Oral CCR5 inhibitors: will they make it through?

The therapeutic armamentarium against HIV has recently gained a drug belonging to a novel class of antiretrovirals, the entry inhibitors. The last decade has driven an in-depth knowledge of the HIV entry process, unravelling the multiple engagements of the HIV envelope proteins with the cellular receptorial complex that is composed of a primary receptor (CD4) and a co-receptor (CCR5 or CXCR4). The vast majority of HIV-infected subjects exhibit biological viral variants that use CCR5 as a co-receptor. Individuals with a mutated CCR5 gene, both homo- and heterozygotes, appear to be healthy. For these and other reasons, CCR5 represents an appealing target for treatment intervention, although certain challenges can not be ignored. Promising small-molecule, orally bioavailable CCR5 antagonists are under development for the treatment of HIV-1 infection.     

Oral CCR5 inhibitors: will they make it through?

The therapeutic armamentarium against HIV has recently gained a drug belonging to a novel class of antiretrovirals, the entry inhibitors. The last decade has driven an in-depth knowledge of the HIV entry process, unravelling the multiple engagements of the HIV envelope proteins with the cellular receptorial complex that is composed of a primary receptor (CD4) and a co-receptor (CCR5 or CXCR4). The vast majority of HIV-infected subjects exhibit biological viral variants that use CCR5 as a co-receptor. Individuals with a mutated CCR5 gene, both homo- and heterozygotes, appear to be healthy. For these and other reasons, CCR5 represents an appealing target for treatment intervention, although certain challenges can not be ignored. Promising small-molecule, orally bioavailable CCR5 antagonists are under development for the treatment of HIV-1 infection.     

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.     

Potential drug targets on the HIV-1 envelope glycoproteins,gp120 and gp41

HIV-1 entry is an attractive target for anti-HIV-1 therapy. However, there are no entry inhibitors approved for the clinical treatment of HIV-1 infection. This is likely to be changed in the near future since promising HIV-1 entry inhibitors, such as T20 and some chemokine receptor antagonists, are in the pipeline to join the repertoire of anti-HIV-1 therapeutics. This review will focus on what might be potential targets on the key components of the viral entry machinery, gp120 and gp41. These two molecules are the viral proteins responsible for HIV-1 entry. Binding to CD4 induces a series of structural changes in gp120 and allows it to interact with chemokine receptors. The receptor binding eventually triggers conformational changes in gp41, which result in the formation of a fusion active molecule to attack the cell membrane. The structural and functional motifs that operate this delicate fusion machinery could become the Achilles' heel of the virus.     

Chemokine receptors: emerging opportunities for new anti-HIV therapies

The chemokine receptors CCR5 and CXCR4 are G-protein coupled receptors (GPCRs) of the immune system and the major co-receptors required for entry of HIV into CD4(+) target cells. CCR5 is critical for both human immunodeficiency virus (HIV) disease transmission and progression, whereas CXCR4 may be very important in late stages of disease. Additional co-receptors have been shown to function under certain conditions in vitro but evidence of supporting roles in HIV disease is currently lacking. The sheer number of co-receptors potentially used by HIV and the complexity of co-receptors usage are major challenges confronting usage of these molecules as drug development targets. Balanced against this, is a long history of success by the pharmaceutical industry in developing small molecule antagonists for many other classes of GPCRs. In this review, we discuss the current state of understanding of the co-receptor-based antiviral agents designed to block viral entry. The therapeutic potential of this field will be judged from future studies on the efficacy of these novel inhibitors in clinical trials. The data so far obtained from a number of studies point to the potential clinical use of this emerging class of therapeutic agents. Here we review current progress in co-receptor-based antiretroviral drug development and discuss the potential advantages and disadvantages of this approach.     

Small molecules anti-HIV therapeutics targeting CXCR4

HIV cellular entry is a multistep process that requires the interaction of a viral envelope glycoprotein (gp120) and a host receptor (CD4) followed by binding to a co-receptor. The CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4) have been identified as the major HIV co-receptors and therefore are promising targets for the development of new anti-HIV drugs. CXCR4 is also involved in several diseases such as angiogenesis, metabolic and neurological disorders, rheumatoid arthritis and in different forms of metastatic cancer. Herein, we present a review focusing on small molecule CXCR4 antagonists. These compounds are divided into 11 classes that include cyclic penta- and tetrapeptides, diketopiperazine mimetics, bicyclams, non-bicyclams, tetrahydroquinolines, thiazolylisothiourea derivatives, benzodiazepines, alkyl amine analogs and non-peptides derivatives, dipicolylamine-zinc(II) complexes, ampelopsin and distamycin analogs. The most advanced CXCR4 antagonists documented are bicyclam derivatives, which are specific CXCR4 antagonists and exhibit potency in the nanomolar range. Further development of selective CXCR4 antagonists continues to be crucial for the design of second generation of anti-HIV drugs. We aim to provide a comprehensive summary of diverse structural templates that could be useful for optimization and discovery of novel CXCR4 antagonists.     

Immunoreactive cycloimmunogen design based on conformational epitopes derived from human immunodeficiency virus type 1 coreceptors: cyclic dodecapeptides mimic undecapeptidyl arches of extracellular loop-2 in chemokine receptor and inhibit human immunodeficiency virus type 1 infection

Human immunodeficiency virus type 1 (HIV-1) requires a chemokine receptor (CCR5 or CXCR4) as a coreceptor not only for initiate viral entry but also protecting highly conserved neutralization epitopes from the attack of neutralizing antibodies. Over the past decade, many studies have provided new insights into the HIV entry mechanism and have focused on developing an effective vaccine strategy. However, to date, no vaccine that can provide protection from HIV-1 infection has been developed. One reason for the disappointing results has been the inability of current vaccine candidates to elicit a broadly reactive immunity to viral proteins such as the envelope (env) protein. Here, we propose that chemokine receptors are attractive targets of vaccine development because their structures are highly conserved and that our synthetic cycloimmunogens can mimic conformational-specific epitopes of undecapeptidyl arches (UPAs: R(168)-C(178) in CCR5, N(176)-C(186) in CXCR4) and be useful for HIV-1 novel vaccine development.     

HIV-1协同受体及其抑制剂研究进展

协同受体CCR5和CXCR4分别是嗜巨噬细胞性HIV-1和嗜T细胞性TIV-1侵入靶细胞的主要受体。CCR5抑制剂如TAK-779、SCH—C等，和CXCR4抑制剂如AMD3100、T22等，能分别与CCR5和CXCR4结合，从而阻断HIV-1侵入靶细胞。本文综述了HIV-1与CCR5和CXCR4的结合机制及其抑制剂的研究进展。     

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.     

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.     

Pharmacological modulation of chemokine receptor function

G protein-coupled chemokine receptors and their peptidergic ligands are interesting therapeutic targets due to their involvement in various immune-related diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, chronic obstructive pulmonary disease, HIV-1 infection and cancer. To tackle these diseases, a lot of effort has been focused on discovery and development of small-molecule chemokine receptor antagonists. This has been rewarded by the market approval of two novel chemokine receptor inhibitors, AMD3100 (CXCR4) and Maraviroc (CCR5) for stem cell mobilization and treatment of HIV-1 infection respectively. The recent GPCR crystal structures together with mutagenesis and pharmacological studies have aided in understanding how small-molecule ligands interact with chemokine receptors. Many of these ligands display behaviour deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. This review aims to give an overview of the evidence supporting modulation of this intriguing receptor family by a range of ligands, including small molecules, peptides and antibodies. Moreover, the computer-assisted modelling of chemokine receptor-ligand interactions is discussed in view of GPCR crystal structures. Finally, the implications of concepts such as functional selectivity and chemokine receptor dimerization are considered.     

HIV co-receptor inhibitors as novel class of anti-HIV drugs

Entry inhibitors constitute a new class of drugs to treat infection by human immunodeficiency virus type 1 (HIV-1). The first member of this class, enfuvirtide, previously known as T-20 and targeting gp41, has now been licensed for therapeutic use. Several other entry inhibitors are in various stages of pre-clinical or clinical development. In this review we focus on the chemokine receptor inhibitors targeting CCR5 and CXCR4 that are the main HIV co-receptors for viral entry.