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)

L-nucleoside analogs represent an important class of small molecules for treating both viral infections and cancers. These pro-drugs achieve pharmacological activity only after enzyme-catalyzed conversion to their tri-phosphorylated forms. Herein, we report the crystal structures of human deoxycytidine kinase (dCK) in complex with the L-nucleosides (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC)--an approved anti-human immunodeficiency virus (HIV) agent--and troxacitabine (TRO)--an experimental anti-neoplastic agent. The first step in activating these agents is catalyzed by dCK. Our studies reveal how dCK, which normally catalyzes phosphorylation of the natural D-nucleosides, can efficiently phosphorylate substrates with non-physiologic chirality. The capability of dCK to phosphorylate both D- and L-nucleosides and nucleoside analogs derives from structural properties of both the enzyme and the substrates themselves. First, the nucleoside-binding site tolerates substrates with different chiral configurations by maintaining virtually all of the protein-ligand interactions responsible for productive substrate positioning. Second, the pseudo-symmetry of nucleosides and nucleoside analogs in combination with their conformational flexibility allows the L- and D-enantiomeric forms to adopt similar shapes when bound to the enzyme. This is the first analysis of the structural basis for activation of L-nucleoside analogs, providing further impetus for discovery and clinical development of new agents in this molecular class.
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PMID:Structural basis for activation of the therapeutic L-nucleoside analogs 3TC and troxacitabine by human deoxycytidine kinase. 1715 55

Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Apricitabine is phosphorylated to its active triphosphate by deoxycytidine kinase, which is also responsible for the intracellular phosphorylation of lamivudine (3TC) and emtricitabine (FTC); hence, in vitro studies were performed to investigate possible interactions between apricitabine and these agents. Human peripheral blood mononuclear cells (PBMC) were incubated for 24 h with various concentrations of (3)H-labeled or unlabeled apricitabine, 3TC, or FTC. Intracellular concentrations of parent compounds and their phosphorylated derivatives were measured by high-performance liquid chromatography. In other experiments, viral reverse transcriptase activity was measured in PBMC infected with HIV-1 bearing M184V in the presence of various concentrations of apricitabine and 3TC. [(3)H]apricitabine and [(3)H]3TC were metabolized intracellularly to form mono-, di-, and triphosphates. 3TC and FTC (1 to 10 microM) produced concentration-dependent decreases in apricitabine phosphorylation; in contrast, apricitabine at concentrations of up to 30 muM had no effect on the phosphorylation of 3TC or FTC. The combination of apricitabine and 3TC reduced the antiviral activity of apricitabine against HIV-1: apricitabine concentrations producing 50% inhibition of viral reverse transcriptase were increased two- to fivefold in the presence of 3TC. These findings suggest that nucleoside reverse transcriptase inhibitors with similar modes of action may show biochemical interactions that affect their antiviral efficacy. It is therefore essential that potential interactions between combinations of new and existing agents be thoroughly investigated before such combinations are introduced into clinical practice.
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PMID:In vitro interactions between apricitabine and other deoxycytidine analogues. 1751 47

The nucleoside analog 2',3'-dideoxycytidine (ddC) has been used for treatment of human immunodeficiency virus (HIV) infections. ddC causes delayed toxicity when cells are exposed to the drug at low concentration for prolonged periods of time. The delayed toxicity is due to inhibition of mitochondrial DNA (mtDNA) replication, which results in mtDNA depletion and mitochondrial dysfunction. In the present study we have cultured CEM T-lymphoblast cells in the presence of low concentrations of ddC to generate two cell lines resistant to the delayed toxicity of the drug. Both cell lines were resistant to mtDNA depletion by ddC. The mechanism of ddC resistance was investigated and we showed that the resistant cells had decreased mRNA expression of the nucleoside kinases deoxycytidine kinase and thymidine kinase 2. We also studied the mitochondrial DNA in the cells and showed that the ddC-resistant cells had structurally intact mtDNA but 1.5-2-fold increased mtDNA copy-number as well as increased levels of the mitochondrial transcription factor A (Tfam). Our study suggests that cells may increase their level of mtDNA to counteract mtDNA depletion induced by ddC, while keeping pronounced antiviral activity of the drug.
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PMID:Increased mitochondrial DNA copy-number in CEM cells resistant to delayed toxicity of 2',3'-dideoxycytidine. 1820 54

One of the formidable challenges in therapy of infections by human immunodeficiency virus (HIV) is the emergence of drug-resistant variants that attenuate the efficacy of highly active antiretroviral therapy (HAART). We have recently introduced 4'-ethynyl-nucleoside analogs as nucleoside reverse transcriptase inhibitors (NRTIs) that could be developed as therapeutics for treatment of HIV infections. In this study, we present 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine (EFdA), a second generation 4'-ethynyl inhibitor that exerted highly potent activity against wild-type HIV-1 (EC50 approximately 0.07 nM). EFdA retains potency toward many HIV-1 resistant strains, including the multi-drug resistant clone HIV-1A62V/V75I/F77L/F116Y/Q151M. The selectivity index of EFdA (cytotoxicity/inhibitory activity) is more favorable than all approved NRTIs used in HIV therapy. Furthermore, EFdA efficiently inhibited clinical isolates from patients heavily treated with multiple anti-HIV-1 drugs. EFdA appears to be primarily phosphorylated by the cellular 2'-deoxycytidine kinase (dCK) because: (a) the antiviral activity of EFdA was reduced by the addition of dC, which competes nucleosides phosphorylated by the dCK pathway, (b) the antiviral activity of EFdA was significantly reduced in dCK-deficient HT-1080/Ara-Cr cells, but restored after dCK transduction. Further, unlike other dA analogs, EFdA is completely resistant to degradation by adenosine deaminase. Moderate decrease in susceptibility to EFdA is conferred by a combination of three RT mutations (I142V, T165R, and M184V) that result in a significant decrease of viral fitness. Molecular modeling analysis suggests that the M184V/I substitutions may reduce anti-HIV activity of EFdA through steric hindrance between its 4'-ethynyl moiety and the V/I184 beta-branched side chains. The present data suggest that EFdA, is a promising candidate for developing as a therapeutic agent for the treatment of individuals harboring multi-drug resistant HIV variants.
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PMID:2'-deoxy-4'-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variants. 1848 70

Mutations in the gene encoding adenosine deaminase (ADA), a purine salvage enzyme, lead to immunodeficiency in humans. Although ADA deficiency has been analyzed in cell culture and murine models, information is lacking concerning its impact on the development of human thymocytes. We have used chimeric human/mouse fetal thymic organ culture to study ADA-deficient human thymocyte development in an "in vivo-like" environment where toxic metabolites accumulate in situ. Inhibition of ADA during human thymocyte development resulted in a severe reduction in cellular expansion as well as impaired differentiation, largely affecting mature thymocyte populations. Thymocyte differentiation was not blocked at a discrete stage; rather, the paucity of mature thymocytes was due to the induction of apoptosis as evidenced by activation of caspases and was accompanied by the accumulation of intracellular dATP. Inhibition of adenosine kinase and deoxycytidine kinase prevented the accumulation of dATP and restored thymocyte differentiation and proliferation. Our work reveals that multiple deoxynucleoside kinases are involved in the phosphorylation of deoxyadenosine when ADA is absent, and suggests an alternate therapeutic strategy for treatment of ADA-deficient patients.
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PMID:Restoration of adenosine deaminase-deficient human thymocyte development in vitro by inhibition of deoxynucleoside kinases. 1901 8

Optically active structural isomers (1b-f and dst-1b-f) of 3',4'-di-(O)-(-)-camphanoyl-(+)-khellactone (DCK) were synthesized and their anti-human immunodeficiency virus (HIV) activity was investigated. The value of the sensitivity index (SI) of 1b was greater than that of DCK.
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PMID:Synthesis and anti-human immunodeficiency virus activity of the skeleton isomers of 3',4'-Di-(O)-(-)-camphanoyl-(+)-khellactone. 2180 60


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