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 migration of neutrophils into sites of acute and chronic inflammation is mediated by chemokines. We used degenerate-primer reverse transcriptase-polymerase chain reaction (RT-PCR) to analyze chemokine receptor expression in neutrophils and identify novel receptors. RNA was isolated from human peripheral blood neutrophils and from neutrophils that had been stimulated for 5 h with granulocyte-macrophage colony-stimulating factor or by coculturing with primary human bronchial epithelial cells. Amplification products were cloned, and clone redundancy was determined. Seven known G-protein-coupled receptors were identified among 38 clones-CCR1, CCR4, CXCR1, CXCR2, CXCR4, HM63, and FPR1-as well as a novel gene, EX33. The full-length EX33 clone was obtained, and an in silico approach was used to identify the putative murine homologue. The EX33 gene encodes a 396-amino-acid protein with limited sequence identity to known receptors. Expression studies of several known chemokine receptors and EX33 revealed that resting neutrophils expressed higher levels of CXCRs and EX33 compared with activated neutrophils. Northern blot experiments revealed that EX33 is expressed mainly in bone marrow, lung, and peripheral blood leukocytes. Using RT-PCR analysis, we showed more abundant expression of EX33 in neutrophils and eosinophils, in comparison with that in T- or B-lymphocytes, indicating cell-specific expression among leukocytes.
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PMID:Cloning and expression analysis of a novel G-protein-coupled receptor selectively expressed on granulocytes. 1140 93

We have previously found that T140, a 14-amino acid residue peptide, inhibits infection of target cells by T cell-line-tropic strains of HIV-1 (X4-HIV-1) through its specific binding to a chemokine receptor, CXCR4. Here, we report synthesis and evaluation of bifunctional anti-HIV compounds, which are composed of T140 analogues and a reverse transcriptase inhibitor, 3'-azido-3'-deoxythymidine (AZT). Novel conjugated analogues have been proved to have the ability for controlled release of AZT in neutral aqueous media as well as mouse and feline sera, and high selectivity indexes (SIs, 50% cytotoxic concentration/50% effective concentration) caused by a synergistic effect of two different regenerating agents. Thus, these bifunctional compounds have several potential advantages. T140 analogues can possibly work as a carrier of AZT targeting T cells due to their specific affinity for CXCR4 on T cells. A synergistic effect by two types of regenerating agents may enable drug dosage to be reduced, and thus it may effectively suppress toxic side effects and the appearance of drug-resistant virus.
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PMID:Synthesis and evaluation of bifunctional anti-HIV agents based on specific CXCR4 antagonists-AZT conjugation. 1150 55

Feline immunodeficiency virus (FIV) is a lentivirus that causes feline acquired immunodeficiency syndrome. Infection can be transmitted experimentally via the vagina and rectum, making the cat a useful model for human immunodeficiency virus (HIV) infection. Some strains of FIV use the CXCR4 chemokine receptor in vitro to gain entry to feline cell lines, thymocytes and peripheral blood leucocytes (PBLs). In this study, the tissue expression of messenger ribonucleic acid (mRNA) encoding the CCR3, CXCR4 and CCR5 receptors was examined by reverse transcriptase polymerase chain reaction (RT-PCR). mRNA encoding each receptor was expressed by two feline T-cell lines (Mya-1 and FeTJ), a feline kidney fibroblast cell line (FKCU) and PBLs. Mesenteric lymph node, colon, rectum, uterus, cervix and vagina all expressed mRNA for CXCR4 and CCR5 whilst only lymph node expressed CCR3 mRNA. In order to locate this receptor mRNA expression, in-situ hybridization studies were performed with DNA probes specific for the chemokine receptor mRNAs. CCR5 and CXCR4 receptor mRNA was expressed by epithelial cells and some lamina propria cells of the colon and rectum. Epithelial cell expression of chemokine receptor mRNA was reduced in intensity towards the base of the crypts. Expression of CXCR4 receptor was also demonstrated immunohistochemically on some lamina propria and intraepithelial cells. The expression of these receptor molecules may be important in mucosal infection with FIV.
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PMID:Expression of chemokine receptors in the feline reproductive tract and large intestine. 1205 77

Human immunodeficiency virus (HIV) gp120 induces multiple cellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3-kinase) pathway. The role of the PI3-kinase pathway in HIV-1 replication is not understood. Here we examined whether HIV-1 gp120 upregulates the PI3-kinase pathway and whether PI3-kinase activity plays a role in virus replication in primary human CD4(+) T cells and macrophages. Soluble and virion-associated HIV-1 gp120 induced calcium mobilization and phosphorylation of the PI3-kinase downstream effectors PKB/Akt and p70 S6 kinase. gp120-induced PI3-kinase activity and calcium mobilization were inhibited by pertussis toxin and blocking antibodies directed against CCR5 and CXCR4, suggesting that the signaling is mediated through the chemokine receptor. The PI3-kinase inhibitor LY294002 inhibited infection of CD4(+) T cells and macrophages with X4 and R5 HIV-1-pseudotyped viruses at concentrations that did not induce cell toxicity or downregulate HIV-1 coreceptor expression. When gp120-induced signaling was bypassed with the vesicular stomatitis virus G envelope protein, infection was still sensitive to PI3-kinase inhibition, suggesting that basal PI3-kinase activity is required for infection. LY294002 inhibited HIV-1 infection when added after viral entry and did not affect formation of the HIV-1 reverse transcriptase products R/U5 and long terminal repeat/Gag in the presence of the inhibitor. However, when the inhibitor was added after viral integration had occurred, no inhibition of HIV infection was observed. Our studies show that inhibition of the PI3-kinase signaling pathway suppresses virus infection post-viral entry and post-reverse transcription but prior to HIV gene expression. This type of host-virus interaction has implications for anti-HIV therapeutics that target cellular signaling machinery.
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PMID:Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages. 1255 92

Despite the availability of 16 antiretroviral drugs approved for the treatment of HIV infection, current combination regimens present challenges. Newer antiretroviral drugs are needed to improve convenience, reduce toxicity and, of particular importance, to provide antiretroviral activity against viral strains resistant to the currently available antiretroviral agents. Candidate drugs with novel properties are in development in the two currently available drug classes: HIV reverse transcriptase inhibitors (nucleoside analogs, non-nucleoside analogs and nucleotide analogs) and HIV protease inhibitors (PI). Investigational nucleoside analog reverse transcriptase inhibitors (nRTI) include emtricitabine (FTC) and amdoxovir (DAPD), and investigational non-nucleoside reverse transcriptase inhibitors (NNRTI) include DPC 083 and TMC 125. New protease inhibitors under investigation include atazanavir (BMS-232 632), tipranavir, and TMC 114. In addition, newer agents with novel mechanisms of action such as HIV entry inhibitors (that inhibit the three steps of HIV entry: CD4 attachment, chemokine receptor binding and membrane fusion) and HIV integrase inhibitors are under investigation. Investigational entry inhibitors include PRO 542 (a CD4 attachment inhibitor), Schering C (a chemokine receptor inhibitor), enfuvirtide (T-20) and T-1249, inhibitors of membrane fusion. Investigational HIV integrase inhibitors include S-1360. Continued progress in the treatment of HIV disease will result from the development of new antiretroviral drugs.
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PMID:New antiretroviral drugs. 1266 50

When injected subcutaneously, mouse plasmacytoma (MOPC315) grew rapidly in situ, and metastatic cells became detectable first in the lymph nodes (LNs) and bone marrow, and later in the liver and lungs. We studied MOPC315 cell migration by tracking metastatic cells labelled with green fluorescent protein (GFP). We measured the levels of their chemokine receptor mRNA (by semiquantitative and real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), because chemokines can regulate organ predilection of metastasis. Freshly sorted metastatic cells and tumour cell lines derived from the liver of BALB/c mice overexpressed functional CCR6 and CCR7 molecules compared with primary tumour. Preincubation with the CCR6 ligand (CCL20) induced liver-sorted tumour cells to preferentially colonize the liver, demonstrating an association between liver metastasis and CCR6 expression in the mouse. Because the liver is a common site for metastasis, second only to draining LNs, we wished to ascertain whether this finding could be generalized, i.e. whether other cancers can use the similar mechanism of metastasis to the liver, and whether it holds true for humans. We found that CCR6 is overexpressed in small liver metastases of colon, thyroid and ovarian carcinomas compared with normal liver. Because human liver constitutively expresses CCL20, it could attract and select CCR6+ cancer cells. We suggest that chemotaxis via CCR6 might be a common mechanism by which malignant cancers metastasize to the liver. As metastasis in patients with cancer poses the biggest peril for survival, inhibition of CCR6 signalling, either during or after medical or surgical treatment, might be useful in preventing liver metastasis.
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PMID:Liver metastasis of cancer facilitated by chemokine receptor CCR6. 1279 Oct 91

A phosphorothioate oligonucleotide composed of deoxyguanosine and thymidine was identified as an inhibitor of HIV-1 infection at an early stage of the HIV-1 replication cycle in vitro. The phosphodiester and phosphorothioate chimeric oligonucleotides were found to be potent inhibitors of several steps of HIV-1 infection: the interaction with CD4 and the chemokine receptor, the reverse transcriptase activity, and the integrase activity. To elucidate the mechanism of the anti-HIV-1 function of these oligonucleotides in terms of their structure, we focussed on their G-serial sequences and investigated the characteristics of their solution structures. These oligonucleotides were proved to be able to adopt G-quadruplex structures by UV and CD measurements. We presume that the anti-HIV-1 activities of these oligonucleotides are consequently attributable to G-quadruplex formation.
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PMID:Properties of quadruplex oligonucleotides with anti-HIV-1 activity. 1290 28

CCR5, a beta-chemokine receptor, plays an important role in human immunodeficiency virus (HIV) infection of human immune cells, as it is a primary coreceptor for HIV entry into macrophages. We have applied a newly developed real-time reverse transcriptase PCR (RT-PCR) assay for the quantification of CCR5 mRNA in human blood immune cells. The CCR5 real-time RT-PCR assay has a sensitivity of 100 mRNA copies, with a dynamic range of detection between 10(2) and 10(6) copies of the CCR5 mRNA transcripts per reaction. The assay is highly reproducible, with an intra-assay coefficient of variation of the threshold cycle of less than 2.07%. When used for quantification of CCR5 mRNA in human monocyte-derived macrophages (MDM) and peripheral blood lymphocytes (PBL), the assay has precision and reproducibility. MDM expressed higher levels of CCR5 mRNA than did PBL. Thus, this assay has the potential and a wide application for the investigation of the role of CCR5 in inflammatory diseases and viral infections, including HIV disease.
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PMID:Quantification of CCR5 mRNA in human lymphocytes and macrophages by real-time reverse transcriptase PCR assay. 1460 77

CXCR3, predominately expressed on memory/activated T cells, is a receptor for both interferon-gamma inducible protein-10/CXC ligand 10 (CXCL10) and monokine induced by interferon-gamma/CXCL9. We reported here that CXCR3 was highly up-regulated on infiltrating eosinophils in Schistosoma japonicum egg-induced granuloma in the mouse liver. It was also highly and functionally up-regulated on peritoneal exudate eosinophils in mice infected with S. japonicum. The phenomena were demonstrated at protein and mRNA levels using immunohisto- and immunocytochemistry evaluation of biopsy, flow cytometry and real-time quantitative reverse transcriptase-polymerase chain reaction technique, and verified by Northern blotting and chemotaxis assay in vitro. We also found that CCR3 expression on the infiltrating and peritoneal exudate cells was significantly decreased, CXCR4 expression was unchanged during the 42-day period of infection. We screened mRNA expression levels of the all known chemokine receptors in purified peritoneal exudate eosinophils and liver granuloma dominated by eosinophils. CXCR3 was highly and functionally up-regulated on peritoneal exudate eosinophils in mice infected with S. japonicum, meanwhile CCR3 was significantly and functionally down-regulated in these cells. The findings could lead to a better understanding of the chemokine receptor expression pattern of eosinophils at inflamed tissue sites caused by parasites. These could be also crucial for establishing a therapeutic strategy for eosinophilic inflammation via intervention in chemokine actions.
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PMID:Highly up-regulated CXCR3 expression on eosinophils in mice infected with Schistosoma japonicum. 1467 5

The chemokine receptors CXCR4 and CCR5 are used as the main co-receptors by the T-cell-tropic (CXCR4-dependent, X4) and macrophage-tropic (CCR5-dependent, R5) HIV-1 strains, respectively, for entering their target cells. The natural ligands for CXCR4, the CXC-chemokine SDF-1 and CCR5, the CC-chemokines RANTES, MIP-1alpha and MIP-1beta are described to inhibit viral entry. In this review we focus on chemokine receptor/HIV co-receptor inhibitors. Modified chemokines such as Met-RANTES and AOP-RANTES showed antiviral activity against R5 viruses. Several low-molecular weight CCR5 antagonists have been described (such as TAK-779 and SCH-C) with potent antiviral activity. The latter compound is also orally available and is able to decrease R5 viral load levels in HIV-infected subjects. Several peptidic compounds, such as T22 (an 18-mer), T134 (a 14-mer), ALX40-4C (a 9-mer) and CGP 64222 (also a 9-mer) have anti-HIV activity and have been identified as CXCR4 antagonists. Also, the HIV-1 Tat protein has been described as a "natural" CXCR4 antagonist with anti-HIV-1 activity. The most potent and specific CXCR4 antagonists are the bicyclam derivatives, which also potently inhibit X4 HIV replication. AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks X4 viral replication in any target cell-type evaluated so far. AMD3100 was selected as the clinical drug candidate, which, after initial phase I (safety) studies, had proceeded to phase II (efficacy) trials. The compound dose-dependently inhibited X4 viruses after 10 days of continuous infusion of the drug. Recently, the orally bioavailable CXCR4 antagonist, AMD070, is presented as a candidate HIV drug. We believe that chemokine receptor antagonists will become important new antiviral drugs to combat AIDS. Both (CXCR4 and CCR5) chemokine receptor inhibitors will be needed in combination to inhibit viral replication and even in combinations of antiviral drugs that also target other aspects of the HIV replication cycle, such as reverse transcriptase and protease, to obtain optimum therapeutic effects.
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PMID:HIV co-receptors as targets for antiviral therapy. 1513 47


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