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)

A rapid expansion of our knowledge of drugs that intervene with human immunodeficiency virus (HIV) infection has taken place. This review covers known and potential anti-HIV targets, including receptor blocking agents, membrane stabilisers, reverse transcriptase inhibitors and chain terminators, RNases, agents altering activation, assembly, budding or regulation of transcription and translation, post-transcriptional modifications and other areas. Important or promising agents, such as zidovudine (ZVD; azidothymidine, AZT), dideoxycytidine, dideoxyinosine, foscarnet, interferons, imuthiol, isoprinosine and others that are either on the market or in advanced clinical trials are emphasised. Four years after the discovery of the aetiological agent, the first drug, zidovudine, has been registered. Many questions about this drug remain, however, owing to the haste with which it was developed. An unprecedented number of other compounds are under evaluation, making it difficult to assess the relative merits of the different compounds and thus set priorities for their development. The point has been reached where a better economical and intellectual framework is necessary so that researchers and physicians are not overwhelmed by the difficulties of conducting clinical trials during the epidemic and have a reasonable chance of keeping up with laboratory developments.
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PMID:Antiviral therapy in human immunodeficiency virus infection. 268 Apr 36

1. The development of effective drugs targeted at the underlying causative agent of AIDS (eg, HIV) is paramount to reducing morbidity and mortality. 2. Antiretroviral drugs may either inhibit HIV replication at the reverse transcriptase phase of the replication cycle or they may attack the cycle before HIV enters the healthy target cell. 3. AZT has been found to reduce the mortality of patients with AIDS and AIDS-related complex, decrease the frequency and severity of opportunistic infections, and may improve neurologic functioning.
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PMID:Future hope? Antiretroviral therapy to treat HIV. 268 56

A combination of antiviral therapies that target different sites in the human immunodeficiency virus type 1 (HIV-1) replicative cycle may be necessary for optimal treatment of HIV-1 infections. We evaluated the interactions of a soluble virus receptor (recombinant soluble CD4 or rsT4) and a reverse transcriptase inhibitor (azidothymidine, AZT) against HIV-1 replication in vitro. A variety of cell types was studied including peripheral blood mononuclear cells, a CD4-positive T-cell line, and a CD4-positive human monocyte cell line. The combination of rsT4 and AZT inhibited HIV-1 synergistically over a broad range of drug concentrations and multiplicities of infection in several different HIV-1 replication assays. Drug interactions were evaluated by the median-effect principle and the isobologram technique using a computer analysis. In all of the cell types tested, combinations of rsT4 and AZT were synergistic in vitro, without additive cytotoxicity.
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PMID:Synergistic inhibition of human immunodeficiency virus type 1 (HIV-1) replication in vitro by recombinant soluble CD4 and 3'-azido-3'-deoxythymidine. 278 46

Effective antiviral drugs are urgently needed to treat individuals who are infected with the human immunodeficiency virus (HIV). Several compounds, such as nucleoside analogs (AZT, ddCyd), phosphonoformate, and HPA-23 inhibit reverse transcriptase. The mode of action of ribavirin and interferon alpha A is less clear. A number of compounds have been tested in early clinical trials, and AZT so far looks the most promising. New drugs should undergo rapid but thorough in vitro and animal testing. Promising compounds should be made available as soon as possible for phase I trials.
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PMID:Treatment of human immunodeficiency virus infections. 333 93

Current thrust in controlling the Acquired Immune Deficiency Syndrome (AIDS) focuses on antiviral drug development targeting the infection and replication of the human immunodeficiency virus (HIV), the causative agent of AIDS. To date, treatment of AIDS has relied on nucleoside reverse transcriptase inhibitors such as AZT, ddI, and ddC, which eventually become ineffective upon the emergence of resistant mutants bearing specific nucleotide substitutions. The Anti-AIDS Drug Screening Program of the NCI conducts and coordinates a high-capacity semi-robotic in vitro screening of synthetic or natural compounds submitted by academic, research and pharmaceutical institutions world-wide. About 10,000 synthetic compounds are screened annually for anti-HIV activity. Confirmed active agents are subjected to in-depth studies on range and mechanism of action. Emerging from this intense screening activity were a number of potentially promising categories of nonnucleoside reverse transcriptase inhibitors (NNRTI) with structural diversity but strong and reproducible anti-HIV activity. Over 2500 active compounds were evaluated for their inhibitory activity against a panel of both laboratory and clinical virus isolates in the appropriate established cell line or fresh human peripheral blood leukocyte and macrophage preparations. Out of these, 40 agents could be placed structurally in nine categories with an additional 16 unique compounds that share the characteristics of NNRTI. These NNRTIs were shown to inhibit reverse transcriptase enzymatically using homopolymeric or ribosomal RNA as templates. NNRTIs demonstrated similarity in their inhibitory pattern against the HIV-1 laboratory strains IIIB and RF, and an AZT-resistant strain; all were inactive against HIV-2. These compounds were further tested against NNRTI-resistant HIV-1 isolates. NNRTI-resistant HIV-1 isolates were selected and characterized with respect to the change(s) in the viral reverse transcriptase nucleotide sequence. Also, differential cross-resistance or sensitivity patterns to NNRTIs were studied in detail among NNRTI-resistant mutants. When tested in combination with AZT, all of the NNRTI's uniformly exhibited synergistic inhibition of HIV-1, suggesting that combination antiviral therapy of NNRTIs with AZT may be therapeutically promising for AIDS treatment.
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PMID:Characteristics of a group of nonnucleoside reverse transcriptase inhibitors with structural diversity and potent anti-human immunodeficiency virus activity. 747 21

The antiviral drugs didanosine (ddI) and zidovudine (AZT), synthetic nucleoside analogs, have been used in the treatment of acquired immunodeficiency syndrome (AIDS). Although clinical use of zidovudine (AZT) is still widely used, it is associated with the development of virus disease resistance and toxicity to the hematopoietic system. Alternative nucleoside reverse transcriptase derivatives such as didanosine (ddI) have been developed in order to reduce the incidence of virus disease resistance and hematological toxicity. We report here studies designed to ev evaluate the toxicity profile comparing didanosine (ddI) with zidovudine (AZT) when used alone or in combination with normal non-adherent, T-cell depleted human marrow cells plated in the presence or absence of the human cytokine fusion protein of granulocyte-macrophage colony stimulating factor and interleukin-3 (PIXY321). As expected, didanosine (ddI) was less toxic for human hematopoietic progenitor cells, i.e., CFU-GEMM, CFU-GM, CFU-Meg, and BFU-E than zidovudine. Toxicity was additive when didanosine (ddI) and zidovudine (AZT) were combined. In the absence of drugs PIXY321 colony formation was increased for all progenitor cells cultured. In the presence of didanosine (ddI) or zidovudine (AZT), either as single-agents or combined, PIXY321 reduced toxicity significantly. These results demonstrate PIXY321 is an effective cytokine capable of reversing the toxicity associated with anti-viral drugs when used in vitro where didanosine (ddI) is less toxic than zidovudine (AZT); however their suppression of hematopoietic progenitors is additive when combined.
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PMID:Influence of human granulocyte-macrophage colony stimulating factor/interleukin-3 fusion protein (PIXY321) on the hematopoietic toxicity associated with anti-viral drugs (zidovudine and didanosine) in vitro using normal human marrow cells. 747 1

A series of substituted imidazo[1,5-b]pyridazines have been prepared and tested for inhibitory activity against the reverse transcriptase of HIV-1 (RT) and their ability to inhibit the growth of infected MT-4 cells. Crystal data are reported on two compounds, 15c and 33. From the structure-activity relationships developed within this and other series, it is proposed that key features of the interaction with RT include hydrogen-bond acceptor and aromatic pi-orbital bonding with the imidazopyridazine nucleus and a benzoyl function separated from the heterocycle by a suitable spacer group. Exceptional activity against the reverse transcriptase of HIV-1 (IC50 = 0.65 nM) was obtained with a 2-imidazolyl-substituted derivative, 7-[2-(1H-imidazol-1- yl)-5-methylimidazo-[1,5-b]pyridazin-7-yl]-1-phenyl-1-heptanone (33) which is attributed to additional binding of the imidazole sp2 nitrogen atom. A number of the compounds in this series also inhibit the replication of HIV-1 in vitro in MT-4 and C8166 cells at levels observed with the nucleoside AZT.
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PMID:Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines. 750 33

Several mutations are associated with resistance to zidovudine (3'-azido-3'-deoxythymidine, AZT) in cultured human immunodeficiency virus type 1 (HIV-1) isolates. Little is known as to what extent drug resistance occurs in vivo and whether its development within the CNS differs from that in peripheral blood. We therefore performed comparative nucleotide sequence analysis of the HIV-1 reverse transcriptase (RT) gene in proviral DNA obtained from blood and CSF of three patients, all of whom had progressed to AIDS under long-term zidovudine treatment. Six to 11 individual proviral copies per patient and compartment were analyzed by polymerase chain reaction (PCR)-mediated direct sequencing. In all samples, mutations associated with zidovudine resistance could be identified. They occurred in multiple HIV-1 copies in both blood and CSF, indicating that molecular determinants of resistance are reflected in most individual proviruses in vivo. Comparable positions and frequencies of mutations in isolates derived from both compartments do not argue for independent development of zidovudine resistance in CSF.
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PMID:In vivo comparison of zidovudine resistance mutations in blood and CSF of HIV-1-infected patients. 750 98

We have selected and plaque purified zidovudine (3'-azido-3'-deoxythymidine [AZT])-resistant mutants from an infectious molecular clone of feline immunodeficiency virus (FIV). The patterns of cross-resistance and drug susceptibilities of these mutants were similar to those of the AZT-resistant FIV that we previously selected in vitro from a wild-type FIV population and to those of the most common AZT-resistant clinical isolates of human immunodeficiency virus type 1. Two AZT-resistant mutants of FIV, one selected from a normal population and one selected from the molecular clone, each reverted rapidly to an AZT-sensitive phenotype when passaged in the absence of drug. Sequence analysis of the reverse transcriptase (RT)-encoding region from the plaque-purified AZT-resistant FIV revealed a single base change at position 2939, resulting in a Glu-to-Lys substitution at amino acid 202 of the RT. Similar analyses of plaque-purified revertants showed that the phenotypic reversion was not the result of a genotypic reversion at this position and that no additional mutations existed within the RT-encoding region of the revertants. Moreover, RTs purified from the mutant and revertant were both resistant to the 5'-triphosphate of AZT. These results indicate the complexity of AZT resistance and suggest the presence of additional factors, outside the RT-encoding region, which may contribute to AZT resistance.
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PMID:Rapid phenotypic reversion of zidovudine-resistant feline immunodeficiency virus without loss of drug-resistant reverse transcriptase. 750 82

R82913 and R86183, two derivatives of tetrahydroimidazo[4,5,1-jk][1,4]-benzodiazepin-2(1H)-thione (TIBO), were found to potently and selectively inhibit the replication and cell killing effects of a panel of biologically diverse laboratory and clinical strains of HIV-1. The two compounds exhibited significant activity in all human cell lines tested, as well as in fresh human peripheral blood lymphocytes and macrophages. One of these two compounds (R82913) was found to significantly inhibit the replication of a murine retrovirus (Rauscher murine leukemia virus) in both UV-XC plaque formation and virus yield reduction assays. R86183, despite differing from R82913 only in the positioning of a single chlorine molecule, was not active against the murine retrovirus but was 10-fold more potent in inhibiting HIV-1 replication. Combination antiviral assays with other reverse transcriptase inhibitors, including AZT, ddC, and carbovir, yielded synergistic anti-HIV activity with both TIBO derivatives. Additive to slightly synergistic results were obtained in combinations with ddI and phosphonoformic acid whereas additive to antagonistic activity was detected in combination with dextran sulfate.
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PMID:Differential antiviral activity of two TIBO derivatives against the human immunodeficiency and murine leukemia viruses alone and in combination with other anti-HIV agents. 750 23


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