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 sequence-specific recognition of double-helical DNA by oligodeoxyribonucleotide-directed triple-helix formation is limited mostly to purine tracts. Within the geometric constraints of the phosphate-deoxyribose position of a purine-purine-pyrimidine triple-helical structure, model building studies suggested that the deoxyribonucleoside 2'-deoxynebularine (dN) might form one specific hydrogen bond with cytosine (C) or adenine (A) of Watson-Crick cytosine-guanine (CG) or adenine-thymine (AT) base pairs. 2-Deoxynebularine (dN) was incorporated by automated methods into purine-rich oligodeoxyribonucleotides. From affinity cleavage analysis, the stabilities of base triplets within a purine.purine.pyrimidine (Pu.Pu.Py) triple helix were found to decrease in the order N.CG approximately N.AT >> N.GC approximately N.TA (pH 7.4, 37 degrees C). Oligodeoxyribonucleotides containing two N residues were shown to bind specifically within plasmid DNA a single 15 base pair site of the human immunodeficiency virus genome containing two CG base pairs within a purine tract. This binding event occurs under physiologically relevant pH and temperature (pH 7.4, 37 degrees C) and demonstrates the utility of the new base. Quantitative affinity cleavage titration reveals that, in the particular sequence studied, an N.CG base triplet interaction results in a stabilization of the local triple-helical structure by 1 kcal.mol-1 (10 mM NaCl, 1 mM spermine tetrahydrochloride, 50 mM Tris-acetate, pH 7.4, 4 degrees C) compared to an A.CG base triplet mismatch.
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PMID:Specific recognition of CG base pairs by 2-deoxynebularine within the purine.purine.pyrimidine triple-helix motif. 844 59

A series of phosphonoalkenyl and (phosphonoalkenyl)oxy derivatives of purines and a pyrimidine were synthesized. These compounds are the first reported acyclonucleotides which incorporate the alpha,beta-unsaturated phosphonic acid moiety as the phosphate mimic and include compounds in which the acyclic substituent is attached to N-9 of a purine or N-1 of a pyrimidine by either a nitrogen-carbon or a nitrogen-oxygen bond. The phosphonoalkenyl-substituted compounds 7a-c, 8a-c, 9, 10, and 12 were prepared either by Mitsunobu coupling of alcohols with purine or pyrimidine derivatives or by alternative alkylations of the heterocyclic bases. The (phosphonoalkenyl) oxy derivatives 7d-g, 8d-g, and 11 were synthesized by coupling of alcohols with 9-hydroxypurines or a 1-hydroxypyrimidine under Mitsunobu conditions. The novel acyclonucleotides were tested for activity against herpes simplex types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), visna virus, and human immunodeficiency virus type 1 (HIV-1). Guanine derivatives were moderately to extremely cytotoxic, but the adenines were less toxic to cells. At the concentrations tested, (Z)-isomers in the unbranched series had no activity against herpes viruses or HIV-1. (E)-9-[(4-Phosphonobut-3-enyl) oxy]adenine (7d) displayed selective activity against HIV-1, (E)-2,6-diamino-9-(4-phosphonobut-3-enyl) purine (9) showed selective antiretrovirus activity, and (E)-9-[2-(hydroxymethyl)-4-phosphonobut-3-enyl]adenine (7c) showed selective antiherpesvirus (VZV and CMV) activity.
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PMID:Novel acyclonucleotides: synthesis and antiviral activity of alkenylphosphonic acid derivatives of purines and a pyrimidine. 849 3

Proliferative defects have been reported at the level of DNA synthesis, even in T-lymphocytes from asymptomatic human immunodeficiency virus type-1+ (HIV-1+) patients. Since purine and pyrimidine ribonucleotide availability is crucial for proliferation, we compared the ability of HIV-1- and HIV-1+ T-lymphocytes (> 95% CD4+ and CD8+) to activate de novo biosynthetic and salvage pathways following phytohemagglutinin stimulation using 14C-labeled precursors. The striking abnormality already detectable in asymptomatic patients' cells was the impaired ability of CTP, UDP-Glc, and UTP pools to expand over 72 h (44-70% of control), although ATP and GTP pools and responses were normal. In symptomatic patients, resting T-cells showed markedly reduced pyrimidine pools (53-74% of control) with no change following activation. Relatively normal ATP, GTP, and NAD pools masked the same impaired response of de novo synthesis to activation, with ATP and GTP being reduced by 50% at 48 h. Purine salvage was more active than the control in unstimulated HIV-1+ cells. This impaired de novo synthesis in HIV-1+ T-lymphocytes severely restricts the availability of ribonucleotides for vital growth-related activities such as membrane expansion and strand break repair as well as DNA and RNA synthesis. The data indicate that resting T-lymphocytes from symptomatic patients survive through enhanced salvage, but the stimulation induces metabolic cell death, and provide an explanation for the activation-associated lymphocyte death seen in HIV-1+ T-lymphocytes.
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PMID:T-lymphocytes from AIDS patients are unable to synthesize ribonucleotides de novo in response to mitogenic stimulation. Impaired pyrimidine responses are already evident at early stages of HIV-1 infection. 853 Mar 57

9-(2-Phosphonylmethoxyethyl)adenine (PMEA), the acyclic phosphonate analog of adenine monophosphate, is a promising antiviral drug with activity against herpesviruses, Epstein-Barr virus, and retroviruses, including the human immunodeficiency virus. In order to be active, it must be converted to the diphosphate derivative, the putative inhibitor of viral DNA polymerases. The metabolic pathway responsible for activation of PMEA is unclear. The metabolism of PMEA was investigated in human T-lymphoid cells (CEMss) and a PMEA-resistant subline (CEMss(r-1)) with a partial deficiency in adenylate kinase activity. Experiments with [3H]PMEA showed that extracts of CEMss phosphorylated PMEA to its mono- and diphosphate in the presence of ATP as the phosphate donor. No other nucleotides or 5-phosphoribosyl pyrophosphate displayed appreciable activity as a phosphate donor. Subcellular fractionation experiments showed that CEMss cells contained two nucleotide kinase activities, one in mitochondria and one in the cytosol, which phosphorylated PMEA. The PMEA-resistant CEMss mutant proved to have a deficiency in the mitochondrial adenylate kinase activity, indicating that this enzyme was important in the phosphorylation of PMEA. Other effective antiviral purine phosphonate derivatives of PMEA showed a profile of phosphorylating activity similar to that of PMEA. By comparison, phosphorylation of the pyrimidine analog (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl) cytosine proceeded by an enzyme present in the cytosol. We conclude from these studies that adenylate kinase which has been localized in the intermembrane space of mitochondria is the major route for PMEA phosphorylation in CEMss cells but that another hitherto unidentified enzyme(s) present in the cytosol may contribute to the anabolism of the phosphonates.
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PMID:Metabolic pathways for activation of the antiviral agent 9-(2-phosphonylmethoxyethyl)adenine in human lymphoid cells. 861 86

Maintenance immunosuppressive drugs act by partially blocking rate-limiting steps in the immune response. The new maintenance immunosuppressive drugs are either inhibitors of de novo synthesis of nucleotides (purines or pyrimidines), or are immunophilin-binding drugs that inhibit signal transduction in lymphocytes. The new inhibitors of de novo nucleotide synthesis include mycophenolate mofetil (MMF), mizoribine (MZ), brequinar (BQR), and leflunomide (LEF). MMF and MZ act to inhibit de novo purine synthesis, by inhibition of inosine monophosphate dehydrogenase (IMPDH). They create a selective immunodeficiency in T and B lymphocytes. MMF is hydrolyzed to mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH. MPA reduces the pools of guanine nucleotides, and increases some adenine nucleotides, inhibiting the cell cycle. Thus the number of specific effector T and B lymphocytes is reduced by limiting clonal expansion. MZ is a competitive inhibitor of IMPDH, which creates a similar defect. The relative clinical effectiveness of MMF versus MZ is not known. MMF has been approved in a number of countries; MZ has been approved in Japan. The inhibitors of de novo pyrimidine synthesis (BQR, LEF) act on the enzyme dehydroorotate dehydrogenase. Neither is currently in clinical trials in transplantation. The new immunophilin-binding drugs inhibit either the calcium-dependent phosphatase calcineurin (CN) [tacrolimus (or FK-506) and the microemulsion form of cyclosporine (CsA)] or signaling from growth factor receptors [rapamycin (sirolimus)]. Tacrolimus binds to FK binding protein-12 (FKBP-12) to create a complex that inhibits CN. CsA binds to cyclophilin to create a complex that inhibits CN. Inhibition of CN prevents activation of cytokine genes in T cells. The relative clinic effectiveness of tacrolimus versus microemulsion CsA is unknown. Rapamycin inhibits signaling from growth factor receptors, such as IL-2R. Rapamycin binds to FKBP to create a complex that engages proteins called TOR (target of rapamycin), or RAFT (rapamycin and FKBP target), which may be kinases. The result is a block in the ability of cytokine receptors to activate cell cycling, interfering with clonal expression. Deoxyspergualin, a parenteral drug in development for induction or antirejection therapy, may inhibit intracellular chaperoning by Hsc70, a member of the heat shock protein family. It may have its principal effect by inhibiting the activation of transcription factor NF-kappa B in antigen-presenting cells and monocytes.
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PMID:Molecular mechanisms of new immunosuppressants. 868 47

In Xenopus and other vertebrates, ribosomal protein mRNAs share a common sequence in the 5' untranslated region (5' UTR), in particular a pyrimidine tract at the 5' end, which has been demonstrated to be involved in the translational regulation of this class of mRNAs. In previous studies, carried out in the Xenopus system, we demonstrated the specific binding of two proteins (57 kDa and 47 kDa) to the pyrimidine tract of the mRNAs for three different ribosomal proteins. Here, we show that the two binding proteins are in fact one; one being the cleavage product of the other. By immunoprecipitation and protein purification, this binding protein has been identified as the Xenopus homologue of the human La autoantigen, an RNA-binding protein previously reported to be implicated in RNA polymerase III transcription termination and in translation initiation of poliovirus and immunodeficiency virus type 1 RNAs. We show that the specific interaction of La with the 5' pyrimidine tract of ribosomal protein mRNA is mediated by a protease-sensitive factor, which, after assisting La-RNA binding, dissociates from the complex and becomes again available to promote further binding. We show that mutations in the 5' UTR pyrimidine tract, known to disrupt the translational control of ribosomal protein mRNA, severely impair La binding. Although a direct relationship between ribosomal protein mRNA translation and La binding is not yet available, the properties of the interaction suggest that La protein, possibly together with other components, might be involved in translational regulation.
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PMID:A Xenopus laevis homologue of the La autoantigen binds the pyrimidine tract of the 5' UTR of ribosomal protein mRNAs in vitro: implication of a protein factor in complex formation. 868 93

The anti-human immunodeficiency virus (anti-HIV) agent 2',3'-didehydro-3'-deoxythymidine (D4T), like other 2',3'-dideoxynucleosides, requires conversion to its 5'-triphosphate to exert its pharmacological effect. Although D4T-triphosphate is unusually potent as an inhibitor of HIV-1 reverse transcriptase, the phosphorylation of the drug at low dose levels is inefficient because of its low affinity as an alternate substrate for the initial phosphorylation enzyme thymidine kinase. Because thymidine kinase is under feedback regulatory control by the physiological deoxynucleoside-5'-triphosphate dTTP, we examined the effect on D4T phosphorylation and thus, potentially, on its antiviral activity, of a variety of agents that lower intracellular dTTP pools. We found that agents that inhibit the de novo pyrimidine biosynthetic pathway have the ability to increase D4T phosphorylation, the most effective being two inhibitors of thymidylate formation, methotrexate and 5-fluoro-2'-deoxyuridine, compounds that block the enzymes dihydrofolate reductase and thymidylate synthetase, respectively. Because HIV itself lacks the capacity to synthesize dTTP and the other deoxynucleoside triphosphates essential for viral replication, combinations of D4T with modulatory agents that deplete host-cell dTTP, unlike conventional anti-HIV drug monotherapy directed solely at viral enzymes, have the ability to inhibit replication of mutant HIV strains as well as of wild-type virus.
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PMID:2',3'-Didehydro-3'-deoxythymidine: regulation of its metabolic activation by modulators of thymidine-5'-triphosphate biosynthesis. 870 Jan 8

This paper presents the first attempt to evaluate the potential of clinical UV exposures to induce the human immunodeficiency (HIV) promoter and, thus, to upregulate HIV growth in those skin cells that are directly affected by the exposure. Using the data for HIV promoter activation in vitro, we computed UVB and psoralen plus UVA (PUVA) doses that produce 50% of the maximal promoter activation (AD50). Then, using (a) literature data for UV transmittance in the human skin, (b) a composite action spectrum for HIV promoter and pyrimidine dimer induction by UVB and (c) an action spectrum for DNA synthesis inhibition by PUVA, we estimated the distribution of medical UVB and PUVA doses in the skin. This allowed us to estimate how deep into the skin the HIV-activating doses might penetrate in an initial and an advanced stage of UVB or PUVA therapy. Such analysis was done for normal type II skin and for single exposures. The results allow us to predict where in the skin the HIV promoter may be induced by selected small and large therapeutic UVB or PUVA doses. To accommodate changes in skin topography due to disease and UV therapy, our considerations would require further refinements. For UVB we found that, when the incident dose on the surface of the skin is 500 J/m2 (290-320 nm) (initial stage of the therapy), the dose producing 50% of the maximal HIV promoter activation (ADUVB50) is limited to the stratum corneum. However, with an incident dose of 5000 J/m2 (an advanced stage of the therapy), ADUVB50) may be delivered as far as the living cells of the epidermis and even to some parts of the upper dermis. For PUVA we found that, when the incident UVA doses are 25 or 100 kJ/m2 (320-400 nm) (an initial and an advanced stage of therapy, respectively), and the 8-methoxypsoralen concentration in the blood is 0.1 microgram/mL (the desired level), the combined doses to the mid epidermis (and some areas of the upper dermis) are well below the 50% HIV promoter-activating PUVA dose (ADPUVA50). Only under the worst scenario conditions, i.e. an exceptionally high drug concentration in the patient's tissues and localization of HIV in the nearest proximity to the skin surface, would the combined PUVA dose expected during photochemotherapy exceed ADPUVA50. These results suggest that the probability of HIV activation in the epidermis by direct mechanisms is higher for UVB than for PUVA treatment. However, complexities of the UV-inducible HIV activation and immunomodulatory phenomena are such that our results by themselves should not be taken as an indication that UVB therapy carries a higher risk than PUVA therapy when administered to HIV-infected patients.
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PMID:Medical UV exposures and HIV activation. 876 May 63

A series of purine and pyrimidine N-(2-(phosphonomethoxy)ethyl) derivatives bearing aminomethyl, (dimethylamino)methyl, morpholinomethyl, and (trimethylammonio)methyl groups at the 2'-position were synthesized. The compounds were prepared by alkylation of the heterocyclic bases with appropriately substituted (aminoalkyl)oxiranes followed by condensation of the resulting intermediates with dialkyl ((p-tolylsulfonyl)oxy)methanephosphonate and subsequent treatment of the obtained diester with bromotrimethylsilane. 9-(3-Amino-2-(phosphonomethoxy)propyl)adenine (2a) proved active against varicella zoster virus (VZV), cytomegalovirus (CMV), and Moloney murine sarcoma virus (MSV) in the concentration range of 7-35 micrograms/mL. None of the other aminoalkyl derivatives demonstrated significant antiviral activity against herpes simplex virus type 1 and 2 (HSV-1 and HSV-2), VZV, (CMV), vaccinia virus (VV), MSV, and human immunodeficiency virus type 1 and 2 (HIV-1 and HIV-2).
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PMID:Synthesis of 2'-aminomethyl derivatives of N-(2-(phosphonomethoxy)ethyl) nucleotide analogues as potential antiviral agents. 876 9

The extension of mismatched 3'-termini of DNA was implicated as a major determinant that contributes to the low fidelity of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). However, HIV-1 RT exhibits variations in its comparative efficiency to extend different 3'-mismatched base pairs that can result either from the differences in the binding capacity of the enzyme to various mispaired DNAs or from differences in the rate of extension of mispairs by a DNA-bound enzyme. In the current study we have examined the interaction of HIV-1 RT with mispaired template-primer 3'-termini, using a gel retardation assay. HIV-1 RT was found to bind mismatched template-primers with purine-pyrimidine (i.e., A . C) and purine-purine (i.e., A . A and A . G) 3'-terminal mispairs to about the same extent. Hence, HIV-1 RT can be considered (in addition to its other basic features) as a 3'-mismatched DNA binding protein. The stability of the complexes formed between HIV-1 RT and the mismatched template-primers tested seems to be unaffected significantly by neighboring sequences and by the presence of the next complementary dNTP. Thus, the dissimilarities observed previously in extension frequencies in the extension of 3'-terminal mismatches are likely to be due to an inherent property of the HIV-1 RT. The fact that HIV-1 RT binds 3'-mismatch-containing template-primers suggests that unextended mismatched DNA can undergo a rebinding process followed by a 3'-mismatch extension, contributing to further understanding of the low fidelity characteristic of HIV-1 RT. It is possible, therefore, that the interaction of the RT with the DNA may constitute an additional suitable target for the development of specific anti-HIV-1 RT drugs.
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PMID:The interaction of the reverse transcriptase of human immunodeficiency virus type 1 with 3'-terminally mispaired DNA. 883 43


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