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)

Acquired immunodeficiency syndrome (AIDS) results from infection by the retrovirus, human immunodeficiency virus (HIV). HIV is the most significant risk factor for many opportunistic infections like tuberculosis, hepatitis, bacterial infections, etc. In this paper, we designed aminopyrimidinimino isatin lead compound as a novel non-nucleoside reverse transcriptase inhibitor with broad-spectrum chemotherapeutic properties for the effective treatment of AIDS and AIDS-related opportunistic infections. Compound 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7[[N(4)-[3'-(4'-amino-5'-trimethoxybenzylpyrimidin-2'-yl)imino-1'-(5-fluoroisatinyl)]methyl]-N(1)-piperazinyl]-3-quinoline carboxylic acid (12) emerged as the most potent broad-spectrum chemotherapeutic agent active against HIV, HCV, Mycobacterium tuberculosis and various pathogenic bacteria.
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PMID:Design, synthesis and biological evaluation of novel non-nucleoside HIV-1 reverse transcriptase inhibitors with broad-spectrum chemotherapeutic properties. 1549 62

The genome of Mycobacterium leprae, the etiologic agent of leprosy, has been sequenced and annotated revealing a genome in apparent disarray and in stark contrast to the genome of the related human pathogen, M. tuberculosis. With less than 50% coding capacity of a 3.3-Mb genome and 1,116 pseudogenes, the remaining genes help define the minimal gene set necessary for in vivo survival of this mycobacterial pathogen as well as genes potentially required for infection and pathogenesis seen in leprosy. To identify genes transcribed during infection, we surveyed gene transcripts from M. leprae growing in athymic nude mice using reverse transcriptase-polymerase chain reaction (RT-PCR) and cross-species DNA microarray technologies. Transcripts were detected for 221 open reading frames, which included genes involved in DNA replication, cell division, SecA-dependent protein secretion, energy production, intermediary metabolism, iron transport and storage and genes associated with virulence. These results suggest that M. leprae actively catabolizes fatty acids for energy, produces a large number of secretory proteins, utilizes the full array of sigma factors available, produces several proteins involved in iron transport, storage and regulation in the absence of recognizable genes encoding iron scavengers and transcribes several genes associated with virulence in M. tuberculosis. When transcript levels of 9 of these genes were compared from M. leprae derived from lesions of multibacillary leprosy patients and infected nude mouse foot pad tissue using quantitative real-time RT-PCR, gene transcript levels were comparable for all but one of these genes, supporting the continued use of the foot pad infection model for M. leprae gene expression profiling. Identifying genes associated with growth and survival during infection should lead to a more comprehensive understanding of the ability of M. leprae to cause disease.
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PMID:Biological implications of Mycobacterium leprae gene expression during infection. 1574 41

The Mycobacterium marinum-zebrafish infection model was used in this study for analysis of a host transcriptome response to mycobacterium infection at the organismal level. RNA isolated from adult zebrafish that showed typical signs of fish tuberculosis due to a chronic progressive infection with M. marinum was compared with RNA from healthy fish in microarray analyses. Spotted oligonucleotide sets (designed by Sigma-Compugen and MWG) and Affymetrix GeneChips were used, in total comprising 45,465 zebrafish transcript annotations. Based on a detailed comparative analysis and quantitative reverse transcriptase-PCR analysis, we present a validated reference set of 159 genes whose regulation is strongly affected by mycobacterial infection in the three types of microarrays analyzed. Furthermore, we analyzed the separate datasets of the microarrays with special emphasis on the expression profiles of immune-related genes. Upregulated genes include many known components of the inflammatory response and several genes that have previously been implicated in the response to mycobacterial infections in cell cultures of other organisms. Different marker genes of the myeloid lineage that have been characterized in zebrafish also showed increased expression. Furthermore, the zebrafish homologs of many signal transduction genes with relationship to the immune response were induced by M. marinum infection. Future functional analysis of these genes may contribute to understanding the mechanisms of mycobacterial pathogenesis. Since a large group of genes linked to immune responses did not show altered expression in the infected animals, these results suggest specific responses in mycobacterium-induced disease.
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PMID:Transcriptome profiling of adult zebrafish at the late stage of chronic tuberculosis due to Mycobacterium marinum infection. 1582 8

Human immuno deficiency virus (HIV) weakens the immune system so that many opportunistic infections (OIs) like tuberculosis, hepatitis, bacterial infections etc can develop. In this paper, we designed aminopyrimidinimino isatin lead compound as a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) with broad-spectrum chemotherapeutic properties for the effective treatment of AIDS and AIDS-related OIs. Compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-[[N4-[3'-(4'-amino-5'-trimethoxybenzyl pyrimidin-2'-yl)imino-1'-(5-methylisatinyl)]methyl]-N1-piperazinyl]-3-quinoline carboxylic acid (10) emerged as the most potent broad-spectrum chemotherapeutic agent active against HIV, HCV, Mycobacterium tuberculosis and various pathogenic bacteria.
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PMID:Newer aminopyrimidinimino isatin analogues as non-nucleoside HIV-1 reverse transcriptase inhibitors for HIV and other opportunistic infections of AIDS: design, synthesis and biological evaluation. 1587 36

The authors investigated the effects of inhalation of diesel exhaust (DE) on murine mycobacterial infection in vivo. Eight-week-old female BALB/c mice were exposed to DE (3 mg/m3 of diesel exhaust particles [DEPs]) for 1 month, 2 months, or 6 months (for 7 hours a day, 5 days a week). Control mice were housed in a clean room for the same periods. On the day following the last DE exposure, control mice and DE-exposed mice were aerially infected with Mycobacterium tuberculosis (1 x 10(6) colony-forming units (CFU), Kurono strain). At 7 weeks after mycobacterial infection, the authors examined the lung tissues for histopathological changes and performed reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the messenger RNA (mRNA) expression of several proinflammatory cytokines and inducible nitric oxide synthase (iNOS). Then, the homogenates of lungs and spleens were cultured on 1% (v/v) Ogawa's egg slant medium, and after a 4-week incubation period at 37 degrees C, colonies on the medium were counted. After 1 month of DE exposure, the mycobacterial infection had slightly ameliorated. After 2 months of DE exposure, the expression levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-12p40, interferon (IFN)-gamma, and iNOS mRNAs were slightly increased. However, after 6 months of DE exposure, the expression levels of IL-1beta , IL-12p40, IFN-gamma, and iNOS mRNAs were decreased, and the infection as measured by increased lung burden (CFU) actually increased. These results indicate that long-term DE exposure may increase pulmonary mycobacterial burden.
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PMID:The effects of inhalation of diesel exhaust on murine mycobacterial infection. 1602 21

An unprecedented international effort to expand high activity antiretroviral therapy (HAART) to resource-poor nations has been launched. The World Health Organization (WHO) has created antiretroviral (ARV) treatment guidelines adapted to resource-poor settings. The first-line regimen is two nucleoside reverse transcriptase inhibitors (NsRTIs) and one nonnucleoside reverse transcriptase inhibitor (NNRTI). Therapy is initiated by clinical staging and CD4 T-cell counts when available. Adherence is the responsibility of health care workers. The use of ARV therapy in resource-poor settings faces several challenges, including the poverty of patients, political and social upheavals and violence, social stigma associated with HIV/AIDS, unreliable pharmacy systems, tuberculosis, and lack of trained health care workers. Using our experience in Haiti, we describe how we have addressed these challenges with the goal of increasing access to care for the poor with HIV/AIDS.
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PMID:HIV antiretroviral therapy in resource-limited settings: experiences from Haiti. 1609 Dec 55

In the revised guideline 'Antiretroviral treatment' produced by the Dutch Society of Aids-Treating Physicians and the Dutch Institute for Healthcare Improvement (CBO), the following major changes have been made to the 2000 guideline. Treatment of adult HIV-infected patients should start when the number of CD4 cells remains consistent at >200 cells x 10(6)/l. Antiretroviral therapy is recommended when CD4-cell levels are 200-350 cells x 10(6)/l and HIV-RNA load is higher than 100,000 copies/ml. In therapy-naive adults combinations of 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) and combinations of 2 NRTIs plus 1 protease inhibitor are equally effective; NNRTIs are preferable to protease inhibitors due to their relatively easy dosage regimen. In order to optimize individual dosage regimens, plasma drug levels should be measured at 4 and 24 weeks after the start of treatment in therapy-naive patients. Patients with pre-existing disturbances of lipid metabolism or familial hypercholesterolaemia should not receive protease inhibitors as therapy of first choice. Genotyping is indicated in virological failure and before the start of initial therapy in patients infected in Europe and the United States of America. In order to prevent HIV transmission from mother to child, all pregnant HIV-infected women (also if their HIV-RNA load is undetectable) should receive HIV treatment starting in the 24th week of gestation. Children of HIV-seropositive mothers should be treated with antiretrovirals for 4 weeks after birth. In co-infected patients, the choice of anti-hepatitis B drugs should be determined by whether or not there is also an indication for HIV treatment. Treatment for tuberculosis should preferably be initiated 1-2 months prior to the start of HIV treatment in co-infected patients. Following an occupational needlestick accident or unprotected-sex event, post-exposure prophylaxis should be offered due to the increased risk of HIV transmission.
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PMID:[Revised guideline "Antiretroviral Treatment"]. 1627 29

According to the World Health Organization guidelines, a non-nucleoside reverse transcriptase inhibitor (NNRTI) along with two nucleoside reverse transcriptase inhibitors (NRTI) is the treatment of choice as first-line antiretroviral therapy. The results of the 2NN and different cohort studies performed in developed countries do not provide sufficient evidence by which to select between nevirapine and efavirenz as the first-line NNRTI for antiretroviral therapy in Africa. The current first-line NNRTI-containing antiretroviral therapy regimens used in Africa are certainly not ideal. Nevirapine interacts with rifampicin and therefore is not indicated in patients with tuberculosis. On the other hand, efavirenz should not be given to pregnant women. NNRTI-containing regimens may be less effective in women who received nevirapine monotherapy at delivery. Stavudine, used in the nucleoside backbone, may lead to lipoatrophy, lactic acidosis and polyneuritis. Zidovudine may cause serious anemia. Mainly because of cost considerations, the generic fixed-drug combination of nevirapine plus two NRTI seems at the moment to be the best choice. It is clear, however, that antiretroviral programs should not rely only on this combination for initial antiretroviral treatment. Most importantly, more HIV clinical trials need to be conducted in Africa, and African cohorts of patients on antiretroviral therapy need to be established in order to develop recommendations that are evidence based.
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PMID:First-line antiretroviral therapy in Africa--how evidence-base are our recommendations? 1630 62

In the murine model of infection, a Mycobacterium tuberculosis mce1 operon mutant elicits an aberrant granulomatous response, resulting in uncontrolled replication and failure to enter a persistent state. In this study, we demonstrate that the mce1 genes can be transcribed as a 13-gene polycistronic message encompassing Rv0166 to Rv0178. Quantitative reverse transcriptase PCR and immunoblot analyses revealed that the mce1 genes and proteins are expressed during in vitro growth but are significantly down-regulated in intracellular bacilli isolated from murine macrophages. A homologue of the FadR subfamily of GntR transcriptional regulators, Rv0165c (designated Mce1R), lies upstream and is divergently transcribed from the operon. To investigate whether this gene plays a role in regulation of mce1 expression, we created an M. tuberculosis mce1R deletion mutant. There was no difference in expression of mce1 operon genes in Deltamce1R compared to expression in the wild type during logarithmic growth in vitro. However, in bacilli isolated from murine macrophages, expression of mce1 genes was significantly higher in Deltamce1R. In addition, overexpression of mce1R resulted in repression of the mce1 genes. These data demonstrate that Mce1R is a negative regulator that acts intracellularly to repress expression of the mce1 operon. We propose that Mce1R facilitates balanced temporal expression of the mce1 products required for organized granuloma formation, which is both protective to the host and necessary for the persistence of M. tuberculosis.
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PMID:Regulation of the Mycobacterium tuberculosis mce1 operon. 1638 33

On 2 earlier occasions, in 2002 and 2003, the Swedish Medical Products Agency (MPA) and the Swedish Reference Group for Antiviral Therapy (RAV) have jointly publicized recommendations for the treatment of HIV infection. A working group from the same expert team that produced the 2002 report has now revised the text again. Since the publication of the last treatment recommendations, 4 new medicines have become available: emtricitabine, atazanavir, fosamprenavir, and enfuvirtid. The last-mentioned belongs to a new class of HIV medications called fusion inhibitors (Box 1). It is likely that tipranavir will also be on the market soon. Simultaneously, the drug zalcitabin has been deregistered. The following updated recommendations parallel the earlier ones, but increased knowledge allows us to be more specific in our recommendations. Thus, it is now suggested that the initial treatment for HIV infection consist of 2 nucleoside reverse transcriptase inhibitors (NRTIs) and 1 non-nucleoside reverse transcriptase inhibitor (NNRTI); or 2 NRTIs and 1 protease inhibitor (PI). In the group of the NRTIs, stavudine is no longer recommended for this purpose. In the NNRTI group, efavirenz should be preferred to nevirapine, except under special circumstances. Finally, PIs ought to be boosted with ritonavir (PI/r). Also new are recommendations regarding treatment choices for patients co-infected with hepatitis B virus (HBV) or tuberculosis (TB). As in the case of the previous publication, recommendations are evidence-graded in accordance with the Oxford Centre for Evidence Based Medicine, 2001 (see http://www.cebm.net/levels_of_evidence.asp#levels), and have been supplemented with references to newly-added sections and data not referred to in earlier background documentation.
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PMID:Antiretroviral treatment of HIV infection: Swedish recommendations 2005. 1656 61


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