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: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Novel beta-L-2',3'-dideoxy-3'-fluoro nucleosides were synthesized and further converted to their 5'-triphosphates. Their inhibitory activities against hepatitis B virus (HBV) and duck hepatitis B virus (DHBV) DNA polymerases, human immunodeficiency virus (HIV) reverse transcriptase (RT), and the cellular DNA polymerases alpha, beta, gamma, delta, and epsilon were investigated and compared with those of the corresponding 3'-fluoro-modified beta-d-analogues. The 5'-triphosphates of 3'-deoxy-3'-fluoro-beta-L-thymidine (beta-L-FTTP), 2',3'-dideoxy-3'-fluoro-beta-L-cytidine (beta-L-FdCTP), and 2',3'-dideoxy-3'-fluoro-beta-l-5-methylcytidine (beta-L-FMetdCTP) emerged as effective inhibitors of HBV/DHBV DNA polymerases (IC50 = 0.25-10.4 microM). They were either equally (FTTP) or less (FMetdCTP, FdCTP) effective than their beta-d-counterparts. Also the 5'-triphosphate of beta-L-thymidine (beta-L-TTP) was shown to be a strong inhibitor of these two viral enzymes (IC50 = 0.46/1.0 microM). However, all beta-L-FdNTPs (also beta-L-TTP) were inactive against HIV-RT, a result which contrasts sharply with the high efficiency of the beta-D- FdNTPs against this polymerase. Between the cellular DNA polymerases only the beta and gamma enzymes displayed a critical susceptibility to beta-D-FdNTPs which is largely abolished by the beta-L-enantiomers. These results recommend beta-L-FTdR, beta-L-FCdR, and beta-L-FMetCdR for further evaluation as selective inhibitors of HBV replication at the cellular level.
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PMID:Newly synthesized L-enantiomers of 3'-fluoro-modified beta-2'-deoxyribonucleoside 5'-triphosphates inhibit hepatitis B DNA polymerases but not the five cellular DNA polymerases alpha, beta, gamma, delta, and epsilon nor HIV-1 reverse transcriptase. 962 45

The racemic nucleoside analogue 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC) is in clinical development for the treatment of human immunodeficiency virus (HIV) type 1 (HIV-1) infection. dOTC is structurally related to lamivudine (3TC), but the oxygen and sulfur in the furanosyl ring are transposed. Intracellular metabolism studies showed that dOTC is phosphorylated within cells via the deoxycytidine kinase pathway and that approximately 2 to 5% of dOTC is converted into the racemic triphosphate derivatives, which had measurable half-lives (2 to 3 hours) within cells. Both 5'-triphosphate (TP) derivatives of dOTC were more potent than 3TC-TP at inhibiting HIV-1 reverse transcriptase (RT) in vitro. The K(i) values for dOTC-TP obtained against human DNA polymerases alpha, beta, and gamma were 5,000-, 78-, and 571-fold greater, respectively, than those for HIV RT (28 nM), indicating a good selectivity for the viral enzyme. In culture experiments, dOTC is a potent inhibitor of primary isolates of HIV-1, which were obtained from antiretroviral drug-naive patients as well as from nucleoside therapy-experienced (3TC- and/or zidovudine [AZT]-treated) patients. The mean 50% inhibitory concentration of dOTC for drug-naive isolates was 1.76 microM, rising to only 2.53 and 2.5 microM for viruses resistant to 3TC and viruses resistant to 3TC and AZT, respectively. This minimal change in activity is in contrast to the more dramatic changes observed when 3TC or AZT was evaluated against these same viral isolates. In tissue culture studies, the 50% toxicity levels for dOTC, which were determined by using [(3)H]thymidine uptake as a measure of logarithmic-phase cell proliferation, was greater than 100 microM for all cell lines tested. In addition, after 14 days of continuous culture, at concentrations up to 10 microM, no measurable toxic effect on HepG2 cells or mitochondrial DNA replication within these cells was observed. When administered orally to rats, dOTC was well absorbed, with a bioavailability of approximately 77%, with a high proportion (approximately 16.5% of the levels in serum) found in the cerebrospinal fluid.
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PMID:Anti-human immunodeficiency virus type 1 activity, intracellular metabolism, and pharmacokinetic evaluation of 2'-deoxy-3'-oxa-4'-thiocytidine. 1042

An external evaluation program for measuring the performance of laboratories testing for cytokines and immune activation markers in biological fluids was developed. Cytokines, chemokines, soluble cytokine receptors, and other soluble markers of immune activation (CSM) were measured in plasma from a healthy human immunodeficiency virus (HIV)-seronegative reference population and from HIV-seropositive individuals as well as in supernatant fluids from in vitro-stimulated human immune cells. The 14 components measured were tumor necrosis factor (TNF) alpha, gamma interferon, interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-10, Rantes, MIP-Ia, MIP-Ibeta, soluble TNF receptor II, soluble IL-2 receptor alpha, beta(2)-microglobulin, and neopterin. Twelve laboratories associated with the Adult and Pediatric AIDS Clinical Trial Groups participated in the study. The performance features that were evaluated included intralaboratory variability, interlaboratory variability, comparison of reagent sources, and ability to detect CSM in the plasma of normal subjects as well as the changes occurring in disease. The principal findings were as follows: (i) on initial testing, i.e., before participating in the program, laboratories frequently differed markedly in their analytic results; (ii) the quality of testing of a CSM in individual participating laboratories could be assessed; (iii) most commercial kits allowed distinction between normal and abnormal plasma CSM levels and between supernatants of stimulated and unstimulated cells; (iv) different sources of reagents and reference standards frequently provided different absolute values; (v) inexperienced laboratories can benefit from participating in the program; (vi) laboratory performance improved during active participation in the program; and (vii) comparability between analyses conducted at different sites can be ensured by an external proficiency testing program.
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PMID:Need for an external proficiency testing program for cytokines, chemokines, and plasma markers of immune activation. 1088 48

CD8+ cells from human immunodeficiency virus type 1 (HIV-1) infected individuals have been shown to suppress HIV-1 replication both through a major histocompatibility complex (MHC)-restricted cytolytic pathway as well as through a noncytolytic pathway mediated through soluble factors. To characterize this soluble activity and its potential role in disease progression further, we studied the HIV-1 inhibition by supernatants derived from herpesvirus saimiri-transformed CD8+ cells isolated from infected children. Three of the six CD8+ cell lines derived had a phenotype consistent with an unusual natural killer (NK) cells phenotype with low CD3, high CD56, and low CD16. Supernatants from some of the cell lines derived from children with rapid progression as well as long-term nonprogressors exhibited broad HIV-1-inhibitory activity in primary CD4+ cells as well as in primary macrophages. In contrast to a cocktail of beta-chemokines, the supernatants inhibited T-tropic as well as M-tropic viruses, efficiently inhibited infection in primary macrophages, and inhibited HIV-1 activation in the chronically infected U1 cell line. The HIV-1-inhibitory activity was heat stable and active over a broad pH range. Fractionation of the supernatant by size and ion exchange chromatography demonstrated activity in the complete absence of RANTES as well as interferons-alpha, beta, and gamma and in a size range of less than 10 kD and greater than 3 kD. CD8+ cell supernatants contain additional unidentified factors that have anti-HIV activity to account for this broad phenomenon.
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PMID:CD8+ cell lines isolated from HIV-1-infected children have potent soluble HIV-1 inhibitory activity that differs from beta-chemokines. 1119 95

The C-type lectin human dendritic cell (DC)-specific intercellular adhesion molecule (ICAM)-3-grabbing non-integrin (DC-SIGN) plays important roles in pattern recognition by dendritic cells in the immune system. In addition to binding human immunodeficiency virus (HIV), this type II membrane protein binds with high affinity to the adhesion molecules ICAM-3 and -2 to promote important dendritic cell interactions with naive T cells and endothelial cells, respectively. DC-SIGNR, a human DC-SIGN homologue expressed on sinusoidal endothelial cells in liver and lymph node, also binds and transmits HIV virus. We describe the cloning and characterization of a family of murine complementary DNAs (cDNAs) called SIGNR1, expressed in skin and spleen, that encode C-type lectins highly related to human DC-SIGN and DC-SIGNR. We also report the genomic structure of the SIGNR1 gene and compare it to that of human DC-SIGN and DC-SIGNR. The different transcripts (alpha, beta, gamma, delta) are generated by differences in 5' untranslated sequences, alternative splicing and/or the use of different polyadenylation sites. The predicted open reading frames encoded by the cDNAs are most closely related to human DC-SIGN and DC-SIGNR in the cytoplasmic domain, the transmembrane region and the carbohydrate recognition domain. Moreover, the alternatively spliced transcripts encode proteins that lack the transmembrane region or have modified carbohydrate recognition domains. Northern hybridization experiments with several different SIGNR1 cDNA probes reveal transcripts of 1.3 and 2.1 kb that are expressed in a tissue-restricted fashion in murine skin, spleen and lung. In situ hybridization and immunocytochemistry experiments demonstrate that, like human DC-SIGN, the murine messenger RNAs are expressed in subsets of dendritic cells in the spleen and skin.
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PMID:Molecular characterization of the murine SIGNR1 gene encoding a C-type lectin homologous to human DC-SIGN and DC-SIGNR. 1213 41

Human immunodeficiency virus (HIV) infection leads to a profound T cell dysfunction well before the clinical onset of acquired immunodeficiency syndrome (AIDS). We have been accumulating evidence that one of the mechanisms responsible for this T cell deficiency may be the dysregulation of signal transduction via the interleukin (IL)-2/IL-2 receptor (R) complex. In CD4 T cells, we have observed previously that viral envelope (env) glycoproteins induce IL-2 unresponsiveness and the down-regulation of the three chains making up the IL-2R (alpha, beta, gamma) in vitro. We have now established further that this disruption of the IL-2/IL-2R system manifests itself in defective signal propagation via the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway in response to IL-2. The treatment of CD4 T cells with HIV env or surface ligation of CD4 with anti-CD4 monoclonal antibodies inhibited the IL-2-induced activation of Jak-1 and Jak-3, as well as their targets, STAT5a and STAT5b. This Jak/STAT deficiency may contribute to the crippling of CD4 T cell responses to a cytokine central to the immune response by HIV.
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PMID:Human immunodeficiency virus-1 envelope glycoproteins and anti-CD4 antibodies inhibit interleukin-2-induced Jak/STAT signalling in human CD4 T lymphocytes. 1260 94

We found a novel inhibitor specific to eukaryotic DNA polymerase epsilon(pol epsilon) from plant cultured cells, Nicotina tabacum L. The compound (compound 1) was a dipeptide alcohol, L-homoserylaminoethanol. The 50% inhibition of pol epsilon activity by the compound was 43.6 microg/mL, and it had almost no effect on the activities of the other eukaryotic DNA polymerases such as alpha, beta, gamma and delta, prokaryotic DNA polymerases, nor DNA metabolic enzymes such as human telomerase, human immunodeficiency virus type 1 reverse transcriptase, T7 RNA polymerase, human DNA topoisomerase I and II, T4 polynucleotide kinase and bovine deoxyribonuclease I. Kinetic studies showed that inhibition of pol epsilon by the compound was non-competitive with respect to both template-primer DNA and nucleotide substrate. We succeeded in chemically synthesizing the stereoisomers, L-homoserylaminoethanol and D-homoserylaminoethanol, and found both were effective to the same extent. The IC(50) values of L- and D-homoserylaminoethanols for pol epsilon were 42.0 and 41.5 microg/mL, respectively. This represents the second discovery of a pol epsilon-specific inhibitor, and the first report on a water-soluble peptide-like compound as the inhibitor, which is required in biochemical studies of pol epsilon.
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PMID:L-Homoserylaminoethanol, a novel dipeptide alcohol inhibitor of eukaryotic DNA polymerase from a plant cultured cells, Nicotina tabacum L. 1498 Jun 8

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

We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) of a nucleoside reverse transcriptase inhibitor, 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), which has potent activity against wild-type and multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 microM [(3)H]EFdA or [(3)H]3'-azido-2',3'-dideoxythymidine (AZT) for 6 h, the intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10(9) cells, while that of AZT was 396.5 pmol/10(9) cells. When CEM cells were exposed to 10 microM [(3)H]EFdA, the amount of EFdA-TP increased by 22-fold (2,090 pmol/10(9) cells), while the amount of [(3)H]AZT-TP increased only moderately by 2.4-fold (970 pmol/10(9) cells). The intracellular half-life values of EFdA-TP and AZT-TP were approximately 17 and approximately 3 h, respectively. When MT-4 cells were cultured with 0.01 microM EFdA for 24 h, thoroughly washed to remove EFdA, further cultured without EFdA for various periods of time, exposed to HIV-1(NL4-3), and cultured for an additional 5 days, the protection values were 75 and 47%, respectively, after 24 and 48 h with no drug incubation, while those with 1 microM AZT were 55 and 9.2%, respectively. The 50% inhibitory concentration values of EFdA-TP against human polymerases alpha, beta, and gamma were >100 microM, >100 microM, and 10 microM, respectively, while those of ddA-TP were >100 microM, 0.2 microM, and 0.2 microM, respectively. These data warrant further development of EFdA as a potential therapeutic agent for those patients who harbor wild-type HIV-1 and/or multidrug-resistant variants.
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PMID:Activity against human immunodeficiency virus type 1, intracellular metabolism, and effects on human DNA polymerases of 4'-ethynyl-2-fluoro-2'-deoxyadenosine. 1754 98

Biologicals are proteins used as drugs. Biologicals target clearly defined molecular structures, being part of established pathogenetic pathways. Therefore, their focused mode of action seems to render them superior to classic small molecular drugs regarding "off-target" adverse drug reactions (ADR). Nevertheless, the increasing use of biologicals for the treatment of different diseases has revealed partially unexpected adverse reactions. The often direct interaction of a biological with the immune system provides a clue to most side effects, which have consequently been subclassified, based on pathogenetic principles, into 5 subtypes named alpha, beta, gamma, delta, and epsilon, reflecting overstimulation (high cytokine values, type alpha), hypersensitivity (type beta), immune deviation (including immunodeficiency, type gamma), cross-reactivity (type delta), and nonimmune mediated side effects (type epsilon). This article presents typical clinical manifestations of these subtypes of ADR to biologicals, proposes general rules for treating them, and provides a scheme for a thorough allergological workup. This approach should help in future handling of these often very efficient drugs.
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PMID:The complex clinical picture of side effects to biologicals. 2060 63


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