Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the absence of a vaccine which could stop the HIV/AIDS pandemic, the development of therapeutic options is of utmost interest. The combined use of inhibitors of reverse transcriptase and protease as highly active antiretroviral therapy (HAART) provided the first effective treatment of HIV/AIDS and significantly decreased the number of AIDS related deaths in industrialized countries. However, the emergence of resistant viruses and the toxic side effects of HAART highlights that novel therapies are urgently required. The inhibition of HIV-1 entry is a promising option. Entry of HIV-1 into target cells involves interactions of the viral envelope protein (Env) with CD4 and a coreceptor, usually CCR5 or CXCR4. Env binding to receptor triggers several conformational rearrangements in Env, which involve the creation and/or exposure of structural intermediates pivotal to fusion of the viral and cellular membranes. Both, cellular receptors and structures in Env associated with membrane fusion are targets for therapeutic intervention. Here, we will discuss how HIV-1 enters cells and introduce strategies how this process can be inhibited.
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PMID:Cellular entry of HIV: Evaluation of therapeutic targets. 1678 41

Although combinations of drugs that target the HIV reverse transcriptase and protease enzymes have clearly revolutionized the treatment of HIV/AIDS, problems with these agents, such as viral escape mutants, persistence of viral reservoirs, poor patient compliance due to complicated regimens, and toxic side effects, have emphasized the need for development of new drugs with novel mechanisms of action, as well as an HIV vaccine. Recently two new classes of drugs have been identified that interfere with the membrane fusion reaction required for HIV entry of target cells. Two such agents, T-20 (enfuvirtide) and T-1249, which have been approved by the Food and Drug Administration (FDA), block the action of the fusogenic envelope glycoprotein gp41. Others target the HIV coreceptors CCR5 and CXCR4, and are now in clinical trials. Also under development are novel agents that target the HIV integrase and HIV regulatory gene products as well as immunomodulators such as IL-12 and IL-2. This article will focus on these and other novel approaches to HIV therapeutics.
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PMID:Anti-HIV therapy: Current and future directions. 1678 46

Drugs in development for the management of HIV type 1 (HIV-1) infection include agents in existing classes and agents of novel classes. Of existing classes, new protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors are in development. Novel therapeutic approaches include the development of chemokine receptor (CCR)5 antagonists, integrase inhibitors and maturation inhibitors. CCR5 antagonists are thought to inhibit HIV-1 entry into host cells by occupying a specific site on the CCR5 receptor, preventing attachment of the HIV-1 envelope protein gp120. Integrase inhibitors are small synthetically prepared molecules that block RNA/DNA interactions and modify protein or enzyme synthesis. Data on the pharmacokinetics and pharmacodynamics of these new antiretroviral agents continue to generate interest. This review reports the known data on the pharmacokinetics of experimental antiretrovirals, and describe the main drug-drug interactions studied so far.
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PMID:The clinical pharmacology of antiretrovirals in development. 1686 45

The chemokine receptor CCR5 provides a portal of entry for human immunodeficiency virus type 1 (HIV-1) into susceptible CD4(+) cells. Both monoclonal antibody (MAb) and small-molecule CCR5 inhibitors have entered human clinical testing, but little is known regarding their potential interactions. We evaluated the interactions between CCR5 MAbs, small-molecule CCR5 antagonists, and inhibitors of HIV-1 gp120, gp41, and reverse transcriptase in vitro. Inhibition data were analyzed for cooperative effects using the combination index (CI) method and stringent statistical criteria. Potent, statistically significant antiviral synergy was observed between the CCR5 MAb PRO 140 and the small-molecule CCR5 antagonists maraviroc (UK-427,857), vicriviroc (SCH-D), and TAK-779. High-level synergy was observed consistently across various assay systems, HIV-1 envelopes, CCR5 target cells, and inhibition levels. CI values ranged from 0.18 to 0.64 and translated into in vitro dose reductions of up to 14-fold. Competition binding studies revealed nonreciprocal patterns of CCR5 binding by MAb and small-molecule CCR5 inhibitors, suggesting that synergy occurs at the level of receptor binding. In addition, both PRO 140 and maraviroc synergized with the chemokine RANTES, a natural ligand for CCR5; however, additive effects were observed for both small-molecule CCR5 antagonists and PRO 140 in combination with other classes of HIV-1 inhibitors. The findings provide a rationale for clinical exploration of MAb and small-molecule CCR5 inhibitors in novel dual-CCR5 regimens for HIV-1 therapy.
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PMID:Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. 1700 7

There are many promising new agents in development for the treatment of HIV type 1 (HIV-1). The targets of antiretroviral drugs include the three major HIV-1 enzymes (reverse transcriptase, protease, and integrase), final packaging and export of mature virions, and entry mediated by the CD4 receptor and the CCR5 and CXCR4 coreceptors. Drugs in development in existing classes are primarily designed to provide new options for those with resistance to existing agents. Novel agents such as those targeting integrase, entry inhibitors, and those targeting viral processing likely will be useful the treatment of antiretroviral-experienced patients. Depending on safety, efficacy, tolerability, and convenience of dosing, new agents may also alter the current treatment paradigms for first-line therapy. This review summarizes data on several drugs that could move forward into the clinical arena and affect the lives of those infected with HIV-1.
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PMID:Novel antiretroviral agents in HIV therapy. 1706 43

The majority of HIV isolated from infected patients uses CCR5 as a coreceptor (R5-HIV). Although R5-HIV fails to replicate efficiently in human transformed T-cell lines, HIV using CXCR4 (X4-HIV) can replicate well in such cell lines. Therefore, most of screening systems using the T-cell lines detect only X4-HIV replication. Here we report a new assay to monitor the replication of R5- as well as X4-HIV. An MTT assay using CD4-, CXCR4-, and CCR5-transduced human glioma NP-2 cells (NCK45 cells) was established and then compared with the representative assays including multinuclear activation of a galactosidase indicator assay (MAGI assay). The antiviral activities of not only an adsorption inhibitor and reverse transcriptase inhibitors but also a Tat antagonist in the NCK45 cells, were comparable to those obtained from the MTT assay using MT-4 cells or the MAGI assay. However, the activity of protease inhibitors (PIs) was underestimated, even though expressions of major multidrug resistant genes involved in efflux of PIs were comparable in MT-2, NP-2, and NCK45 cells. After cultivation of more than 6 months, NCK45 cells remained susceptible to HIV infection since NCK45 cells consistently expressed CD4, CXCR4, and CCR5. On the other hand, MAGI cells lost the CD4 expression during culture. Thus, this assay system can stably detect the replication of both X4- and R5-HIV, indicating that it should be useful for the evaluation of HIV replication and drug susceptibility.
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PMID:A novel colorimetric assay for CXCR4 and CCR5 tropic human immunodeficiency viruses. 1706 99

The current testing of anti-HIV drugs is hampered by the lack of a small animal that is readily available and easy to handle; can be infected systemically with HIV type 1 (HIV-1); harbors the major HIV-1 target cells in a physiological frequency, organ distribution, and activation state; and is established as a pharmacological model. Here, we explored the potential of outbred Sprague-Dawley rats that transgenically express the HIV-1 receptor complex on CD4 T cells and macrophages as a model for the preclinical evaluation of inhibitors targeting virus entry or reverse transcription. The concentrations of the peptidic fusion inhibitor enfuvirtide or the nonnucleoside reverse transcriptase inhibitor efavirenz required to inhibit HIV-1 infection of cultured primary CD4 T cells and macrophages from human CD4 and CCR5-transgenic rats differed by no more than 3-fold from those required for human reference cultures. Prophylactic treatment of double-transgenic rats with a weight-adapted pediatric dosing regimen for either enfuvirtide (s.c., twice-daily) or efavirenz (oral, once-daily) achieved a 92.5% or 98.8% reduction, respectively, of the HIV-1 cDNA load in the spleen 4 days after i.v. HIV-1 challenge. Notably, a once-daily dosing regimen for enfuvirtide resulted in a approximately 5-fold weaker inhibition of infection, unmasking the unfavorable pharmacokinetic characteristics of the synthetic peptide in the context of an efficacy trial. This work provides proof of principle that HIV-susceptible transgenic rats can allow a rapid and predictive preclinical evaluation of the inhibitory potency and of the pharmacokinetic properties of antiviral compounds targeting early steps in the HIV replication cycle.
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PMID:HIV-susceptible transgenic rats allow rapid preclinical testing of antiviral compounds targeting virus entry or reverse transcription. 1720 12

Nucleoside reverse transcriptase inhibitors (NRTIs) are known to produce painful neuropathies and to enhance states of pain hypersensitivity produced by HIV-1 infection. It has also been observed that in some neuropathic pain models, chemokines and their receptors are upregulated, perhaps contributing to the pain state. In order to understand if chemokines are involved in NRTI-mediated sensory neuropathies, we treated rats with the anti-retroviral drug, 2',3'-dideoxycytidine (ddC), which is known to produce an extended period of hyperalgesia and allodynia. Using in situ hybridization, we observed that under normal conditions, CXCR4 chemokine receptors were widely expressed by satellite glia in the dorsal root ganglia (DRG) and Schwann cells in the sciatic nerve. A limited number of DRG neurons also expressed CXCR4 receptors. The chemokine SDF-1/CXCL12 was similarly expressed in glial cells in the DRG and peripheral nerve. Following a single administration of ddC, expression levels of CXCR4 mRNA in glia and neurons and SDF-1 mRNA in glia increased considerably. The functional nature of increased CXCR4 mRNA expression was confirmed by measuring SDF-1 induced [Ca2+]i increases in acutely isolated DRG neurons and glia. In contrast, the expression of the chemokine receptors CCR2 and CCR5 did not change following ddC treatment. Pain hypersensitivity produced by ddC could be inhibited by treatment with the CXCR4 antagonist, AMD3100. Hence, we postulate that NRTIs produce pain hypersensitivity through the upregulation of CXCR4 signaling in the DRG. Increased numbers of CXCR4 receptors would also explain the synergism observed between NRTI treatment and the proalgesic effects of HIV-1 infection.
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PMID:CXCR4 chemokine receptor signaling mediates pain hypersensitivity in association with antiretroviral toxic neuropathy. 1729 84

The chemokine receptors CCR5 and CXCR4 were identified as HIV-1 co-receptors in 1996. Since then, a range of agents that bind these receptors and potently block HIV-1 infection have been described, including monoclonal antibodies, peptides and modified chemokines. However, small organic molecules that bind CCR5 are currently the most promising of the co-receptor antagonists for the potential treatment of HIV. These agents are now in advanced stages of clinical development and should soon augment current therapies, as well as being candidates for inclusion in microbicides. Unlike existing drugs that target HIV proteins (eg, reverse transcriptase and protease), co-receptor antagonists bind receptors encoded by the host. As a consequence, blockade of these receptors may result in immunosuppressive effects or other disorders. Furthermore, co-receptor inhibitors may also be more toxic than currently available HIV therapies, and it is not yet clear whether they will become candidates for first-line therapy. Nonetheless, safer, less toxic versions of such inhibitors may be achievable in the future. The use of CCR5 inhibitors as a second-line treatment increases the possibility that these reagents will select for more pathogenic CXCR4-using variants. The development of effective CXCR4 antagonists for dual treatment would be beneficial; however, whether long-term treatment with antagonists of the widely expressed CXCR4 receptor is feasible without toxicity is unknown. This review discusses the current status of CCR5 antagonists, their modes of action and their development for therapeutic use.
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PMID:The promise of CCR5 antagonists as new therapies for HIV-1. 1732 29

Several CCR5 ligands, including small molecules and monoclonal antibodies (MAbs), are being developed as therapies for infection with strains of human immunodeficiency virus type 1 (HIV-1) that use CCR5 for entry (R5 viruses). The efficacy of such therapies could be influenced by inter-individual differences in host factors, such as CCR5 expression levels. To study this, we used peripheral blood mononuclear cells (PBMCs) from humans and rhesus macaques. The half-maximal inhibitory concentrations (IC(50)) of the small-molecule CCR5 ligands CMPD167, UK427,857 and SCH-D, and of the PRO 140 MAb, differ by >2 logs in a donor-dependent manner. We studied this variation by using flow cytometry to measure CCR5 expression on PBMCs from six of the human donors: the IC(50) values of both SCH-D and PRO 140 correlated with CCR5 expression (R(2)=0.64 and 0.99, respectively). We also determined the efficacy of the CCR5 ligands against HIV-1 infection of HeLa-derived cell lines that express CD4 at the same level but vary 2-fold in CCR5 expression (JC.48 and JC.53 cells). The moderately greater CCR5 expression on the JC.53 than the JC.48 cells was associated with proportionately higher median IC(50) values for all four CCR5 ligands but not for a soluble CD4-based inhibitor or a non-nucleoside reverse transcriptase inhibitor. We conclude that differences in CCR5 expression on human PBMCs, which can be affected by CCL3L1 gene dose, may influence the antiviral potency of CCR5 ligands in vitro, but other host factors are also likely to be involved. These host factors may affect the clinical activity of CCR5 inhibitors, including their use as topical microbicides to prevent HIV-1 transmission.
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PMID:Cell surface expression of CCR5 and other host factors influence the inhibition of HIV-1 infection of human lymphocytes by CCR5 ligands. 1742 18


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