HIV-1 entry inhibitors: closing the front door

Highly active antiretroviral therapy (HAART) has led to major declines in morbidity and mortality of HIV-1-infected individuals, but the increasing prevalence of drug-resistant viral isolates, combined with the toxicity and other limitations of current treatments, make the development of new therapies a high priority. As knowledge of viral entry has expanded, this step of the viral life cycle has become a target for novel therapeutic strategies. An emerging group of antiretrovirals, known collectively as entry inhibitors, targets several distinct steps in viral entry including CD4 binding, chemokine receptor engagement and the structural changes in the viral envelope required for fusion between viral and cellular membranes. Many entry inhibitors are in various stages of clinical development, with one already licensed for use. This review will provide an overview of the mechanisms involved in the entry process, highlight promising entry blockers under development and discuss several considerations related to treatment that are unique to this class of antiretroviral drugs.     

人类免疫缺陷病毒进入抑制剂的临床开发与应用

耐药性是目前用抗病毒药物治疗获得性免疫缺陷综合征(艾滋病,AIDS)的主要问题。HIV进入抑制剂可以阻断HIV病毒进入人体细胞,具有新的作用机制,对其开发是目前解决耐药性问题的主要方向之一。目前国内已有多家单位在进行HIV进入抑制剂研究,有些即将进入临床试验阶段。本文结合我们自身的研究工作,着重综述了HIV进入抑制剂在预防与治疗艾滋病中的应用研究情况,特别讨论了其临床试验的目的、设计方案,以及进入抑制剂与目前药物联合使用的思路。     

Inhibiting HIV-1 entry with fusion inhibitors

In recent years, tremendous progress has been made in understanding the HIV-1 entry process in which the viral and cellular membranes are fused, resulting in the subsequent delivery of the viral genome into the host cell. The mechanistic insight gained from these studies has led to the formulation of exciting new approaches for therapeutic intervention. One of the first and clinically most advanced drugs to emerge from this effort is the fusion inhibitor T20. T20 acts by freezing a transient structural intermediate of the HIV-1 fusion process, thus blocking an essential step in viral entry. With phase III clinical trials already well underway, the success of T20 indicates that targeting of the viral entry process will soon be an important component of antiretroviral therapy. This review addresses this rapidly developing area of HIV research, with a focus on the mechanistic role of fusion inhibitors targeted to the HIV-1 gp41 transmembrane glycoprotein. We will review the results of recent clinical trials with T20 and discuss possible mechanisms of viral escape through the evolution of drug-resistant HIV-1 variants. We will also discuss ongoing research on fusion inhibitor susceptibility testing and the development of new improved fusion inhibitors.     

HIV-resistance to viral entry inhibitors

An increasing number of human immunodeficiency virus (HIV)-infected patients have detectable viraemia despite treatment with multiple-drug combinations or have developed resistance to all available classes of antiretroviral therapy. HIV entry has become an important pharmacological target. Enfuvirtide is the first HIV entry inhibitor to be approved for the treatment of drug-experienced patients but several other agents are progressing through preclinical and clinical trials. However, because different entry inhibitors target different parts of the entry process their combined effects could be synergistic or generate different distinct profiles of drug-resistance. The HIV envelope glycoprotein that drives HIV entry is highly variable. Its plasticity allows HIV to escape the immune system and its variability is associated with HIV tropism, fitness and replicative capacity. Thus, mutations that confer resistance to entry inhibitors will modify these parameters. Therapeutic strategies that aim at blocking virus entry may also be used to alter the natural evolution of HIV in an unprecedented way. Here, we will describe the structure and function of the envelope glycoprotein complex that constitute the basis for the emergence of resistance to HIV entry inhibitors, review those HIV entry inhibitors for which drug-resistance has been evaluated and discuss the interplay between viral resistance to inhibitors of HIV entry and the pathogenicity of HIV and AIDS.     

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。     

CD4 down-modulating compounds with potent anti-HIV activity

The use of HAART with double or triple drug combinations has significantly improved the survival of AIDS patients. However, the emergence of virus-drug resistance and both short- and long-term drug-related side effects are among the main reasons for continuing the development of new classes of effective anti-HIV drugs that target the replicative cycle at different sites. In recent years, tremendous progress has been made in understanding HIV-1 entry, a multistep process that comprises viral attachment, coreceptor interactions and fusion. The mechanistic insight gained from these studies has enabled the design of specific agents that can inhibit each step in the HIV entry process. The successful results from clinical trials with enfuvirtide (T-20), the first approved entry inhibitor, indicate that targeting of HIV entry will soon be an important component of antiretroviral therapy and further encourage the development of effective entry inhibitors. In this article the recent developments of therapeutic agents endowed with inhibitory properties against the binding of the HIV envelope glycoprotein gp120 to the CD4 receptor (e.g., PRO 542, BMS-378806, TNX-355, PRO 2000 and CV-N) are briefly outlined. Major focus is placed on the anti-HIV activity of cyclotriazadisulfonamides (CADA), a novel class of compounds with a unique mode of action by down-modulating the CD4 receptor in lymphocytic and monocytic cells.     

Maraviroc: new drug. Multiple antiretroviral treatment failure: too soon to reach conclusions

(1) The choice of treatment for HIV-infected patients in whom several lines of antiretroviral therapy have failed is particularly difficult. Some antiretroviral drugs (enfuvirtide and some HIV protease inhibitors) remain effective, at least in the short term. (2) Maraviroc is the first CCR5 antagonist to be licensed for use in this setting. It acts by blocking one of the two coreceptors, CCR5, needed for HIV entry into CD4+ lymphocytes. It is approved for use in HIV-infected patients with multiple antiretroviral failure. (3) Two double-blind placebo-controlled trials including 1076 patients infected by HIV strains using only the CCR5 coreceptor tested the effect of adding maraviroc at a dose of 300 mg twice a day to an optimised treatment. After 8 weeks, maraviroc was more effective than placebo in reducing viral load (undetectable in 45.5% versus 16.7% of patients) and in increasing the CD4+ cell count (+124 cells/mm3 versus +61 cells/mm3); both of these differences are statistically significant. (4) After treatment with maraviroc, 50% to 60% of patients harboured viruses that did not exclusively rely on CCR5 for host cell entry. The possible clinical consequences of this change in tropism are unclear. (5) A double-blind trial of maraviroc included 190 patients with multiple antiretroviral failure who were infected by HIV variants not requiring CCR5 for host cell entry; maraviroc was not shown to be effective. (6) Data obtained with other CCR5 antagonists, and preclinical data obtained with maraviroc, point to a possible increase in the risk of hepatitis, infections, cancer, and QT prolongation. More data are also needed concerning the risk of muscle toxicity and ischaemic cardiovascular events. (7) Maraviroc is metabolised by the cytochrome P450 isoenzyme CYP 3A4, hence a high risk of interactions with CYP 3A4 inducers and inhibitors. (8) In practice, given the absence of long-term evaluation, clinical assessment of maraviroc is too limited to recommend the use of this drug outside the clinical trial setting.     

HIV resistance to the fusion inhibitor enfuvirtide: mechanisms and clinical implications.

The increasing prevalence of HIV isolates resistant to one or multiple antiretroviral drugs has fueled the search for new agents that work by novel mechanisms. Enfuvirtide (ENF), licensed in 2002, is the first marketed antiretroviral (ARV) agent that targets viral entry. ENF blocks the virus replication cycle by binding to gp41, a critical component of the machinery used by HIV to enter host cells. As with all ARVs, HIV can evolve resistance to ENF. However, resistance to ENF appears to be somewhat more complex and can derive through either direct or indirect pathways. Direct resistance occurs when mutations in the first heptad repeat of gp41, which constitutes the ENF-binding site, reduce ENF binding. Indirect resistance is not attributable to changes in the ENF-binding site per se, but rather to changes in the HIV envelope glycoprotein (gp120) that reduce ENF susceptibility by more complex mechanisms. The extensive gp120 amino-acid sequence heterogeneity found in primary viral isolates results in unusually broad variability in susceptibility to ENF, and indeed to other classes of HIV entry inhibitors. Clinical data reported to date do not provide clear evidence that virological outcome of ENF therapy can be predicted by either genotypic or phenotypic analysis of viruses present in patients at initiation of ENF therapy. Although ENF offers an exciting opportunity to treat multi-drug resistant HIV, these observations suggest a greater understanding of ENF resistance may be required to ensure the most effective use of ENF in infected patients. Many aspects of the complexities observed in ENF resistance are likely to be relevant for other classes of HIV entry inhibitors currently in development.     

Small molecule HIV entry inhibitors: Part II. Attachment and fusion inhibitors: 2004-2010

INTRODUCTION: The first US FDA approved HIV entry inhibitor drug Enfuvirdine belongs to the fusion inhibitor category. Earlier efforts in this area were focused on peptides and monoclonal antibodies; recently, the focus has shifted towards the development of small molecule HIV attachment and fusion inhibitors. They can be used for prophylactic purposes and also hold potential for the development of HIV microbicides. AREAS COVERED: In a previous paper ('Small molecule HIV entry inhibitors: Part I'), we reviewed patents and patent applications for small molecule chemokine receptor antagonists from major pharmaceutical companies. In this paper, the development of small molecule HIV attachment and fusion inhibitors is discussed in detail. It covers patents and patent applications for small molecule HIV attachment and fusion inhibitors published between 2004 and 2010 and related literature with a focus on recent developments based on lead generation and lead modification. EXPERT OPINION: To augment the potency of currently available antiretroviral drug combinations and to fight drug-resistant virus variants, more effective drugs which target additional steps in the viral replication cycle are urgently needed. HIV attachment and fusion processes are such targets. Inhibitors of these targets will provide additional options for the treatment of HIV drug-resistant strains. Small molecule HIV attachment inhibitors such as BMS-378806 and analogs from Bristol Myers Squibb, N-aryl piperidine derivatives from Propharmacon, and NBD-556 and NBD-557 from New York Blood Center may have potential as vaginal microbicidal agents and can be an economical alternative to monoclonal antibodies.