anti-HIV drugs. The most potent CXCR4 antagonists described until today are the bicyclams. The prototype compound, AMD3100, exhibits potent and selective anti-HIV activity against CXCR4-using (X4) viruses and showed antiviral efficacy in X4 HIV-1-infected persons in a phase II clinical trial. However, AMD3100 lacks oral bioavailability due to its high overall positive charge. Initial structure-activity relationship studies with bicyclam analogues suggested that the bis-macrocyclic structure was a prerequisite for anti-HIV activity. Now, we report that the N-pyridinylmethylene cyclam AMD3465, which lacks the structural constraints mentioned above, fully conserves all the biological properties of AMD3100. Like AMD3100, AMD3465 blocked the cell surface binding of both CXCL12 (the natural CXCR4 ligand), and the specific anti-CXCR4 monoclonal antibody 12G5. AMD3465 dose-dependently inhibited intracellular calcium signaling, chemotaxis, CXCR4 endocytosis and mitogen-activated protein kinase phosphorylation induced by CXCL12. Compared to the bicyclam AMD3100, AMD3465 was even 10-fold more effective as a CXCR4 antagonist, while showing no interaction whatsoever with CCR5. As expected, AMD3465 proved highly potent against X4 HIV strains (IC50: 1-10 nM), but completely failed to inhibit the replication of CCR5-using (R5) viruses. In conclusion, AMD3465 is a novel, monomacrocyclic anti-HIV agent that specifically blocks the interaction of HIV gp120 with CXCR4. Although oral bioavailability is not yet achieved, the monocyclams, with their decreased molecular charge as compared to the bicyclams, embody an important step forward in the design of oral CXCR4 antagonists that can be clinically used as anti-HIV drugs.     

The therapeutic potential of CXCR4 antagonists in the treatment of HIV

Since the identification of the chemokine receptors CXCR4 and CCR5 as co-receptors for HIV-1 entry, several antagonists against these receptors have been synthesised. A highly selective CXCR4 antagonist, T22, and its downsized analogues T140 and TC14012, which inhibit X4-HIV-1 infection through their specific binding to CXCR4, have been identified. Besides T22 analogues, several other CXCR4 antagonists have been reported, such as AMD3100, ALX40-4C, KRH-1120 and AMD8664. Discovery of entry inhibitors, such as chemokine antagonists, may lead to the development of a new generation of antiHIV agents, since these inhibitors are thought to be useful for the clinical treatment of HIV-1-infected patients, especially at the late stage of treatment for AIDS patients developing multi-drug-resistant strains. In this review, recent research into CXCR4 antagonists in comparison with development of other antagonists is summarised.     

Altered sensitivity of an R5X4 HIV-1 strain 89.6 to coreceptor inhibitors by a single amino acid substitution in the V3 region of gp120

The replication of several R5X4 strains is blocked by single CXCR4 inhibitors such as AMD3100 or T140 although the target cells express both CXCR4 and CCR5 in vitro. To identify which region(s) of the Env are involved in the increased sensitivity to CXCR4 inhibitors, we isolated a T140-escape mutant using R5X4 HIV-1 strain 89.6. An isolated mutant harbored a single amino acid substitution in the V3 region of the Env (arginine 308 to serine R308S). Luciferase-reporter HIV-1 pseudotyped with the mutant Env showed that the substitution conferred total resistance to CXCR4 antagonists but increased sensitivity to a CCR5 antagonist TAK-779 in the infection of the cells expressing both CCR5 and CXCR4. Analyses using the cells expressing a single coreceptor showed that the mutant Env predominantly and efficiently utilized CCR5 rather than CXCR4 while retaining R5X4 phenotype. These results indicated that the sensitivities of the R5X4 strain to coreceptor inhibitors were altered by a single amino acid substitution in the V3 region of gp120.     

Maraviroc,a CCR5 Coreceptor Antagonist That Blocks Entry of Human Immunodeficiency Virus Type 1

Inhibition of the human immunodeficiency virus type 1 (HIV-1) coreceptor is an encouraging new approach to pharmacotherapy against HIV. The HIV-1 strain makes use of either the CCR5 or the CXCR4 coreceptor to gain access into host CD4⁺ cells. Maraviroc, the first HIV-1 CCR5 coreceptor antagonist, blocks entry of HIV-1. This recently approved drug has demonstrated clinically significant decreases in plasma concentrations of HIV-1 RNA and increases in CD4⁺ cell counts; however, it is indicated only for use as salvage therapy. Drug resistance is a concern, as is selective pressure on viral coreceptor use, because viral coreceptor targets may switch as disease progresses. In addition, before maraviroc therapy can be started, costly assays are required to determine the host's viral coreceptor tropism. Emerging therapies targeting CXCR4, the other HIV coreceptor, have shown promise in decreasing plasma concentrations of HIV-1 RNA. Long-term studies with both targets are required to explore the critical issues of efficacy and immunologic safety, as the function of these coreceptors is linked to host chemokine pathways.