Entry and fusion inhibitors of HIV

Considerable advances have been made towards finding compounds that are active as inhibitors of the entry and fusion of HIV. The discovery of chemokines a few years ago focused the attention on coreceptor inhibitors, in addition to fusion and attachment blockers. During the past 5 years there has been intense research activity, both from private companies and academic institutions, in order to find effective compounds that are able to inhibit the initial steps in the HIV lifecycle. Some of the presented compounds demonstrated in vitro synergism, thus there is rationale for their combined use in HIV-infected individuals. Many entry and fusion inhibitors of HIV are currently under investigation in controlled clinical trials and a number of them are bioavailable as oral formulations. This is an essential feature for the extended use of these compounds with the purpose of ameliorating patients adherence to medications, thus preventing the development of drug resistance. The focus of this review will be on the most recent developments in this field, with particular attention focused on promising compounds in preclinical and clinical trials.     

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.     

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.     

The use of Envelope for HIV therapeutics: from vaccines to co-receptors

The Envelope protein (Env) of the human immunodeficiency virus (HIV) has been a primary target and tool for antiviral drug and vaccine development since the discovery of the virus. The study of Env has led to a knowledge of the virus life-cycle, structure and immunological response that has helped lead HIV-directed therapeutic strategies in new, unexpected directions. In particular, the discovery of chemokine receptors as the HIV co-receptors in 1996 is allowing a new generation of antiviral and vaccine candidates to be developed that are based on the ability to block the function of Env in mediating viral entry. This review discusses the primary roles of Env throughout its course of investigation as a tool for vaccine development and as a target for drug screening, emphasising the recent role of Env in the discovery and exploration of the co-receptors. The use of gp120/chemokine binding assays, chemokine receptor structure-function studies and co-receptor polymorphisms are discussed in the context of the development of high-throughput screening assays, creation of immunogens with enhanced vaccine potential and targeting of the co-receptors CCR5 and CXCR4 by small-molecule inhibitors of HIV entry.     

Anti-HIV agents targeting the interaction of gp120 with the cellular CD4 receptor

Perhaps one of the most effective approaches to prevent and inhibit viral infections is to block host cell receptors that are used by viruses to gain cell entry. Major advances have been made over the past decade in the understanding of the molecular mechanism of HIV entry into target cells. A crucial step in this entry process is the interaction of the external HIV envelope glycoprotein, gp120, with the cellular CD4 receptor molecule. This binding step represents a potential target for new antiviral agents, and current efforts to develop safe and effective HIV entry inhibitors are focused on natural ligands and/or monoclonal antibodies that interfere with gp120/CD4 interaction. Also, small synthetic compounds obtained either by high-throughput screening of large compound libraries or by structure-guided rational design have recently entered the antiretroviral arena. In this review, the anti-HIV activity of novel entry inhibitors targeting gp120/CD4 interaction is outlined, and special attention is given to the cyclotriazadisulfonamide compounds, which are the most specific CD4-targeted antiviral drugs described so far.     

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。     

Annotated Patent Selections

Availability of a vast array of recombinant and synthetic immunomodulators represents a significant milestone toward the development of effective therapies for infectious diseases. This is attested by the licensing of several recombinant human cytokines, including colony-stimulating factors, interleukins, interferons and erythropoietin, for clinical use in patients. The identification of the essential role of coreceptors for the entry of HIV into the host cell focused attention on chemokines as important targets for pharmacological intervention. This generated an intense search for molecules possessing therapeutic potential as inhibitors of chemokine receptors and several new compounds have been advocated. Diverse combinations with interferons and other cytokines for the treatment of various viral infections, including hepatitis B and C, have been proposed. Considerable advances have been made on compounds exhibiting cytokine inhibitory properties useful for new treatments of infectious and inflammatory diseases. Many of the major developments and current trends in the area of cytokine biology and therapy are highlighted in this review. Novel strategies based on the engineering of cytokines and inhibitors are poised to revolutionise therapeutic options in the coming decades.     

Recent patents regarding the discovery of small molecule CXCR4 antagonists

Background: The chemokine receptors, CCR₅ and CXCR₄, are the primary co-receptors responsible for mediating HIV-1 cell entry. Small molecules that antagonize these receptors utilize a fundamentally different approach for controlling viral replication than most other classes of antiretroviral agents in that they act on host cell factors rather than viral enzymes. Although CCR₅ modulators that demonstrate efficacy in the clinic against HIV have now become available, CXCR₄ antagonist development is at present at a more nascent stage. Due to the ability of HIV to switch between CCR₅ and CXCR₄ entry co-receptors, the development of a CXCR₄ antagonist is probably critical to prolonging the effectiveness of HIV therapies in patients. In addition, CXCR₄ antagonists represent a novel class of drugs that could be used for the treatment of diseases other than HIV/AIDS. Objective: An overview of the most pertinent chemical classes that modulate the CXCR₄ receptor, in addition to discussions of lead compound development. Methods: The review primarily covers patents and patent application publications filed in the past 8 years. However, earlier patents are included to provide a historical context. Results/conclusion: The early bicyclam class proved untenable for HIV treatment due to cardiotoxicity and lack of desirable pharmacokinetic properties. Second generation bicyclam mimics have the benefit of oral bioavailability but have, as yet, not proven successful in the clinic. The peptidomimetic analogues discussed capitalize on known receptor binding site interactions, which could lead to the development of potent and orally available CXCR₄ antagonists.     

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.     

Developing clinical role of a CCR5 co-receptor antagonist in HIV-1 infection

Background: Maraviroc is the only approved CCR5 coreceptor antagonist on the market for treatment of HIV-1 infection. It uses a previously untargeted step in the HIV-1 replication cycle necessary for viral entry into the host cell. Objective: This review will describe and evaluate recent clinical literature regarding maraviroc, focusing on safety, efficacy, and mechanisms of treatment failure. Methods: A search of the primary literature and conference abstracts was conducted using the keywords CCR5 antagonist, maraviroc, and UK-427857. Resulting articles were then compiled and analyzed in this review. Conclusion: Maraviroc is a potent inhibitor of HIV-1 replication and contributes to effective viral suppression in combination with traditional antiretroviral medications. Due to its numerous drug interactions, potential for severe adverse events, and relative paucity of clinical data in long-term randomized, controlled trials, maraviroc should be one of the final agents utilized in salvage therapy in combination with other active antiretroviral agents.     

HIV entry inhibitors:progress in development and application

This review discusses recent progress in the development of anti-HIV agents, with emphasis on small molecule HIV-1 entry inhibitors.  The entry inhibitors primarily target HIV-1 envelope glycoproteins or the cellular receptors, CD4 and chemokine receptors.  Two of the entry inhibitors, enfuvirtide and maraviroc, have been approved by the US FDA for AIDS therapy.  The drug resistance associated with some of the entry inhibitors will also be discussed.     

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。     

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.     

Novel inhibitors of the early steps of the HIV-1 life cycle

Considerable advances have been made on compounds that are active as inhibitors of HIV entry and fusion. The discovery of chemokines a few years ago focused the attention on coreceptor inhibitors in addition to fusion and attachment blockers. During the last 5 years, there has been an intense research activity from both private companies and academic institutions to find effective compounds that are capable of inhibiting the initial steps in the HIV life cycle. Some of the presented compounds demonstrated in vitro synergism, thus there is the rationale of their combined use in HIV-infected individuals. Many entry and fusion inhibitors of HIV are being investigated in controlled clinical trials and there are a number of them that are bioavailable as oral formulations. This is an essential feature for an extended use of these compounds with the purpose of ameliorating patients’ adherence to medications; therefore, preventing the development of drug resistance. Among the many compounds that are being investigated, some are in the preclinical arena and others are more advanced in development stages. Overall, the main aim is to establish the action of these compounds on the immune system (e.g., the balance of the system after shutting off CCR5 or CXCR4 coreceptors) and the possible burden of unexplained side effects. This review focuses on the recent developments in this field with a particular attention on promising compounds in preclinical and clinical trials.