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)

Despite the success of combination HAART in improving the clinical prognosis of HIV-infected patients, therapeutic options are limited for many patients, particularly those with extensive treatment experience. Resistance, cross-resistance, and toxicity combine to threaten the durability of antiviral response, necessitating the development of novel agents. The HIV life cycle has many potential targets for inhibition in addition to the current reverse transcriptase and protease targets. These include the HIV integrase, nucleocapsid, and Tat proteins and the viral entry process. Entry inhibitors can be classified as attachment, coreceptor, and fusion inhibitors, according to the stage in the entry process at which they act. Most advanced in development of these is the fusion inhibitor enfuvirtide. Enfuvirtide is a potent inhibitor of HIV fusion whose novel mechanism of action and extracellular nature mean that it will induce limited cross-resistance to currently approved antiretrovirals and fewer toxicities.
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PMID:New classes of HIV drugs on the horizon. A review of the presentation at the satellite symposium "New hope: advancing care in HIV infection" at the 15th annual Association of Nurses in AIDS Care conference, November 2002. 1276 59

The replicative cycle of the human immunodeficiency virus (HIV) can be interrupted at several stages. Until recently only the viral reverse transcriptase and protease were the only enzymes targeted by antiretroviral agents. However, the first HIV entry inhibitor (T-20, Enfuvirtide, Fuseon) to be used in humans has been approved by the Food and Drug Administration (FDA). The HIV entry process is considered as an attractive target for chemotherapeutic intervention, as blocking HIV entry into its target cell leads to suppression of viral infectivity, replication and the cytotoxicity induced by virus-cell contacts. HIV-1 entry into target cells is a multistep process: virus attachment is initiated by the binding of trimeric envelope glycoprotein gp120 complexes on the virions to glycosylated T-cell surface receptor (CD4) and HIV GPCR coreceptors (CCR5 or CXCR4) leading to envelope glycoprotein gp41-dependent fusion-pore formation and membrane fusion. A number of compounds are being developed to specifically target each of these steps leading to virus entry and some compounds have reached early clinical development. Conversely, agents such as the CCR5 antagonist Tak-779 and the CXCR4 antagonist AMD3100 are not longer being thought as relevant anti-HIV agents but have given way to new analogues with improved properties. This review summarizes the current state of HIV entry inhibitors, their mechanisms of action and their therapeutic value against HIV infection and AIDS.
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PMID:Virus entry as a target for anti-HIV intervention. 1287 Nov 11

Enfuvirtide is a novel antiretroviral that blocks HIV-1 cell fusion and viral entry. This Phase II, controlled, open-label, randomized, multicentre dose-ranging trial explored the safety, antiviral activity and pharmacokinetics of enfuvirtide, administered by subcutaneous (s.c.) injection, in 71 HIV-1-infected, protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive adults for 48 weeks. Study participants were randomized to receive enfuvirtide at a deliverable dose of 45, 67.5 or 90 mg twice daily; the 45 mg twice daily dose required 2 injections/day, while the higher doses required 4 injections/day. A background oral antiretroviral (ARV) regimen of abacavir (300 mg twice daily), amprenavir (1200 mg twice daily), ritonavir (200 mg twice daily) and efavirenz (600 mg once daily) was provided with enfuvirtide. A control group received the background ARV regimen alone. All potential participants underwent an HIV genotype at screen to ensure a homogenous population and to exclude patients with evidence of genotypic resistance to NNRTIs. Overall, the tolerability of the combination of abacavir, amprenavir, ritonavir, efavirenz and enfuvirtide was generally comparable to control through 48 weeks. No enfuvirtide dose-dependent adverse events (AEs) were observed across treatment groups. Injection site reactions (ISRs) occurred at least once in 68.5% of the enfuvirtide-treated population, and most ISRs were mild to moderate in severity, with no apparent dose relationship. Excluding ISRs, the most common treatment-emergent AEs were nausea, diarrhoea, dizziness and fatigue; with no clinically significant differences in the incidence of AEs observed between the control and enfuvirtide groups. Each treatment group benefited from ARV therapy, with a trend of increasing antiviral and immunological activity associated with increasing enfuvirtide dose. At 48 weeks, the median HIV-1 RNA change from baseline for the ITT population was -2.24 log10 copies/ml for the combined enfuvirtide groups compared with -1.87 log10 copies/ml for the control group. In addition, 54.9% of patients in the enfuvirtide group achieved HIV-1 RNA < or = 400 copies/ml versus 36.8% of patients in the control group. These results indicate that enfuvirtide has a favourable safety profile and is a promising new antiviral agent for HIV-infected patients who have been on previously failing ARV regimens.
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PMID:A controlled Phase II trial assessing three doses of enfuvirtide (T-20) in combination with abacavir, amprenavir, ritonavir and efavirenz in non-nucleoside reverse transcriptase inhibitor-naive HIV-infected adults. 1451 96

With the number of people living with HIV infection increasing and the problems of drug resistance and long-term toxicity associated with current antiretroviral agents continuing, there is a growing need for new therapy options. Enfuvirtide is the first fusion inhibitor, a new class of drug, to be licensed for the treatment of HIV infection and is a welcome addition to the arsenal of antiretrovirals. This paper, which is the result of a multidisciplinary discussion meeting, reviews current practice in treating HIV infection, the clinical data available on enfuvirtide and discusses its introduction into clinical practice. Data available to date indicate that enfuvirtide is appropriate for use in patients who have previously taken nucleoside reverse transcriptase inhibitor (NRTI), non-NRTI and protease inhibitor containing regimens and are either intolerant of them or have experienced virological failure. Enfuvirtide should ideally be used while the patient still has other active drug options available to them to combine with enfuvirtide in an effective therapy regimen.
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PMID:Enfuvirtide (Fuzeon): the first fusion inhibitor. 1471 92

Human immunodeficiency virus (HIV) is a retrovirus that is the causative agent of acquired immunodeficiency syndrome (AIDS). Current HIV therapy is based on targeting two critical enzymes in the viral replication machinery: reverse transcriptase and a virally encoded protease. Although mortality rates due to HIV infection have been dramatically reduced, AIDS remains a major health problem throughout the world. The emergence of HIV variants that are resistant to current therapies and potential toxicity associated with their chronic use has highlighted the need for new approaches to HIV inhibition. Identification of the mechanisms underlying viral entry into the host cell has provided a number of novel therapeutic targets and the first of these HIV fusion inhibitors (enfuvirtide [pentafuside, T-20, Fuzeon; Roche Laboratories and Trimeris]) has recently been approved in the US and Europe. This review will focus on recent progress in the development of therapeutics that target the HIV entry process.
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PMID:HIV entry and fusion inhibitors. 1515 32

The gp41 subunit of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein plays an important role in HIV-1 entry and severs as an attractive target for development of HIV-1 entry inhibitors, a new class of anti-HIV drugs. Triggered by gp120 binding to CD4 and a coreceptor, gp41 undergoes a conformation shift from a native prefusogenic state to a fusogenic state, in which the N-terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR) associate to form a six-helix bundle, representing the fusion-active gp41 core. Any compound that disrupts the gp41 six-helix bundle formation may inhibit the gp41-mediated membrane fusion, thereby blocking HIV-1 entry into target cells. Peptides derived from the gp41 NHR and CHR regions, designated N- and C-peptides, can interact with the counterpart regions in gp41 and interfere with the six-helix bundle formation between the viral NHR and CHR region, thus inhibiting fusion of the virus with the target cell. One of the C-peptides, T-20 (brand name: Fuzeon), was recently approved by the US FDA as the first HIV entry inhibitor which can be used for treatment of AIDS patients who fail to respond to the current antiretroviral drugs, e.g., the reverse transcriptase inhibitors and protease inhibitors. The limitations of T-20 include lack of oral availability and high cost of production. Thus it is essential to develop small molecule HIV-1 entry inhibitors targeting gp41. This review summarizes the newly developed techniques for high throughput screening (HTS) and characterization of the HIV-1 entry inhibitors targeting gp41. The theories behind these techniques are also discussed. It is expected that the "drug-like" compounds with potent HIV-1 fusion inhibitory activity will be identified in the near future and used as leads for development of the low molecular weight HIV-1 entry inhibitors for the chemotherapy of HIV-1 infection and AIDS.
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PMID:High throughput screening and characterization of HIV-1 entry inhibitors targeting gp41: theories and techniques. 1518 May 43

In recent years, significant progress has been made towards the chemotherapy (and prophylaxis) of HIV infections. This progress is situated at three different levels. (i) New anti-HIV drugs have been approved for clinical use and have entered the market: the virus entry inhibitor enfuvirtide (Fuzeon), the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (Emtriva), the nucleotide reverse transcriptase inhibitor (NtRTI) tenofovir disoproxil fumarate (Viread trade mark ) and the HIV protease inhibitor (PI) atazanavir (Reyataz trade mark ). (ii) Other compounds have proceeded through preclinical and/or clinical development: CXCR4 antagonists (i.e. AMD070), CCR5 antagonists (i.e. SCH-C), NRTIs (such as amdoxovir), NNRTIs (such as etravirine), integrase inhibitors (such as S-1360) and PIs (such as tipranavir). (iii) Yet other compounds, acting by novel mechanisms, have recently been identified as anti-HIV agents that seem worthy of further (pre)clinical development: cell receptor CD4 down-modulators (i.e. cyclotriazadisulfonamides), viral envelope gp120-binding agents such as plant lectins and glycopeptide antibiotics, HIV integrase inhibitors such as the pyranodipyrimidine V-165, and two new classes of compounds (i.e. N-aminoimidazoles and pyridine oxide derivatives) which seem to interfere with a post-integration, transcription transactivation event. Taken together, it is obvious that the approaches for the treatment of HIV infections in recent years have become both more diverse and more efficient.
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PMID:HIV-chemotherapy and -prophylaxis: new drugs, leads and approaches. 1518 46

Four antiretroviral drugs were approved in 2003: emtricitabine (FTC, Emtriva), and nucleoside reverse transcriptase inhibitor (NRTI); the protease inhibitors (PIs) atazanavir (Reyataz) and fosamprenavir (Lexiva); and T-20 (enfuvirtide, Fuzeon), the first of a new anti-HIV drug class, entry inhibitors.
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PMID:The pipeline: three to watch. 1538 38

Enfuvirtide is the first of a new class of antiretroviral agents recently approved for the treatment of human immunodeficiency virus (HIV)-1 infection. Present available data suggest that enfuvirtide may be a promising agent for the control of HIV infection in patients who have previously received reverse transcriptase inhibitor and protease inhibitor regimens and who are either intolerant to such drugs and/or who have gone into virological failure. Perhaps the greater limitation to the clinical use of enfuvirtide is the cost, limiting its use in the developing world.
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PMID:Enfuvirtide: a new class of antiretroviral therapy for HIV infection. 1553 6

New treatment modalities for HIV infection in 2005 are based on the availability of new antiretrovirals and new strategies for their use. For reverse transcriptase inhibitors, abacavir/lamivudine and tenofovir/emtricitabine combinations minimize risks of mitochondrial toxicity and are now available as a single daily tablet. New protease inhibitors (PI) are boosted by ritonavir. Some that are already available (atazanavir, fosamprenavir) have good tolerance, resistance and dosing profiles. PIs in advanced stages of development (tipranavir and TMC114) specifically target strains with resistant mutations. Entry inhibitors affecting the CCR5 co-receptor are a new promising drug class. Enfuvirtide, a fusion inhibitor administered in subcutaneous injections, significantly improves the antiretroviral and immunologic response to antiretroviral regimens in patients with previous treatment failures. For successfully treated patients, simplification and treatment interruptions are sometimes possible. For non-responders, thorough virological-pharmacological assessment is necessary, together with access to new molecules and new drug classes.
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PMID:[New antiretroviral treatment modalities]. 1602 64


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