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:5.99.1.3 (topoisomerase)
9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Integration of the human immunodeficiency virus type 1 (HIV-1) cDNA is a required step for viral replication. Integrase, the virus-encoded enzyme important for integration, has not yet been exploited as a target for clinically useful inhibitors. Here we report on the identification of new polyhydroxylated aromatic inhibitors of integrase including ellagic acid, purpurogallin, 4,8, 12-trioxatricornan, and hypericin, the last of which is known to inhibit viral replication. These compounds and others were characterized in assays with subviral preintegration complexes (PICs) isolated from HIV-1-infected cells. Hypericin was found to inhibit PIC assays, while the other compounds tested were inactive. Counterscreening of these and other integrase inhibitors against additional DNA-modifying enzymes revealed that none of the polyhydroxylated aromatic compounds are active against enzymes that do not require metals (methylases, a pox virus topoisomerase). However, all were cross-reactive with metal-requiring enzymes (restriction enzymes, a reverse transcriptase), implicating metal atoms in the inhibitory mechanism. In mechanistic studies, we localized binding of some inhibitors to the catalytic domain of integrase by assaying competition of binding by labeled nucleotides. These findings help elucidate the mechanism of action of the polyhydroxylated aromatic inhibitors and provide practical guidance for further inhibitor development.
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PMID:Human immunodeficiency virus type 1 cDNA integration: new aromatic hydroxylated inhibitors and studies of the inhibition mechanism. 973 43

A series of new hydroxybenzoic and hydroxycinnamic acid flavon-3-yl esters were synthesized in order to obtain compounds targeting the human immunodeficiency virus (HIV) type 1 integrase (IN). The esters were tested for anti-IN and anti-reverse transcriptase (RT) activity in enzyme assays and for anti-HIV-1, anti-proliferative and anti-topoisomerase activity in cell-based assays. In enzyme assays, the two gallic acid flavon-3-yl esters showed a notable IN inhibition (IC50 values were 8.3 and 9.1 microM, respectively), while the two caffeic acid flavon-3-yl esters exhibited a modest activity (IC50 75 and 60 microM, respectively). Replacement of hydroxyl groups resulted in loss of potency. Caffeic acid 3',4'-dichloroflavon-3-yl ester also inhibited the RT activity whereas it was not active on human topoisomerases. It therefore represents an interesting example of a compound specifically targeting more than one step of the virus replication cycle.
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PMID:Synthesis and anti-human immunodeficiency virus type 1 integrase activity of hydroxybenzoic and hydroxycinnamic acid flavon-3-yl esters. 986 88

Vaginal trichomoniasis is a highly prevalent sexually transmitted disease caused by a microaerophilic protozoan Trichomonas vaginalis. The disease is one of the most common sexually transmitted disease and can augment the predisposition of individuals to human immunodeficiency virus (HIV) infection. Although the disease can be treated with metronidazole and related 5-nitroimidazole, cases of trichomonal vaginitis which are refractory to standard treatment seems to be increasing. Clearly, new antitrichomonad agents are needed and DNA topoisomerase II may acts as a new target for antitrichomonad agents. In this study, in vitro sensitivity of T. vaginalis to DNA topoisomerase II was investigated. Axenic culture of local strain of T. vaginalis was performed. Both eukaryotic and prokaryotic DNA topoisomerase II inhibitors such as ellipticine, amsacrine and fluoroquinolones were tested for effectiveness against T. vaginalis in vitro compared to metronidazole. T. vaginalis was sensitive to metronidazole under aerobic conditions. Minimal inhibitory concentrations (MICs) of eukaryotic DNA topoisomerase II inhibitors, ellipticine and amsacrine, were 6.4 mM and 64 mM, respectively. The MICs of prokaryotic DNA topoisomerase II or DNA gyrase inhibitors; ciprofloxacin, ofloxacin and norfloxacin were 64, 960 and 1,280 mM, respectively. Based on the results, among DNA topoisomerase II inhibitors ellipticine was the most effective drug against T. vaginalis in vitro whereas fluoroquinolones did not show high antitrichomonad activity.
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PMID:In vitro sensitivity of Trichomonas vaginalis to DNA topoisomerase II inhibitors. 1102 77

Before embarking on experimental therapies for progressive multifocal leukoencephalopathy (PML), the diagnosis needs to be unequivocally established. Improving the underlying immunodeficiency state is the best initial approach to the management of PML. Immunosuppressive therapies should be discontinued when feasible. In the patient with AIDS, highly active antiretroviral therapy should be administered; this appears to prolong survival. At present, no therapy has been demonstrated to be effective in a well-designed prospective trial. Cytosine arabinoside, which has demonstrated efficacy in vitro against JC virus, has not been effective when administered intravenously or intrathecally to patients with AIDS and PML. The failure of regimens employing cytosine arabinoside in PML may have been the consequence of inadequate penetration of the drug to sites of infection in the brain. Other drugs with established in vitro activity against JC virus, such as topoisomerase and camptothecin, are poorly tolerated. The use of cidofovir in patients with AIDS and PML remains anecdotal, although it is currently under investigation. Interferon alfa may improve survival in patients with AIDS and PML and may have general applicability to PML regardless of the cause of the underlying immunodeficient state. Approximately 7% to 9% of patients with PML demonstrate prolonged survival (>12 months) and associated improvement in clinical and radiographic abnormalities in the absence of specific therapy. In patients with AIDS-related PML, prolonged survival correlates with PML as the presenting manifestation of AIDS, higher CD4 T-lymphocyte counts, and contrast enhancement of PML lesions on radiographic imaging. A brisk inflammatory response may also be associated with improved survival. The increased understanding of the pathophysiology of JC virus provides hope for the development of curative strategies. The growing number of persons affected with PML has allowed the organization of carefully designed therapeutic trials to address this issue.
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PMID:Progressive Multifocal Leukoencephalopathy. 1109 61

(R)-(-)-Elenic acid (R-2,4-dimethyl-22-(p-hydroxyphenyl)-docos-3(E)-enoic acid) (EA) is a DNA topoisomerase II inhibitor found in an Indonesian sponge, Plakinastrella sp. We found and report here that it is a potent inhibitor of calf DNA polymerase alpha (IC(50)=7.7 microM) and rat DNA polymerase beta (IC(50)=12.9 microM). EA did not bind to DNA directly. EA did not influence the activities of DNA polymerases such as plant DNA polymerases I and II and prokaryotic DNA polymerases such as Escherichia coli DNA polymerase I, or other DNA metabolic enzymes such as human immunodeficiency virus (HIV) reverse transcriptase, T7 RNA polymerase and bovine deoxyribonuclease I. Interestingly, EA was also an inhibitor of DNA topoisomerases I and II, although the enzymatic characteristics including modes of action, amino acid sequences and three-dimensional structures were markedly different from those of DNA polymerases. EA could prevent the growth of NUGC-3 cancer cells, and the LD(50) value was 22.5 microM. The cells were halted at G1 and G2/M phase in the cell cycle. From these results, the action mode of EA is discussed.
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PMID:Selective inhibition of the activities of both eukaryotic DNA polymerases and DNA topoisomerases by elenic acid. 1185 91

Brain perivascular macrophages are a major target of simian immunodeficiency virus (SIV) infection in rhesus macaques and HIV infection in humans. Perivascular macrophages are distinct from parenchymal microglia in their location, morphology, expression of myeloid markers, and turnover in the CNS. In contrast to parenchymal microglia, perivascular macrophages are continuously repopulated by blood monocytes, which undergo maturation to macrophages on entering the central nervous system (CNS). We studied differences in monocyte/macrophages in vivo that might account for preferential infection of perivascular macrophages by SIV. In situ hybridization for SIV and proliferating cellular nuclear antigen (PCNA) immunohistochemistry demonstrated that SIV-infected and PCNA-positive cells were predominantly found in perivascular cuffs of viremic animals and in histopathological lesions that characterize SIV encephalitis (SIVE) in animals with AIDS. Multilabel techniques including double-label immunohistochemistry and combined in situ hybridization and immunofluorescence confocal microscopy revealed numerous infected perivascular macrophages that were PCNA-positive. Outside the CNS, SIV-infected, PCNA-expressing macrophage subpopulations were found in the small intestine and lung of animals with AIDS. While PCNA is used as a marker of cell proliferation it is also strongly expressed in non-dividing cells undergoing DNA synthesis and repair. Therefore, more specific markers for cell proliferation including Ki-67, topoisomerase IIalpha, and bromodeoxyuridine (BrdU) incorporation were used which indicated that PCNA-positive cells within SIVE lesions were not proliferating. These observations are consistent with perivascular macrophages as terminally differentiated, non-dividing cells and underscores biological differences that could potentially define mechanisms of preferential, productive infection of perivascular macrophages in the rhesus macaque model of neuroAIDS. These studies suggest that within CNS and non-CNS tissues there exist subpopulations of macrophages that are SIV-infected and express PCNA.
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PMID:Proliferating cellular nuclear antigen expression as a marker of perivascular macrophages in simian immunodeficiency virus encephalitis. 1216 82

Bloom syndrome (BS) is a genetic disorder associated with dwarfism, immunodeficiency, reduced fertility, and an elevated risk of cancer. To investigate the mechanism of this disease, we isolated from human HeLa extracts three complexes containing the helicase defective in BS, BLM. Interestingly, one of the complexes, termed BRAFT, also contains five of the Fanconi anemia (FA) complementation group proteins (FA proteins). FA resembles BS in genomic instability and cancer predisposition, but most of its gene products have no known biochemical activity, and the molecular pathogenesis of the disease is poorly understood. BRAFT displays a DNA-unwinding activity, which requires the presence of BLM because complexes isolated from BLM-deficient cells lack such an activity. The complex also contains topoisomerase IIIalpha and replication protein A, proteins that are known to interact with BLM and could facilitate unwinding of DNA. We show that BLM complexes isolated from an FA cell line have a lower molecular mass. Our study provides the first biochemical characterization of a multiprotein FA complex and suggests a connection between the BLM and FA pathways of genomic maintenance. The findings that FA proteins are part of a DNA-unwinding complex imply that FA proteins may participate in DNA repair.
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PMID:A multiprotein nuclear complex connects Fanconi anemia and Bloom syndrome. 1272 1

The chromatin environment and the sites of integration in the host genome are critical determinants of human immunodeficiency virus (HIV) transcription and replication. Depending on the chromosomal location of provirus integration within the genome, HIV-1 long terminal repeat (LTR)-mediated transcription may vary from 0- to 70-fold. Cis-elements such as topoisomerase II cleavage sites, Alu repeats and matrix attachment regions (MARs) are thought to be targets for retroviral integration. Here we show that a novel MAR sequence from the T-cell receptor beta locus (MARbeta) and the IgH MAR mediate transcriptional augmentation when placed upstream of the HIV-1 LTR promoter. The effect of transcriptional augmentation is seen in both transient and stable transfection, indicating its effect even upon integration in the genome. MAR-mediated transcriptional elevation is independent of Tat, and occurs synergistically in the presence of Tat. Further, we show that MAR-mediated transcriptional elevation is specific to the HIV-1 LTR and the Moloney murine leukemia virus LTR promoter. In a transient transfection assay using over-expressed IkappaB, the inhibitor of NF-kappaB, we show that MAR-induced processive transcription is NF-kappaB dependent, signifying the role of local enhancers within the LTR promoter. Furthermore, by RNase protection experiments using proximal and distal probes, we show that MAR-mediated transcriptional upregulation is more prominent at the distal rather than the proximal end, thus indicating the potential role of MARs in promoting elongation.
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PMID:Stimulation of Tat-independent transcriptional processivity from the HIV-1 LTR promoter by matrix attachment regions. 1279 52

Some anticancer drugs, but not all, inhibit replication of human immunodeficiency virus (HIV) and thus, exhibit a therapeutic potential. Such drugs, unlike the traditional HIV enzyme inhibitors, could suppress HIV strains that are resistant to inhibitors of viral enzymes, decrease proviral burden in vivo, or reduce reservoirs of infection via killing infected cells. Thus, they may be an effective adjunct therapy or perhaps result in a cure. The incidence of HIV infection and AIDS mortalities continue to increase worldwide, including the United States and parts of Africa, with a parallel increase in a number of other manifestations, including AIDS defining malignancies. The basis for continual spread of HIV presumably in large part stems from the viral resistance to previously successful drugs and the lack of curative antiretroviral drugs. To reverse these trends, other approaches for AIDS therapy must be developed. One possibility is the development of potent anticancer drugs, that exhibit anti-HIV activities. At least four chemically and pharmacologically distinct classes of anticancer drugs, i.e. certain cyclin-dependent kinase inhibitors (CDKIs), topoisomerase 1 enzyme (top 1) inhibitors, non-nucleoside antimetabolites, and estrogen receptor ligands are promising candidates. These drugs, at high doses are used for cancer therapy; at lower concentrations they exhibit anti-HIV activities in cultured cells. While the antiretroviral and the anticancer activities of the cdk inhibitor flavopiridol appear to be mutually exclusive and unrelated in cells and animal model(s) of HIV disease, the top 1 inhibitor 9-nitrocamptothecin, as well as the cdk-inhibitor roscovitine inhibit replication of HIV via selective sensitization of HIV-infected cells to apoptosis. In contrast, the inhibitory effects of these compounds are different from other cancer therapeutics that, at toxic concentrations, activate HIV either in cultured cells (such as certain ingenol and butyrate derivatives) and/or in patients (such as the widely used cyclophosmamide and cisplatin). This quality may lead to the eradication of proviral reservoirs, which is not accomplished by the currently available antiretroviral drugs. In this review, relevant available clinical and in vitro data that either support or discourage using certain anticancer drugs for treatment of HIV disease, and the rationales for developing novel antiretroviral drugs that may target infected cells rather than viral proteins are discussed.
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PMID:A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics. 1467 May 89

Traditional Chinese medicinal plants are a treasure house for screening novel inhibitors of DNA polymerases and DNA topoisomerases from mammals; in the present study, nine lanostane-type triterpene acids were found in sclerotium of Poria cocos. Among the nine compounds, only dehydroebriconic acid could potently inhibit DNA topoisomerase II (topo II) activity (IC(50) = 4.6 microM), while the compound moderately inhibited the activities of DNA polymerases alpha, beta, gamma, delta, epsilon, eta, iota, kappa and lambda only from mammals, to similar extents. Another compound, dehydrotrametenonic acid, also showed moderate inhibitory effects against topo II (IC(50) = 37.5 microM) and weak effects against all the polymerases tested. Both compounds showed no inhibitory effect against topo I, higher plant (cauliflower) DNA polymerase I (alpha-like polymerase) or II (beta-like polymerase), calf thymus terminal deoxynucleotidyl transferase, human immunodeficiency virus type-1 reverse transcriptase, prokaryotic DNA polymerases such as the Klenow fragment of E. coli DNA polymerase I, Taq DNA polymerase and T4 DNA polymerase, or DNA metabolic enzymes such as T 7 RNA polymerase, T4 polynucleotide kinase and bovine deoxyribonuclease I. These findings suggest that dehydroebriconic acid and dehydrotrametenonic acid should be designated as topo II-preferential inhibitors, although they also moderately inhibited all the mammalian DNA polymerases tested. Both dehydrotrametenonic acid and dehydroebriconic acid could prevent the growth of human gastric cancer cells, and their LD(50) values were 63.6 and 38.4 microM, respectively. The cells were halted at the G1 phase in the cell cycle. The relation between the structure of triterpene acids and their inhibitory activities is discussed.
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PMID:A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane-type triterpene acids from Poria cocos. 1507 95


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