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)

Toll-like receptors (TLR) play an important role in pathogen recognition and innate immunity. We investigated the presence and function of TLRs in the BEAS-2B airway epithelial cell line and primary bronchial epithelial cells. Standard real-time reverse transcriptase-polymerase chain reaction (RT-PCR) analysis and Taqman RT-PCR revealed that BEAS-2B cells express mRNA for TLR1-10. Several TLR ligands were tested for their ability to activate gene expression in BEAS-2B cells using limited microarray analyses focusing on genes of the chemokine and chemokine receptor family, cytokines, and signaling pathways. While the TLR3 ligand double-stranded RNA was the most effective epithelial activator, clear responses to flagellin, lipopolysaccharide, CpG, peptidoglycan, and zymosan were also observed. RT-PCR and/or enzyme-linked immunosorbent assay were used to confirm results obtained with microarrays for five of the induced genes: interleukin-8, serum amyloid A, TLR3, macrophage inflammatory protein-3alpha, and granulocyte-macrophage colony-stimulating factor. Stimulation of epithelial cells with double-stranded RNA induced levels of interleukin-8 exceeding 20 ng/ml and levels of serum amyloid A exceeding 80 ng/ml. Double-stranded RNA, lipopolysaccharide, zymosan A, and flagellin also induced expression of macrophage inflammatory protein-3alpha and granulocyte-macrophage colony-stimulating factor, which may facilitate immature dendritic cell migration and maturation. These results suggest that airway epithelial cells express several TLRs and that they are functionally active. Epithelial expression of TLRs may be of importance in inflammation and immunity in the airways in response to inhaled pathogens.
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PMID:Activation of airway epithelial cells by toll-like receptor agonists. 1519 12

The Iboga alkaloid congener 18-methoxycoronaridine (18-MC) exhibits in vitro leishmanicidal and in vivo anti-addiction properties. In this paper, we describe that 18-MC inhibits HIV-1 infection in human peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages. We found that 18-MC inhibits the replication of primary isolates of HIV-1 in a dose-dependent manner, regardless of the preferential chemokine receptor usage of the isolates, at non-cell-toxic concentrations. The antiretroviral activity of 18-MC resulted in EC (50) values of 22.5 +/- 4.7 microM and 23 +/- 4.5 microM for R5 and X4 isolates, respectively, in PBMCs, and a therapeutic index (TI) of 14.5. Similar findings were observed for inhibition of HIV-1 replication in macrophages: EC (50) equal to 12.8 +/- 5 microM and 9.5 +/- 3 microM for an R5 virus after 14 and 21 days of infection, respectively, with TI equal to 25.6 and 34.5. 18-MC moderately inhibits the HIV-1 enzyme reverse transcriptase (IC (50) = 69.4 microM), which at least partially explains its antiretroviral activity.
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PMID:Anti-HIV-1 activity of the Iboga alkaloid congener 18-methoxycoronaridine. 1538 89

Considerable advances have been made in the last years in the design of derivatives acting as inhibitors of HIV entry and fusion. The discovery of chemokines focused the attention on cellular coreceptors used by the virus for entering within cells, and consequently the various steps of such processes have been characterized in detail. Intense research led to a wide range of effective compounds that are able to inhibit the initial steps of HIV life cycle. All steps in the process of HIV entry into the cell may be targeted by specific compounds that may be developed as novel types of antiretrovirals. Thus, several inhibitors of the gp120-CD4 interaction have been detected so far (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine receptor 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, UK-427857 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Recently, a third family of antivirals started to be used clinically (in addition to the reverse transcriptase and protease inhibitors), with the advent of enfuvirtide (T20), the first fusion inhibitor to be approved as an anti-HIV agent. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, offering thus the rationale for their combination in therapies for HIV-infected individuals. Many HIV entry and fusion inhibitors are currently being investigated in controlled clinical trials, and a number of them is bioavailable as oral formulations. This is an essential feature for an extended use of these compounds with the purpose of ameliorating adherence of patients to these medications and preventing the development of drug resistance.
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PMID:New advances in HIV entry inhibitors development. 1557 75

Involvement of excessive Th1 cell functions and heat shock protein expression in the pathogenesis of Behcet's disease (BD) has been reported. In this study we have characterized immune responses in intestinal lesions of BD. Peripheral blood lymphocytes (PBL) of BD and healthy controls (HC) and tissue specimens of intestinal Behcet's disease (intestinal BD), Crohn's disease (CD) and ulcerative colitis (UC) were analysed for mRNA and protein expression by reverse transcriptase-polymerase chain reaction (PCR) and immunohistochemistry, respectively. PBL of BD patients expressed the Th1-related chemokine receptor, CCR5 and CXCR3 preferentially compared with those of healthy controls. Intestinal lesions of BD expressed interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL)-12 mRNA, indicating Th1 skewed responses in vivo. mRNA of Txk, a Tec family tyrosine kinase specific to Th1 cells, was expressed in the lesions, suggesting its contribution to the Th1-dominant responses. In the intestinal samples, CCR5 was detected in all the cases with BD, whereas Th2-related CCR3 and CCR4 were detected randomly, mainly in the cases with inactive BD and those receiving large amounts of prednisolone, indicating the Th1-dominant immune responses in the intestinal lesions. As the ligands of CCR5, MIP1alpha and MIP1beta were detected, whereas RANTES was not. Heat shock protein (HSP) 60 was expressed in PBL and intestinal tissues of BD. Th1-dominant immune responses and HSP60 expression may induce the inflammatory responses and thus be associated with the pathogenesis of intestinal BD.
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PMID:Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet's disease. 1565 37

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

Despite the availability of 21 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens remain hampered by issues of toxicity, convenience, cost, incomplete viral suppression, and drug resistance. Expansion of the currently available therapeutic options through the reformulation of available agents, discovery of new compounds with antiretroviral activity, and the exploitation of novel drug targets are critical. This review describes the status of new nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and fusion inhibitors. We also summarize new classes of antiretroviral therapy in clinical development including the attachment inhibitors, chemokine receptor antagonists, integrase inhibitors, and maturation inhibitors.
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PMID:New antiretroviral drugs. 1660 66

Drugs in development for the management of HIV type 1 (HIV-1) infection include agents in existing classes and agents of novel classes. Of existing classes, new protease inhibitors, nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors are in development. Novel therapeutic approaches include the development of chemokine receptor (CCR)5 antagonists, integrase inhibitors and maturation inhibitors. CCR5 antagonists are thought to inhibit HIV-1 entry into host cells by occupying a specific site on the CCR5 receptor, preventing attachment of the HIV-1 envelope protein gp120. Integrase inhibitors are small synthetically prepared molecules that block RNA/DNA interactions and modify protein or enzyme synthesis. Data on the pharmacokinetics and pharmacodynamics of these new antiretroviral agents continue to generate interest. This review reports the known data on the pharmacokinetics of experimental antiretrovirals, and describe the main drug-drug interactions studied so far.
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PMID:The clinical pharmacology of antiretrovirals in development. 1686 45

Chemokines help to establish cerebral inflammation after ischemia, which comprises a major component of secondary brain injury. The CXCR4 chemokine receptor system induces neural stem cell migration, and hence has been implicated in brain repair. We show that CXCR1 and interleukin-8 also stimulate chemotaxis in murine neural stem cells from the MHP36 cell line. The presence of CXCR1 was confirmed by reverse transcriptase PCR and immunohistochemistry. Interleukin-8 evoked intracellular calcium currents, upregulated doublecortin (a protein expressed by migrating neuroblasts), and elicited positive chemotaxis in vitro. Therefore, effectors of the early innate immune response may also influence brain repair mechanisms.
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PMID:The MHP36 line of murine neural stem cells expresses functional CXCR1 chemokine receptors that initiate chemotaxis in vitro. 1728 63

HIV entry and fusion are two steps in the viral life cycle that can be targeted by several classes of antiviral drugs. The discovery of chemokines focused the attention on cellular coreceptors used by the virus for entering within cells, and to the various steps of such processes which are subject to interactions with small molecules. Intense research led to a wide range of effective compounds that are able to inhibit these initial steps of viral replication. All steps in the process of HIV entry into the cell may be targeted by specific compounds that may be developed as novel types of antiretrovirals. Thus, several inhibitors of the gp120-CD4 interaction have been detected so far (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine receptor 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). Recently, a third family of antivirals started to be used clinically (in addition to the reverse transcriptase and protease inhibitors), with the advent of enfuvirtide (T20), the first fusion inhibitor to be approved as an anti-HIV agent. Some of these compounds demonstrated in vitro synergism with other classes of antivirals, offering thus the rationale for their combination in therapies for HIV-infected individuals. Many HIV entry and fusion inhibitors are currently investigated in controlled clinical trials, and there are a number of them that is bioavailable as oral formulations. This is an essential feature for an extended use of these compounds with the purpose of ameliorating adherence of patients to these medications and preventing the development of drug resistance.
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PMID:An update in the development of HIV entry inhibitors. 1762 57

Rheumatoid arthritis (RA) is characterized by the recruitment of leukocytes and the accumulation of inflammatory mediators within the synovial compartment. Release of the chemokine CCL18 has been widely attributed to antigen-presenting cells, including macrophages and dendritic cells. This study investigates the production of CCL18 in polymorphonuclear neutrophils (PMN), the predominant cell type recruited into synovial fluid (SF). Microarray analysis, semiquantitative and quantitative reverse transcriptase polymerase chain reaction identified SF PMN from patients with RA as a novel source for CCL18 in diseased joints. Highly upregulated expression of other chemokine genes was observed for CCL3, CXCL8 and CXCL10, whereas CCL21 was downregulated. The chemokine receptor genes were differentially expressed, with upregulation of CXCR4, CCRL2 and CCR5 and downregulation of CXCR1 and CXCR2. In cell culture experiments, expression of CCL18 mRNA in blood PMN was induced by tumor necrosis factor alpha, whereas synthesis of CCL18 protein required additional stimulation with a combination of IL-10 and vitamin D3. In comparison, recruited SF PMN from patients with RA were sensitized for CCL18 production, because IL-10 alone was sufficient to induce CCL18 release. These results suggest a release of the T cell-attracting CCL18 by PMN when recruited to diseased joints. However, its production is tightly regulated at the levels of mRNA expression and protein synthesis.
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PMID:Expression and regulation of CCL18 in synovial fluid neutrophils of patients with rheumatoid arthritis. 1787 2


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