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)

The maturing reticulocyte degrades ribosomal RNA to constituent ribonucleoside phosphates. Guanosine ribonucleotides are retained only in small amounts and pyrimidine ribonucleotides only in trace quantities. In the mature erythrocyte more than 97% of total nucleotides are the interconvertible adenosine mono-, di-, and triphosphates. High energy ATP fuels most of the reactions required to sustain viability. Unable to synthesize adenosine phosphates from small precursor molecules, the red cell relies on certain salvage pathways to replenish its losses from the adenosine phosphate pool. The most important of these involve adenosine. Adenylate kinase deficiency, when severe, is associated with nonspherocytic hemolytic anemia. A genetically-determined deficiency of pyrimidine 5'-nucleotidase prevents the normal dephosphorylation of pyrimidine ribonucleotides, and hence is characterized by the unique accumulation of pyrimidine phosphates intracellularly. Other features are chronic hemolytic anemia, splenomegaly, and a profound increase in basophilic stippling on the stained blood film. The syndrome is transmitted as an autosomal recessive disorder. A similar syndrome is found in severe lead poisoning as a consequence of nucleotidase inhibition by lead. An inherited, dominantly transmitted hemolytic anemia associated with low red cell ATP and a 45-70 fold increase in the enzymatic activity of adenosine deaminase has also been documented. The undefined molecular lesion appears to involve overproduction of an entirely normal enzyme protein. Severe deficiency of either of two sequential enzymes of purine metabolism, adenosine deaminase anemia, but by excessive accumulations of deoxyribonucleotides within red cells and lymphocytes. The clinical counterpart of each is a severe immunodeficiency state secondary to lymphopenia and lymphocyte dysfunction. Certain other rare clinical syndromes involving disturbed nucleotide metabolism also are detectable by red cell assay procedures.
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PMID:Erythrocyte disorders of purine and pyrimidine metabolism. 625 19

The relative in vitro potency of nine human immunodeficiency virus (HIV) type 1 reverse transcriptase inhibitors was evaluated in a coculture assay which measures the frequencies of infectious primary cells from HIV-positive patients by the limiting dilution technique and measures their apparent reduction under increasing concentrations of drugs. An advantage of this assay is that it utilizes a variety of wild-type viruses not selected by in vitro propagation. Potency ranking placed the (-)-L-enantiomer of 2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC], an oxathiolane pyrimidine nucleoside analog (90% effective concentration = 55 nM), before 2',3'-dideoxycytidine (DDC) (74 nM), (-)-2',3'-dideoxy-3'-thiacytidine (3TC) (300 nM), 3'-azido-3'-deoxythymidine (AZT) (530 nM), TIBO R82913 (670 nM), and 2',3'-dideoxyinosine (DDI) (6,400 nM). HIV from AZT-naive patients' lymphocytes was more sensitive to the inhibitory effect of (-)-FTC, 3TC, or DDC than was highly AZT-resistant HIV obtained from AZT-treated patients' cells, indicating partial cross-resistance between thymidine and cytidine analogs. Combined inhibitory concentrations of AZT with (-)-FTC, 3TC, DDC, and DDI produced synergistic interactions as determined by the multiple-drug effect analysis. Synergistic interactions were demonstrable with AZT plus (-)-FTC or with AZT plus DDC with cells bearing AZT-resistant HIV. The inhibitory concentrations of AZT established by this cell-to-cell virus transmission assay are closer than those determined by the conventional assay system to the extracellular AZT concentrations required in patients' plasma to achieve comparable levels of HIV inhibition in vivo.
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PMID:Infectious amplification of wild-type human immunodeficiency virus from patients' lymphocytes and modulation by reverse transcriptase inhibitors in vitro. 750 8

Novel 3,4-dihydro-6-benzyl-4-oxopyrimidines (DABOs), variously substituted at both the C-2 and C-5 positions of the pyrimidine ring, proved to be specific inhibitors of the human immunodeficiency virus type 1 (HIV-1) in vitro. Some compounds showed potency at micromolar doses, no cytotoxicity at the maximum testable doses and selectivity indexes comparable to that of 2'-3'-dideoxyinosine (ddI). Mode of action studies suggested that DABOs interfered with a step of the virus multiplication cycle following adsorption and preceding integration. Enzyme assays indicated that DABOs targeted HIV-1 reverse transcriptase: they inhibited the RNA-dependent DNA polymerase activity in a template-dependent manner and, to a lesser extent, the DNA-dependent DNA polymerase activity. No inhibition of the RNase-H associated activity was observed. When DABOs were assayed in combination with 3'-azido-3'-dideoxythymidine (AZT) or ddI against HIV-1 in cell cultures, a slightly synergistic inhibitory effect was observed. The combination of DABO 546 and AZTTP in enzyme assays showed that the two compounds were kinetically mutually exclusive.
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PMID:Characterization of the anti-HIV-1 activity of 3,4-dihydro-2-alkoxy-6-benzyl-4-oxopyrimidines (DABOs), new non-nucleoside reverse transcriptase inhibitors. 753 70

The trans-activation response element (TAR) found near the 5' end of the viral RNA of the human immunodeficiency virus contains a 3-nt bulge that is recognized by the virally encoded trans-activator protein (Tat), an important mediator of transcriptional activation. Insertion of the TAR bulge into double-stranded RNA is known to result in reduced electrophoretic mobility, suggestive of a bulge-induced bend. Furthermore, NMR studies indicate that Arg causes a change in the structure of the TAR bulge, possibly reducing the bulge angle. However, neither of these effects has been quantified, nor have they been compared with the effects of the TAR-Tat interaction. Recently, an approach for the quantification of bulge-induced bends has been described in which hydrodynamic measurements, employing the method of transient electric birefringence, have yielded precise estimates for the angles of a series of RNA bulges, with the angles ranging from 7 degrees to 93 degrees. In the current study, transient electric birefringence measurements indicate that the TAR bulge introduces a bend of 50 degrees +/- 5 degrees in the absence of Mg2+. Addition of Arg leads to essentially complete straightening of the helix (to < 10 degrees) with a transition midpoint in the 1 mM range. This transition demonstrates specificity for the TAR bulge: no comparable transition was observed for U3 or A3 (control) bulges with differing flanking sequences. An essentially identical structural transition is observed for the Tat-derived peptide, although the transition midpoint for the latter is near 1 microM. Finally, low concentrations of Mg2+ alone reduce the bend angle by approximately 50%, consistent with the effects of Mg2+ on other pyrimidine bulges. This last observation is important in view of the fact that most previous structural/binding studies were performed in the absence of Mg2+.
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PMID:The bend in RNA created by the trans-activation response element bulge of human immunodeficiency virus is straightened by arginine and by Tat-derived peptide. 759 79

Ribonucleotide reductase inhibitors such as hydroxyurea (HU) and related compounds, at low, non-toxic doses, enhance the anti-human immunodeficiency virus type 1 (HIV-1) potency of both purine and pyrimidine 2',3'-dideoxynucleosides (ddNs) in human lymphocytes and macrophages. The most marked enhancement of inhibition of HIV-1 replication reported to date has been seen with the purine ddN 2',3'-dideoxyinosine (ddIno): a low level of HU (0.1 mM) permitted a 4.5-fold reduction in optimal ddIno dosage with no decrease in therapeutic effect or increase in toxicity. We report here even more marked enhancement by HU of the potency of the purine ddN 2'-beta-fluoro-2',3'-dideoxyadenosine (2'-beta-F-ddAdo), where the addition of 0.1 mM HU permitted a 7.1-fold reduction in the optimal dose of 2'-beta-F-ddAdo in the phytohemagglutinin-activated peripheral blood mononuclear cell HIV-1 test system.
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PMID:Enhancement by hydroxyurea of the anti-human immunodeficiency virus type 1 potency of 2'-beta-fluoro-2',3'-dideoxyadenosine in peripheral blood mononuclear cells. 763 73

We and other groups have recently reported the potentiation by ribonucleotide reductase inhibitors such as hydroxyurea of the anti-human immunodeficiency virus type 1 (HIV-1) activity of purine and pyrimidine 2',3'-dideoxynucleosides in both resting and phytohemagglutinin-stimulated peripheral blood mononuclear cells. Little agreement prevails, however, as to the mechanism of the synergistic effects described. We report here that in phytohemagglutinin-stimulated peripheral blood mononuclear cells, two mechanisms exist for the potentiation of the anti-HIV-1 activity by low-dose hydroxyurea of the purine-based dideoxynucleoside 2',3'-dideoxyinosine and the pyrimidine-based dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine. For 2',3'-dideoxyinosine, the enhancement arises from a specific depletion of dATP by hydroxyurea, resulting in a favorable shift of the 2',3'-dideoxyadenosine 5'-triphosphate/dATP ratio. For the pyrimidine dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine, the more modest anti-HIV enhancement results from hydroxyurea-induced increases of pyrimidine kinase activities in the salvage pathway and, hence, increased 5'-phosphorylation of these drugs, while depletion of the corresponding deoxynucleoside 5'-triphosphates (dTTP and dCTP) plays no significant role.
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PMID:Disparate actions of hydroxyurea in potentiation of purine and pyrimidine 2',3'-dideoxynucleoside activities against replication of human immunodeficiency virus. 766 90

The [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'- spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide) (TSAO) derivatives of N1-methylhypoxanthine with linkage to the TSAO moiety through the N9 or N7 atom of the hypoxanthine ring (designated TSAO-m1Hx and 7-TSAO-m1Hx, respectively) are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) but not HIV-2 or simian immunodeficiency virus. Their selectivity indices (ratio of cytotoxic concentration to antivirally active concentration) are > 500. This is a > 15-fold increase in therapeutic index, compared with TSAO-adenine. A HIV-1(IIIB) variant selected for resistance to TSAO-m1Hx (designated HIV-1/TSAO-m1Hx) proved to be cross-resistant to the other TSAO-purine derivatives and to the TSAO-pyrimidine derivatives. However, HIV-1/TSAO-m1Hx was highly sensitive to the HIV-1-specific non-nucleoside tetrahydroimidazobenzodiazepinone, nevirapine, pyridinone L697,661, and several HEPT derivatives. The reverse transcriptase (RT) of HIV-1/TSAO-m1Hx shows a single amino acid change (138-Glu to Lys) that is identical to the amino acid change that has recently been observed in several HIV-1/TSAO-pyrimidine mutant strains. Our observations indicate that the TSAO-purines and TSAO-pyrimidines belong to one pharmacological class of HIV-1-specific RT inhibitors that are targeted at the same molecular site of the HIV-1 RT.
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PMID:Human immunodeficiency virus type 1-specific [2',5'-bis-O-(tert- butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"- oxathiole-2",2"-dioxide)-purine analogues show a resistance spectrum that is different from that of the human immunodeficiency virus type 1-specific non-nucleoside analogues. 767 89

Transactivation of human immunodeficiency virus (HIV) gene expression requires the interaction of Tat protein with the trans-activation responsive region (TAR) RNA, a 59-base stem-loop structure located at the 5'-end of all mRNAs. The TAR RNA contains a six-nucleotide loop and a three-nucleotide pyrimidine bulge which separates two helical stem regions. The trinucleotide bulge is essential for high affinity and specific binding of the Tat protein. Recently, a rhodium complex, Rh(phen)2phi3+, was discovered which promotes RNA cleavage in the open major groove and triply bonded bases [Chow, C. S., et al. (1992) Biochemistry 31, 972-982]. This metal complex does not bind double-helical RNA or unstructured single-stranded regions of RNA. Instead, sites of tertiary interaction which are open in the major groove and accessible to stacking are targeted by the complex through photoactivated cleavage. We have used this rhodium probe to investigate the effect of bulge bases on the major groove opening in TAR RNA. The sites targeted by the rhodium complex have been mapped to single nucleotide resolution on wild-type TAR RNA and on several mutants of the TAR RNA containing different numbers of mismatch bases in the bulge region. A strong cleavage at residues C39 and U40 was observed on the wild-type TAR RNA and in mutant TAR RNA containing two mismatch bases in the bulge. No cleavage at C39 and U40 was observed in a bulgeless and a one-base bulge TAR RNA. By varying the number of mismatch bases, we demonstrated that the trinuclear bulge widens the major groove of TAR RNA to facilitate Tat binding.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Major groove opening at the HIV-1 Tat binding site of TAR RNA evidenced by a rhodium probe. 775 57

With increasing awareness of the mitochondrial toxicity associated with certain 2',3'-dideoxynucleosides used in anti-human immunodeficiency virus therapy, procedures for quantitative analyses of drug effects on mitochondrial DNA (mtDNA) have assumed enhanced importance. For this reason we have developed a method to measure the copy numbers of mtDNA in cultured MOLT-4 cells. First a hybrid competitive DNA template was synthesized by conventional polymerase chain reaction (PCR), using two custom-synthesized 40-mer composite primers incorporating mitochondrial displacement loop sequences linked by a non-mitochondrial cDNA template (a 76-base pair sequence from the tat/rev region of human immunodeficiency virus cDNA). For the competitive assay, increasing known copy numbers of the hybrid competitive template were added as an internal control to samples containing total cellular DNA. With this approach, two competitive PCR products were generated, 1) a mitochondrial displacement loop-derived fragment (182 base pairs) and 2) a competitive DNA template-derived fragment (156 base pairs). Absolute quantitation was achieved by radiometric comparison of the relative amounts of the two products. To test the versatility of this method, varying amounts of competitive template (6.6 x 10(4) to 6.6 x 10(9) copies) were used with a fixed quantity of total cellular DNA taken from cells cultured for 9 days in the presence or absence of selected pyrimidine and purine dideoxynucleosides. The results showed that the copy number of cellular mtDNA is 823 +/- 71 copies/cell in MOLT-4 cells. Little selective depletion of mtDNA, compared with total cellular DNA, was seen with the purine dideoxynucleosides examined; however, when the cells were exposed to the pyrimidine dideoxynucleoside 2',3'-dideoxycytidine (50 nM) for 9 days, mtDNA content was specifically depleted, although total cellular DNA decreased by only 10%. Thus, in addition to the presently used methods of assessing mitochondrial impairment, i.e., Southern blot analysis and electron microscopy, the competitive PCR method provides a third and convenient assay, with particular applicability to determination of mtDNA in very small numbers of cells.
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PMID:Quantitation of mitochondrial DNA in human lymphoblasts by a competitive polymerase chain reaction method: application to the study of inhibitors of mitochondrial DNA content. 780 25

The T-cell immunodeficiency associated with purine nucleoside phosphorylase (PNP) deficiency in man is believed to be due to the accumulation of dGTP which may be preferentially formed from deoxyguanosine in T-lymphocytes or their precursor cells. We found no evidence for dGTP accumulation in thymocytes or spleen leucocytes, < 1 nmol/10(9) cells, nor in erythrocytes, < 0.05 nmol/10(9) cells, of the B6-NPE- or B6-NPF PNP-deficient mice strains. There were no changes in purine or pyrimidine ribonucleotide pools. As these mice had been previously shown to excrete PNP nucleoside substrates, we examined the metabolism of deoxyguanosine. Deoxyguanosine kinase activity as compared to control mice was 6 to 52% for the B6-NPE mutant, 2 to 22% for the B6-NPF mutant. Fractionation of erythrocyte and liver lysates from the F mutation and the background strain, C57BL/6J, by anion exchange chromatography confirmed the secondary deficiency of deoxyguanosine kinase and demonstrated that this activity was distinct from adenosine kinase and two major peaks of deoxycytidine kinase activity. Mouse PNP, expressed and purified as a fusion protein, did not show evidence of being bifunctional and having deoxyguanosine kinase activity. Metabolic modelling revealed that the ratio of deoxyguanosine phosphorylation versus phosphorolysis was < 0.06 in control mice, and < or = 0.3 in lymphocytes of PNP-deficient mice. Were deoxyguanosine kinase not reduced in the PNP-deficient mice, all tissues of the B6-NPF mutant would preferentially phosphorylate deoxyguanosine at low substrate concentrations.
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PMID:Secondary loss of deoxyguanosine kinase activity in purine nucleoside phosphorylase deficient mice. 791 81


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