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)

Plasma concentrations of the two isoenzymes of adenosine deaminase (ADA, E.C. 3.5.4.4), adenosine deaminase1 (ADA1) and adenosine deaminase2 (ADA2), were measured in a cohort of ambulatory patients infected with the human immunodeficiency virus (HIV) and controls. A sensitive isoenzyme-specific radioisotopic assay system was developed for these studies. Among 22 HIV-infected patients, plasma ADA2 was significantly elevated as compared with 16 control subjects (p less than 0.01) and 6 uninfected subjects having a risk factor for HIV infection (p less than 0.01). Plasma ADA2 was not associated with the stage of disease as defined by clinical status (p greater than 0.05) or helper (CD4) lymphocyte count (p greater than 0.05). Available evidence suggests that elevated plasma ADA2 could be a useful surrogate marker for HIV infection that occurs early in the disease process.
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PMID:Plasma adenosine deaminase2: a marker for human immunodeficiency virus infection. 198 54

A series of 6-substituted 2',3'-dideoxypurine ribofuranosides (ddP) was enzymatically synthesized with live E. coli in an effort to enhance the lipophilicity of this class of anti-human immunodeficiency virus (HIV) compounds and thereby facilitate drug delivery into the central nervous system. All 6-halo-substituted ddPs were substantially more lipophilic, as defined by their octanol-water partition coefficient (P), than their nonhalogenated congeners 2',3'-dideoxyinosine (ddI) or 2',3'-dideoxyguanosine (ddG). For this class of compounds, log P's ranged from +0.5 to -1.2 in the following order: 6-iodo, 2-amino-6-iodo greater than 6-bromo, 2-amino-6-bromo greater than 6-chloro, 2-amino-6-chloro greater than 6-fluoro, 2-amino-6-fluoro much greater than ddG greater than ddI. These compounds were evaluated in vitro for ability to suppress the infectivity, replication, and cytopathic effect of HIV. 2-Amino-6-fluoro-, 2-amino-6-chloro-, and 6-fluoro-ddP exhibited a potent activity against HIV comparable to that of ddI or ddG and completely blocked the infectivity of HIV without affecting the growth of target cells. The comparative order of in vitro anti-HIV activity was 2-amino-6-fluoro, 2-amino-6-chloro, 6-fluoro greater than 2-amino-6-bromo greater than 2-amino-6-iodo, 6-chloro greater than 6-bromo greater than 6-iodo. These compounds also exhibited potent in vitro activity against HIV-2 and 3'-azido-3'-deoxythymidine-resistant HIV-1 variants. All 2-amino-6-halo-ddPs and 6-halo-ddPs were substrates for adenosine deaminase (ADA) and were converted to ddG or ddI, respectively. In the presence of the potent ADA inhibitor 2'-deoxycoformycin, 6-halo-substituted ddPs failed to exert an in vitro antiretroviral effect. These dideoxypurine nucleoside analogues represent a new class of lipophilic prodrugs of ddG and ddI that possess the potential for more effective therapy of HIV-induced neurologic disorders.
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PMID:Escherichia coli mediated biosynthesis and in vitro anti-HIV activity of lipophilic 6-halo-2',3'-dideoxypurine nucleosides. 203 86

Diethylaminoethyl-cellulose chromatography was used to separate the two isoenzymes of adenosine deaminase (EC3.5.4.4), adenosine deaminase1 (ADA1) and adenosine deaminase2 (ADA2), in human plasma. One hundred and fifteen purine base, nucleoside, and nucleotide analogs were tested as inhibitors of this partially purified preparation of ADA2. Coformycin and 2'-deoxycoformycin were by far the most potent inhibitors of this isoenzyme (apparent Ki values 20 and 19 nM, respectively). ADA2 was also inhibited by nebularine (apparent Ki 1.5 mM) but was resistant to the potent ADA1 inhibitor (+)-erythro-9(2-S-hydroxy-3-R-nonyl)adenine. alpha-D-Adenosine also inhibited ADA2, as did several halogenated purine and adenine base analogs. Structural requirements for the binding of purine analogs to ADA2 are presented which provide a general basis for the design of specific inhibitors of ADA2. Such inhibitors may be useful in studies designed to provide an understanding of the physiological role of ADA2 both in the normal state and in diseases such as human immunodeficiency virus-1 infection where levels in plasma are increased markedly.
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PMID:Structure-activity relationship of ligands of human plasma adenosine deaminase2. 204 51

Inherited deficiency of the purine salvage enzyme adenosine deaminase (ADA) is responsible for approximately half the cases of autosomal recessive Severe Combined Immunodeficiency (SCID). Deficiency of ADA can also result in a much later-onset, milder immunodeficiency, while lesser degrees of enzyme deficiency can result in either late-onset immunodeficiency or grossly normal immunologic function. The full clinical spectrum of ADA deficiency is currently being more fully defined. Florid pathology is primarily restricted to the immune system and appears to result from accumulation of substrates (adenosine and deoxyadenosine) and metabolites (deoxy ATP). Studies indicate that these metabolites may preferentially accumulate in lymphoid cells and can interfere with lymphoid proliferation and function. There is evidence for several mechanisms, including induction of chromosome breaks, inhibition of ribonucleotide reductase needed for normal DNA synthesis, and inactivation of SAH hydrolase needed for normal methylation reactions. The enzyme is a 40 Kd monomer that is ubiquitous, and diagnosis can be made with many cell types including erythrocytes, lymphocytes and fibroblasts. Prenatal diagnosis has been made with chorionic villous samples, amniotic cells and fetal blood. The gene for ADA resides on the long arm of human chromosome 20, and both the expressed and structural gene have been isolated and characterized. Most patients with ADA SCID have single base pair mutations resulting in amino acid substitutions, although a splicing mutation and a deletion have been described. The treatment of choice is currently bone-marrow transplantation from a histocompatible related donor, if available. Haploidentical transplants have also been successful but appear to have higher failure rates in ADA deficients than in other types of SCID. Enzyme replacement, now using an enzyme modified to increase the half-life and decrease immunogenicity, has been reported as successful but longer-term efficacy remains to be evaluated. The disorder, despite its rarity, is for several reasons considered a prime candidate for gene therapy. Recently success has been obtained in introducing the gene into lymphoid stem cells and achieving long-term expression.
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PMID:Adenosine deaminase deficiency. 207 32

Severe combined immunodeficiency (SCID) due to deficiency of the purine metabolic enzyme adenosine deaminase (ADA) is a fatal childhood immunodeficiency disease. Immune reconstitution by transplantation with HLA-identical bone marrow is the treatment of choice. For patients not candidates for bone marrow transplantation, we propose to attempt immune reconstitution by using infusions of autologous T lymphocytes expanded in tissue culture and genetically corrected by insertion of a normal ADA gene using retroviral-mediated gene transfer. The vector is LASN, in which the human ADA gene is promoted by the LTR while the NeoR gene is driven by the SV40 early gene promoter. The packaging line is PA317. The protocol is designed to have two parts. In Part 1, autologous gene-corrected T lymphocytes would be infused repeatedly in low numbers in order to build an immune repertoire of T cells and also to obtain information as to how long gene corrected T cells survive in vivo. In Part 2A, the gene-corrected T cells would be selected in G418 and/or 2'deoxyadenosine and reinfused into the patient at monthly intervals for approximately 6 months. The goals would be essentially the same as in Part 1. In Part 2B, the number of gene-corrected T cells would be escalated in half-log increments to the predicted therapeutic level (probably around 1 x 10(9)/kg). 1-3 x 10(9)/kg gene-corrected cells would be infused several times and the patients would be monitored in order to determine if significant clinical improvement has occurred.
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PMID:The ADA human gene therapy clinical protocol. 208 Nov 98

Deficiency of the purine metabolic enzyme adenosine deaminase causes severe immunodeficiency. Retroviruses have been reported to decrease the activity of adenosine deaminase, and many retroviruses, including feline leukemia virus, cause immunodeficiency. Levels of purine metabolic enzymes including adenosine deaminase and consequences of adenosine deaminase inhibition were investigated in feline leukemia virus-infected fresh tumor cells and infected and uninfected cell lines. No evidence of virus effect on levels of adenosine deaminase or other purine metabolic enzymes was detected. Neoplastic cells demonstrated considerable heterogeneity of activity levels of purine metabolic enzymes.
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PMID:Purine metabolism in feline lymphomas. 216 Nov 36

Four 2-amino-6-halo- and four 6-halo-2',3'-dideoxypurine ribofuranosides (ddPs) were synthesized and tested for in vitro activity to suppress the infectivity, cytopathic effect, Gag protein expression, and DNA synthesis of human immunodeficiency virus (HIV). The comparative order of in vitro anti-HIV activity of the eight 6-halo-ddPs was as follows: 2-amino-6-fluoro, 2-amino-6-chloro, 6-fluoro greater than 2-amino-6-bromo greater than 2-amino-6-iodo, 6-chloro greater than 6-bromo greater than 6-iodo. 2-Amino-6-fluoro-, 2-amino-6-chloro-, and 6-fluoro-ddPs showed a potent activity against HIV comparable to that of 2',3'-dideoxyinosine (ddI) or 2',3'-dideoxyguanosine (ddG) and completely blocked the infectivity of HIV without affecting the growth of target cells. The lipophilicity order was as follows: 2-amino-6-iodo greater than 2-amino-6-bromo greater than 2-amino-6-chloro greater than 2-amino-6-fluoro much greater than ddG greater than ddI. All eight 6-halo-ddPs were substrates for adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4). The relative rates of hydrolysis by ADA were as follows: ddA, 2-amino-6-fluoro much greater than 2-amino-6-chloro, 2-amino-6-bromo greater than 2-amino-6-iodo. Taken together, these compounds may represent an additional class of lipophilic prodrugs for ddI and ddG and may also provide a strategy for endowing therapeutic purine nucleosides with desirable lipophilicity.
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PMID:Lipophilic halogenated congeners of 2',3'-dideoxypurine nucleosides active against human immunodeficiency virus in vitro. 225 Dec 84

Deoxyadenosine (dAdo) has been recognized as the toxic metabolite in the immunodeficiency disease associated with adenosine deaminase (ADA) deficiency. Under ADA deficient conditions, dAdo accumulates intracellularly as deoxyadenosine triphosphate (dATP) which by interference with ribonucleotide reductase, prevents DNA synthesis. Recently, we and others have demonstrated that in cells rendered ADA deficient by treatment with deoxycoformycin, dAdo affects T-cell activation events which precede DNA synthesis, such as interleukin 2 receptor (IL-2R) expression and IL-2 production. Here we have analyzed interference of dAdo with the early events of T-cell activation. It is shown that dAdo affects the mitogen induced phosphatidyl inositol turnover. Furthermore dAdo interferes with increase of intracellular calcium. Deoxycytidine, although capable of preventing intracellular accumulation of dATP, cannot reverse the functional consequences of dAdo treatment. The ability of a cell to increase its cytoplasmic free Ca2+, as induced by ionomycin, is not affected by dAdo. The exact target for this novel effect of dAdo is at the present unknown.
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PMID:Interference of deoxyadenosine with transmembrane signaling events in human T lymphocytes. 230 14

(+-) Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine (Carbovir; NSC 614846) is an antiretroviral agent which is undergoing preclinical evaluation for the treatment of AIDS. Racemic carbovir was separated into its D and L enantiomers by the action of adenosine deaminase on the 2,6-diaminopurine precursor. Subsequent evaluation of the enantiomers against human immunodeficiency virus type 1 revealed that the antiviral activity of carbovir resides in the (-) isomer that is analogous to the nucleoside, beta-D-2',3'-didehydro-2',3'-dideoxyguanosine.
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PMID:Resolution of racemic carbovir and selective inhibition of human immunodeficiency virus by the (-) enantiomer. 234 92

A number of 2',3'-dideoxynucleosides have been shown to inhibit the in vitro infectivity and cytopathic effect of the human immunodeficiency virus (HIV). These compounds, as their 5'-triphosphates, inhibit viral reverse transcriptase by competing with the natural substrate at the same binding site on the enzyme. Dideoxynucleoside triphosphates can also be incorporated into growing DNA chains which then blocks further DNA elongation because they lack the 3'-hydroxyl group required for further polymerization. Among these nucleosides, 2', 3'-dideoxyadenosine 2',3'-dideoxyadenosine (ddA) and 2',3'-dideoxyinosine (ddI) show promising in vitro activity. Because adenosine is rapidly converted to inosine by adenosine deaminase, the in vivo conversion of ddA to ddI was studied to determine suitability of measuring plasma levels of ddI and to assess the bioavailability and pharmacokinetics of ddA. This report describes and compares the pharmacokinetics of ddA and ddI in the mouse.
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PMID:Comparative pharmacokinetics of new anti-HIV agents: 2',3'-dideoxyadenosine and 2',3'-dideoxyinosine. 249 44


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