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)

The association of a drug with its target protein has the effect of blocking the protein activity and is termed a promiscuous function to distinguish from the protein's native function (Tawfik and associates, Nat. Genet. 37, 73-6, 2005). Obviously, a protein has not evolved naturally for drug association or drug resistance. Promiscuous protein functions exhibit unique traits of evolutionary adaptability, or evolvability, which is dependent on the induction of novel phenotypic traits by a small number of mutations. These mutations might have small effects on native functions, but large effects on promiscuous function; for example, an evolving protein could become increasingly drug resistant while maintaining its original function. Ariel Fernandez, in his opinion piece, notes that drug-binding "promiscuity" can hardly be dissociated from native functions; a dominant approach to drug discovery is the protein-native-substrate transition-state mimetic strategy. Thus, man-made ligands (e.g. drugs) have been successfully crafted to restrain enzymatic activity by focusing on the very same structural features that determine the native function. Using the successful inhibition of HIV-1 protease as an example, Fernandez illustrates how drug designers have employed naturally evolved features of the protein to suppress its activity. Based on these arguments, he dismisses the notion that drug binding is quintessentially promiscuous, even though in principle, proteins did not evolve to associate with man made ligands. In short, Fernandez argues that there may not be separate protein domains that one could term promiscuous domains. While acknowledging that drugs may bind promiscuously or in a native-like manner a la Fernandez, Tawfik maintains the role of evolutionary adaptation, even when a drug binds native-like. In the case of HIV-1 protease, drugs bind natively, and the initial onset of mutations results in drug resistance in addition to a dramatic decline in enzymatic activity and fitness of the virus. A chain of compensatory mutations follows this, and then the virus becomes fully fit and drug resistant. Ben Berkhout and Rogier Sanders subscribe to the evolution of new protein functions through gene duplication. With two identical protein domains, one domain can be released from a constraint imposed by the original function and it is thus free to move in sequence space toward a new function without loss of the original function. They emphasize that the forced evolution of drug-resistance differs significantly from the spontaneous evolution of an additional protein function. For instance, the latter process could proceed gradually on an evolutionary time scale, whereas the acquisition of drug-resistance is an all or nothing process for a virus, leading to the failure or success of therapy. They find no evidence to the thesis that resistance-mutations appear more rapidly in promiscuous domains than native domains. Berkhout and Sanders illustrate the genetic plasticity of HIV-1 by citing examples in which well-conserved amino acid residues of catalytic domains are forced to mutate under drug-pressure. HIV drug resistance biology is very complex. Instead of a viral protein, a drug can be targeted at a cellular protein. For example, Berkhout and Sanders claim, a drug targeted at the cellular protein CCR5 inhibits the binding of the viral envelope glycoprotein (Env) to CCR5. However, Env mutates so that it binds to the CCR5-drug complex and develops drug resistance. Interestingly, CCR5 has not evolved to bind to Env, but to a series of chemokines. Andrzej Kloczkowski, Taner Sen, and Bob Jernigan point out the importance of protein motions for binding. They believe it is likely that different ligands can bind to the diverse protein conformations sampled in the course of normal protein conformational fluctuations. They have been applying simple elastic network models to extract the motions as normal modes, which yield relatively small numbers of conformations that are useful for developing protein mechanisms; while these are typically small motions, for some proteins they can be quite large in scale. One of the major advantages of the approach is that only relatively small numbers of modes are important contributors to the overall motion -- so the approach provides a way to systematically map out a protein's motions. These models successfully represent the conformational fluctuations manifested in the crystallographic B-factors, and often suggest motions related to protein functional behaviors, such as those observed for reverse transcriptase, where two dominant hinges clearly relate to the processing steps -- one showing anti-correlation between the polymerase and ribonuclease H sites related to the translation and positioning of the nucleic acid chain, and another for opening and closing the polymerase site. Disordered proteins represent a more extreme case where the set of accessible conformations is much larger; thus they could offer up a broader range of possible binding forms. Whether evolution controls the functional motions for proteins remains little studied. Intriguingly, buried in the existing databases of protein-protein interactions may be information that can shed light on the extent of promiscuous binding among proteins themselves. Within these data there are cases where large numbers of diverse proteins have been shown to interact with a single protein; some of these could represent promiscuous protein-protein binding. Uncovering these promiscuous behaviors could be important for comprehending the details of how proteins can bind promiscuously to one another, and can exhibit even greater promiscuity in their binding to small molecules. The evolutionary routes, the dynamics of the target protein, and the many other aspects that need to be addressed while designing a drug that may dodge drug resistance, indicate the complexity and multi-disciplinary nature of the issue of drug resistance.
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PMID:Protein promiscuity: drug resistance and native functions--HIV-1 case. 1584 67

Infection of human cell with human immunodeficiency virus type-1 (HIV-1) was suppressed by cellular genetic factor(s) at reverse transcription step. Although same amount of virus adsorbed on both cells, small amount of HIV-1 (IIIB strain) infected HeLa (MAGI/CCR5) cell, while large amount of HIV-1 infected HOS (GHOST/CXCR4) cell. Regulation of virus replication at postentry level by cellular factor(s) had an important role for low efficiency of HIV-1 infection to MAGI/CCR5 cell. Provirus DNA formation in MAGI/CCR5 cell was less efficient than in GHOST/CXCR4 cell. Once GHOST/CXCR4 cell was fused with MAGI/CCR5 cell, susceptibility against HIV-1 decreased. Further, HIV-1 reverse transcriptase (RT) activity was strongly inhibited by cytosolic protein, derived from MAGI/CCR5 cell, in vitro. This research cleared a certain human cell genetically carries some factor(s) which inhibits the activity of HIV-1 RT.
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PMID:Inhibition of human immunodeficiency virus type-1 (HIV-1) replication at a reverse transcription step by human cell factor(s). 1586

Current therapeutic intervention in HIV infection relies upon 20 different drugs. Despite the impressive efficacy shown by these drugs, we are confronted with an unexpected frequency of adverse effects, such as mitochondrial toxicity and lipodystrophy, and resistance, not only to individual drugs but to entire drug classes.Thus, there is now a great need for new antiretroviral drugs with reduced toxicity, increased activity against drug-resistant viruses and a greater capacity to reach tissue sanctuaries of the virus. Two different HIV molecules have been selected as targets of drug inhibition so far: reverse transcriptase and protease. Drugs that target the interactions between the HIV envelope and the cellular receptor complex are a 'new entry' into the scenario of HIV therapy and have recently raised great interest because of their activity against multidrug-resistant viruses. There are several compounds that are at different developmental stages in the pipeline to counter HIV entry, among them: (i) the attachment inhibitor dextrin-2-sulfate; (ii) the inhibitors of the glycoprotein (gp) 120/CD4 interaction PRO 542, TNX 355 and BMS 488043; (iii) the co-receptor inhibitors subdivided in those targeting CCR5 (SCH 417690 [SCH D], UK 427857 GW 873140, PRO 140, TAK 220, AMD 887) and those targeting CXCR4 (AMD 070, KRH 2731); and (iv) the fusion inhibitors enfuvirtide (T-20) and tifuvirtide (T-1249). The story of the first of these drugs, enfuvirtide, which has successfully completed phase III clinical trials, has been approved by the US FDA and by the European Medicines Agency, and is now commercially available worldwide, is an example of how the knowledge of basic molecular mechanisms can rapidly translate into the development of clinically effective molecules.
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PMID:The appealing story of HIV entry inhibitors : from discovery of biological mechanisms to drug development. 1589 86

Highly active antiretroviral therapy (HAART) dramatically changed the course of HIV infection. Currently, this therapy involves the use of agents from at least two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Recently, the third family of antivirals started to be used clinically, with the advent of enfuvirtide, the first fusion inhibitor (FI). Several pharmacological agents are available form these classes of antivirals, NRTIs, NNRTIs, PIs and FIs, which will be briefly reviewed here. Some more agents are in advanced clinical evaluation or have recently been approved (such as tenofovir, a NtRTI; atazanavir, a PI; tipranavir, another PI), mainly against drug-resistant viruses. Compounds inhibiting HIV integrase, the third enzyme of HIV, are also available ultimately, with several such derivatives in clinical trials (L-731, 988 and S-1360). Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. All steps in the process of HIV entry into the cell may be targeted by specific compounds that might be developed as novel types of antiretrovirals. Thus, inhibitors of the gp120-CD4 interaction have been detected (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220, SCH-C, SCH-D, E913, AK-602 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Compounds interacting with Tat/Tar have also been detected which inhibit HIV replication in low micromolar range (EM2487, tamacrazine, CGP 64222 or CGA 137053 among others). Unexploited viral and cellular targets (such as the maturation process-with a first potent compound available, PA-457; the cellular proteins Tsg101, APOBEC3G, or the viral ones Vif, Rev or RNase H) are also presented, together with recently emerged approaches for eradication of HIV reservoirs. A review on the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to these drugs may be managed better by taking them into account.
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PMID:Highly active antiretroviral therapy: current state of the art, new agents and their pharmacological interactions useful for improving therapeutic outcome. 1589 77

There are now exactly 20 anti-HIV drugs licenced (approved) for clinical use, and > 30 anti-HIV compounds under (pre)clinical development. The licensed anti-HIV drugs fall into five categories: nucleoside reverse transcriptase inhibitors (NRTIs: zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine); nucleotide reverse transcriptase inhibitors (NtRTIs: tenofovir disoproxil fumarate); non-nucleoside reverse transcriptase inhibitors (NNRTIs: nevirapine, delavirdine and efavirenz); protease inhibitors (PIs: saquinavir, indinavir, ritonavir, nelfinavir, amprenavir, lopinavir, atazanavir and fosamprenavir); and fusion inhibitors (FIs: enfuvirtide). The compounds that are currently under clinical (Phase I, II or III) or preclinical investigation are either targeted at the same specific viral proteins as the licensed compounds (i.e., reverse transcriptase [NRTIs: PSI-5004, (-)-dOTC, DPC-817, elvucitabine, alovudine, MIV-210, amdoxovir, DOT; NNRTIs: thiocarboxanilide, UC-781, capravirine, dapivirine, etravirine, rilpivirine], protease [PIs: tipranavir, TMC-114]) or other specific viral proteins (i.e., gp120: cyanovirin N; attachment inhibitors: AIs, such as BMS-488043; integrase: L-870,812, PDPV-165; capsid proteins: PA-457, alpha-HCG); or cellular proteins (CD4 downmodulators: CADAs; CXCR4 antagonists: AMD-070, CS-3955; CCR5 antagonists: TAK-220, SCH-D, AK-602, UK-427857). Combination therapy is likely to remain the gold standard for the treatment of AIDS so as to maximise potency, minimise toxicity and diminish the risk for resistance development. Ideally, pill burden should be reduced to once-daily dosing so as to optimise the patient's compliance and reduce the treatment costs.
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PMID:Emerging anti-HIV drugs. 1593 66

Lexigen (formerly Fuji ImmunoPharmaceuticals) is developing FP-21399, a bis-azo compound, for the potential treatment of HIV infections. By March 1998, a phase II clinical study had been initiated to explore the immunologic and virologic activity of the compound. In the phase II study, the compound was being administered once a month for 48 weeks to 40 patients who are failing on protease inhibitor regimens either alone or with the antiretrovirals currently being taken by the patients. In a previous phase II study conducted by the company, researchers observed hints of a cellular immune response in a small subset of subjects at risk for disease progression or development of opportunistic infections [310177]. Phase I clinical trials commenced in the US in 1995 [178794]. In a small 21-patient phase I dose escalation trial of intravenous FP-21399, 13 patients with baseline CD4 cell counts between 50 and 400 received infusions of various doses (1,2 or 3 mg/kg) of the compound once a week for four weeks. The compound was well-tolerated and 9 patients showed an increase in CD4 count of at least 15% over their baseline values, 2 showed a decrease in viral load of 1 log (90%), and 2 went from low viral loads to below the limit of quantification [310771,310177]. FP-21399 has been reported to interfere with the ability of the HIV envelope glycoproteins to use CXCR4 and CCR5 as co-receptors when entering CD4 cells. It concentrates in the lymph nodes, which are important viral reservoirs. In addition, the drug has demonstrated antiviral activity against many clinical and laboratory strains of HIV, including those that are AZT-resistant [310177]. FP-21399 was selected via a screening program of Fuji's compounds developed originally for photographic use. It has been demonstrated, in preclinical studies, that FP-21399 inhibits HIV entry to the target cell by interfering with the V3 loop of the viral envelope. The compound has the advantage that it has lower toxicity than reverse transcriptase inhibitors because it does not enter the cells [178794].
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PMID:FP-21399 (Lexigen Pharmaceuticals). 1594 35

Despite a number of recent therapeutic advancements, there remains an urgent need to develop a new class of therapy for human immunodeficiency virus (HIV). This review summarises attempts at blocking HIV binding and entry into host cells, an approach that would provide theoretical advantages over the currently available drugs targeting enzymes (reverse transcriptase and protease), brought into play in the later stages of the viral life cycle. The multi-step process of HIV entry into cells, binding of the surface glycoprotein (gp120) to the CD4 receptor and one of the chemokine receptors, followed by the membrane fusion step mediated by the transmembrane glycoprotein (gp41), has recently been understood with greater clarity. The importance of the chemokine co-receptors, such as CCR5 and CXCR4, for HIV entry may help to explain the limitations of earlier approaches using recombinant soluble CD4 or polyanionic compounds to interfere non-specifically with HIV glycoprotein function. Conversely, previous investigations demonstrating the in vitro inhibitory potential of beta chemokines themselves, or small-molecule chemokine receptor inhibitors, may now be understood in a new light. Promising laboratory investigations (particularly with the bicyclam compound, AMD3100) and extensive pharmaceutical experience with related chemical structures suggest great potential for targeting the chemokine nexus. Finally, the evolution of transmembrane peptide investigations from the laboratory to early clinical trials is described. Clinical trials of T-20, a peptide designed to inhibit gp-41 mediated fusion, have provided 'proof of concept' that therapeutics targeting a viral entry event can result in safe and potent inhibition of viral replication. The author speculates on the future prospect of using novel therapeutic strategies aimed at the initial interactions between HIV and target cells, in the battle against AIDS.
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PMID:Therapeutic potential of blocking HIV entry into cells: focus on membrane fusion inhibitors. 1599 42

We have identified two N-phenyl-N'-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamide analogs as a novel class of human immunodeficiency virus type 1 (HIV-1) entry inhibitors that block the gp120-CD4 interaction, using database screening techniques. The lead compounds, NBD-556 and NBD-557, are small molecule organic compounds with drug-like properties. These compounds showed potent cell fusion and virus-cell fusion inhibitory activity at low micromolar levels. A systematic study showed that these compounds target viral entry by inhibiting the binding of HIV-1 envelope glycoprotein gp120 to the cellular receptor CD4 but did not inhibit reverse transcriptase, integrase, or protease, indicating that they do not target the later stages of the HIV-1 life cycle to inhibit HIV-1 infection. These compounds were equally potent inhibitors of both X4 and R5 viruses tested in CXCR4 and CCR5 expressing cell lines, respectively, indicating that their anti-HIV-1 activity is not dependent on the coreceptor tropism of the virus. A surface plasmon resonance study, which measures binding affinity, clearly demonstrated that these compounds bind to unliganded HIV-1 gp120 but not to the cellular receptor CD4. NBD-556 and NBD-557 were active against HIV-1 laboratory-adapted strains including an AZT-resistant strain and HIV-1 primary isolates, indicating that these compounds can potentially be further modified to become potent HIV-1 entry inhibitors.
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PMID:Identification of N-phenyl-N'-(2,2,6,6-tetramethyl-piperidin-4-yl)-oxalamides as a new class of HIV-1 entry inhibitors that prevent gp120 binding to CD4. 1599 3

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

A central question in the pathogenesis of HIV-associated thrombotic microangiopathic (HIV-TMA) lesions is whether the HIV-1 envelope glycoprotein (HIV-1 Env) can interact directly with human glomerular endothelial cells (HGECs) through specific HIV-1 co-receptors. The goal of this study was to determine whether cultured primary HGECs express significant levels of the major HIV-1 co-receptors CD4, CXCR4, and/or CCR5 to allow fusion interactions with HIV-1. The expression of CD4, CXCR-4 and CCR-5 was assessed in cultured HGECs by reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry using specific antibodies. The HIV-1 Env-mediated membrane fusion of target glomerular cells was evaluated by a fluorescent dye transfer-based cell-cell fusion microscopic method. HGECs express CXCR4 mRNA and protein as determined by RT-PCR and immunostaining with phycoerythrin-conjugated anti-CXCR4 Mab 12G5. CD4 and CCR5 were not detected in HGECs, either by RT-PCR or by surface immunostaining with specific antibodies. Incubation of HGECs with cells expressing a CD4-independent envelope strain (HIV-1IIIB-8x) and the CD4-dependent envelope strain (HIV-1IIIB) resulted in transfer of fluorescent dyes of approximately 20% after 8-16 h incubation at 37 degrees C. Incubation in the presence of inhibitors (C34, which blocks six-helix bundle formation, and AMD3100, which interacts with CXCR4) reduced dye transfer by 60%-80%, confirming that the dye transfer was specific with respect to gp120-gp41-mediated fusion. Cultured primary HGECs express CXCR4 but not CD4 or CCR5. The ability of HGECs to promote fusion by a CD4-independent HIV-1 envelope glycoprotein suggests that these cells may become a potential direct target of certain HIV-1 isolates.
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PMID:Fusion of HIV-1 envelope-expressing cells to human glomerular endothelial cells through an CXCR4-mediated mechanism. 1604 21


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