Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP) is a potent inhibitor of the replication of human immunodeficiency virus (HIV) in human T-lymphocyte MT-4 cells (50% effective dose: 2 microM). PMEDAP strongly inhibited Moloney murine sarcoma virus (MSV)-induced transformation of murine C3H/3T3 embryo fibroblasts and caused a dose-dependent suppression of tumor formation and mortality in newborn mice inoculated with MSV. Even at a dose as low as 0.25 mg/kg/day, PMEDAP effected a significant delay in tumor appearance and an enhancement of the survival rate of tumor-bearing mice. PMEDAP proved fivefold more efficacious as an anti-MSV agent than 9-(2-phosphonylmethoxyethyl)-adenine (PMEA), which has been previously shown to exhibit strong antiretroviral efficacy in vivo. However, PMEDAP was also more toxic, so that its therapeutic index was equivalent to that of PMEA.
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PMID:9-(2-Phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP): a novel agent with anti-human immunodeficiency virus activity in vitro and potent anti-Moloney murine sarcoma virus activity in vivo. 255 45

Several steps in the replicative cycle of human immunodeficiency virus (HIV) could be envisaged as targets for anti-AIDS drugs. The anionic compound PMEA [9-(2-phosphonyl-methoxyethyl)adenine], the 2'3'-dideoxynucleoside analogues D4T (2',3-deidehydro-2',3'-dideoxythymidine), AzddUrd 3'-azido-2',3'-dideoxyuridine), FddUrd (3'-fluoro-2',3-dideoxyuridine), AzddDAPR (3'-azido-2',3'-dideoxy-2,6' diaminopurine riboside) and the sulfated polysaccharides dextran sulfate and pentosan polysulfate are among the most promising candidate anit-AIDS drugs which have been recently described. They are targeted at either virus-cell binding (dextran sulfate, pentosan polysulfate) or virus-associated reverse transcriptase (PMEA, D4T, AzddUrd, FddUrd, AzddDAPR).
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PMID:Perspectives for the chemotherapy of AIDS. 290 40

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of the replication of human immunodeficiency virus (HIV) in vitro in human T-lymphocyte MT-4, H9, and ATH8 cells. PMEA also inhibits Moloney murine sarcoma virus (Mo-MSV)-induced transformation of murine C3H embryo fibroblasts. Moreover, PMEA causes a dose-dependent suppression of tumor formation and associated mortality in mice inoculated with Mo-MSV. At a dose of 50 or 20 mg/kg per day PMEA effected a 90-100% protection of the mice against Mo-MSV-induced tumor formation and mortality. Even with a PMEA dose as low as 1 to 5 mg/kg per day, tumor formation was significantly delayed and the survival rate was significantly enhanced. In parallel experiments, azidothymidine exhibited a comparable inhibitory effect on Mo-MSV-induced tumor formation and associated death only at a 25-fold higher dose than PMEA. Because PMEA has stronger in vivo antiretrovirus potency and selectivity than azidothymidine and various other compounds currently being subjected to clinical trials, PMEA studies should be pursued to assess the potential of this compound in the treatment of acquired immunodeficiency syndrome (AIDS) and other retrovirus infections in humans.
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PMID:Marked in vivo antiretrovirus activity of 9-(2-phosphonylmethoxyethyl)adenine, a selective anti-human immunodeficiency virus agent. 291 79

Various 3-hydroxy-2-phosphonylmethoxypropyl (HPMP) and 2-phosphonylmethoxyethyl (PME) derivatives of purine [adenine (A), guanine (G), 2,6-diaminopurine (DAP), 2-monoaminopurine (MAP), hypoxanthine (HX)] and pyrimidine [cytosine (C), uracil (U), thymine (T)] have been evaluated for their antiviral properties. PMEDAP, (S)-HPMPA [and the cyclic phosphonate thereof, (S)-cHPMPA)], (S)-HPMPC, PMEG, PMEA, HPMPG and HPMPDAP proved to be effective inhibitors of herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2). (S)-HPMPA and (S)-cHPMPA were the most effective inhibitors of varicella-zoster virus (VZV), and (S)-HPMPC was the most effective inhibitor of cytomegalovirus (CMV). Against adenovirus (types 2, 3 and 4) and vaccinia virus again (S)-HPMPA and (S)-cHPMPA showed the greatest inhibitory activity. As a rule, the PME derivates were much less inhibitory to VZV, CMV, vaccinia and adenovirus than the HPMP derivatives. However, PMEA, PMEDAP and PMEMAP showed marked and selective activity against the human immunodeficiency virus (HIV). (S)-HPMPA was selected for further evaluation in animal model infections. It proved efficacious in the topical treatment of HSV-1 keratitis in rabbits and cutaneous HSV-1 infection in hairless mice, and in the systemic treatment of both HSV-1 and vaccinia virus infections in mice.
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PMID:Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. 345 98

Cloned variants of human immunodeficiency virus type 1 that contain the K65R mutation in reverse transcriptase have previously been shown to display approximately 10- to 30-fold resistance against 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and 2',3'-dideoxy-3'-thiacytidine. On the basis of tissue culture studies with both primary T cells and established cell lines, we now report that the K65R mutation confers approximately 12- to 15-fold resistance to 9-(2-phosphonylmethoxyethyl)adenine (PMEA). Likewise, a chain termination system revealed that mutated recombinant K65R reverse transcriptase displays resistance to PMEA diphosphate, the active metabolite of PMEA, in cell-free enzyme assays. Parallel studies have shown that the M184V mutation in reverse transcriptase, associated with high-level resistance against the (-) enantiomer of 2',3'-dideoxy-3'-thiacytidine, does not confer resistance to PMEA in tissue culture. Viruses and enzymes that included both the K65R and M184V mutations were resistant to PMEA and PMEa diphosphate, respectively, but only to the extent conferred by the K65R mutation alone.
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PMID:K65R mutation of human immunodeficiency virus type 1 reverse transcriptase encodes cross-resistance to 9-(2-phosphonylmethoxyethyl)adenine. 748 42

Long-tailed macaques chronically infected with simian immunodeficiency virus (SIV) were treated for 4 or 8 weeks with daily subcutaneous doses of the antiretroviral compound 9-(2-phosphonylmethoxyethyl)adenine (PMEA). The efficacy of PMEA was evaluated by monitoring cell-free virus in plasma, virus titer and viral DNA in peripheral blood mononuclear cells, and absolute numbers of lymphocyte subsets. In mock-treated control macaques, virus titers changed minimally. However, in treated macaques, PMEA exhibited impressive effects, leading to the disappearance of virus in the blood within the first week of treatment and lasting through the fourth week of treatment. The results indicate that PMEA can effectively reduce SIV in chronically infected macaques and offer an optimistic perspective for therapeutic intervention against human immunodeficiency virus infection.
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PMID:Efficacy of 9-(2-phosphonylmethoxyethyl)adenine treatment against chronic simian immunodeficiency virus infection in macaques. 753 51

The antiviral efficacy of acyclic nucleoside phosphonates, including 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and (R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine [(R)-PMPDAP] against feline immunodeficiency virus (FIV) infection was determined. (R)-PMPDAP showed the highest selectivity index (> 2,000) in vitro. Treatment of experimentally FIV-infected asymptomatic cats with PMEA or (R)-PMPDAP had no effect on the CD4+/CD8+ ratio. However, mean plasma viral RNA concentrations decreased significantly in the (R)-PMPDAP-treated cats. Our data show that, in comparison to PMEA, (R)-PMPDAP is a more potent and less toxic inhibitor of FIV replication both in vitro and in vivo.
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PMID:(R)-9-(2-phosphonylmethoxypropyl)-2,6-diaminopurine is a potent inhibitor of feline immunodeficiency virus infection. 779 84

PMEA (9-(2-phosphonylmethoxyethyl)adenine) is a potent inhibitor of DNA viruses and retroviruses able to enhance natural immune functions such as natural killer cell activity and interferon production. The results reported in this paper show that the treatment with PMEA significatively decreased the mortality of mice challenged with influenza A/PR8 virus (an RNA virus, non sensitive to the antiviral effect of PMEA) compared to untreated, infected controls (median survival 8.64 days and 7.61 days, respectively), and reduced lung weight and consolidation (two surrogate markers of virus infection). Furthermore, virus titer obtained from lung homogenates was substantially decreased in PMEA-treated mice compared to controls. Finally, enhancement of natural killer cell activity was achieved in PMEA-treated A/PR8-infected mice compared to A/PR8-infected controls. Overall, results suggest that PMEA decreases the influenza virus-related mortality and morbidity through the enhancement of some immune functions, and that this effect might be additive or even synergystic with the direct inhibitory effect of DNA viruses or retroviruses induced by PMEA itself. This supports the importance of evaluating this drug in patients with diseases related to herpesviruses or to human immunodeficiency virus.
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PMID:9-(2-Phosphonylmethoxyethyl) adenine increases the survival of influenza virus-infected mice by an enhancement of the immune system. 784 79

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a new antiviral agent with activity against herpes viruses and retroviruses, including human immunodeficiency virus, but its metabolism and mechanism of action remain unclear. We have isolated a human T lymphoid cell line (CEMr-1) that is resistant to the antiproliferative effects of PMEA. The antiviral effects of PMEA against human immunodeficiency virus-1 infection were also greatly reduced in CEMr-1 cells, compared with the parental cells. This mutant showed cross-resistance to the related acyclic nucleoside phosphonates 9-(2-phosphonylmethoxyethyl)diaminopurine and 9-(2-phosphonylmethoxyethyl)guanine and the lipophilic prodrug bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine-( bispome-PMEA), as well as partial resistance to the purine nucleosides 2-chlorodeoxyadenosine, 2-fluro-9-beta-D-arabinosylfuranosyladenine, and adenosine, but did not show resistance to 2'-deoxyadenosine or 9-beta-D-arabinosylfuranosyladenine. We compared the uptake and metabolism of [3H]PMEA and [3H]-bispom-PMEA in the mutant and parental cells. The analysis of radioactive products by high pressure liquid chromatography revealed marked alterations in the ability of the mutant cell line to accumulate PMEA and its anabolites, compared with the parental cells. Accumulation of PMEA, PMEA monophosphate, and PMEA bisphosphate (major metabolites formed with either PMEA or bispom-PMEA) decreased by 50, 95, and 97%, respectively. Compared with the parental cells, the variant cells showed a approximately 7-fold increase in the rate of efflux of PMEA and a 2-fold decrease in the activity of adenylate kinase. In contrast, other enzymes of nucleotide metabolism, such as adenosine kinase, deoxycytidine kinase, and 5-phosphoribosyl-1-pyrophosphate synthetase, showed no significant change in the two cell lines. Overall, these results suggest that the mutation in this resistant cell line is of a novel type, involving an alteration in the cellular efflux of PMEA as the major basis for the resistant phenotype.
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PMID:A human T lymphoid cell variant resistant to the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine shows a unique combination of a phosphorylation defect and increased efflux of the agent. 787 49

The antiretroviral drugs azidothymidine (AZT) and 9-(-2-phosphonyl-methoxyethyl)adenine (PMEA) were individually tested for prevention of simian immunodeficiency virus (SIVmne) infection in macaques (Macaca fascicularis). Macaques were pretreated with either drug before inoculation with SIVmne, and drug treatment was continued for four weeks. The virus, antibody, and clinical status of the macaques was monitored for up to 36 weeks following inoculation. While AZT prophylaxis resulted in reduced virus load in some macaques, PMEA prophylaxis was highly efficacious in preventing acute SIVmne infection.
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PMID:Comparison of the efficacy of AZT and PMEA treatment against acute SIVmne infection in macaques. 796 33


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