Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

9-(2-Phosphonylmethoxyethyl)adenine (PMEA; 1) was acylated with chloromethyl pivalate to afford bis(pivaloyloxymethyl) PMEA (2). The ester prodrug demonstrated enhanced in vitro potency against HSV-2 greater than 150-fold higher than the parent compound. The antiviral activity of 2 was 50-fold better than PMEA against HSV-1, and equipotent against HIV and HCMV. The toxicity of 2 was studied in both resting and growing cells.
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PMID:Synthesis and in vitro evaluation of a phosphonate prodrug: bis(pivaloyloxymethyl) 9-(2-phosphonylmethoxyethyl)adenine. 133 6

HIV inhibitors targeted at the virus-associated reverse transcriptase (RT) can be divided into two groups, depending on whether they are targeted at the substrate or nonsubstrate binding site. To the first group belong the 2',3'-dideoxynucleosides (i.e., DDC, DDI), 3'-azido-2',3'-dideoxynucleosides (i.e., AZT), 3'-fluoro-2',3'-dideoxynucleosides (i.e., FLT), 2',3'-didehydro-2',3'-dideoxynucleosides (i.e., D4C, D4T) and carbocyclic derivatives thereof (i.e., carbovir), 2'-fluoro-ara-2',3'-dideoxynucleosides, 1,3-dioxolane derivatives (i.e., 2',3'-dideoxyl-3'-thiacytidine), oxetanocin analogues and carbocyclic derivatives thereof (i.e., cyclobut-G) and the 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and 9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) derivatives. These compounds need to be phosphorylated intracellularly to their triphosphate forms before they act as competitive inhibitors or alternate substrates (chain terminators) of HIV RT. The second group includes the tetrahydro-imidazo[4,5,l-jk][1,4]-benzodiazepin-2(1H)one (TIBO), 1-[(2-hydroxyethoxy)-methyl]-6-(phenylthio)thymine (HEPT), dipyrido[3,2-b:2',3'-e]-[1,4]diazepin-6-one (nevirapine) and pyridin-2(1H)one derivatives, which interact as such, noncompetitively, with a specific allosteric binding site of HIV-1 RT. Compounds belonging to the two different groups may give rise to synergism which combined, and, likewise, viral resistance to the compounds may arise through different mutations, depending on the nature of the compounds and the group to which they belong.
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PMID:HIV inhibitors targeted at the reverse transcriptase. 137 90

These last years, numerous molecules have been developed to face HIV-1 infection. All viral replication steps are potential targets for new molecules. The most potent inhibitors of virus-cell adsorption are represented by the different sulfated, sulfonated and carboxylated polymers among which aurintricarboxylic acid (ATA). The soluble CD4 are also potent inhibitors of viral adsorption in vitro. Many compounds are active at the level of the reverse transcriptase (RT), particularly the 2',3'-dideoxynucleosides, represented by the three currently most used drugs in the clinic, AZT, ddC and ddI. The acyclic nucleoside phosphonates (PMEA, PMEDAP) have shown a broad spectrum activity against many human and animal retroviruses, and also unique pharmacological properties allowing infrequent administration. Finally, most recently, highly potent activity, without toxicity, has been demonstrated by TIBO, HEPT and other HIV-1 RT-specific inhibitors.
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PMID:[Current acquisitions in antiviral drugs (anti-HIV)]. 138 88

Various new classes of compounds have been recently identified as potent and selective inhibitors of acute HIV infection in vitro. As a rule, these compounds inhibit HIV replication at a concentration of 0.1-1 micrograms/ml, while not being toxic to the host cells at concentrations up to 500 micrograms/ml or higher. Some of the compounds even inhibit HIV replication at a concentration of a few nanograms per ml, thus achieving selectivity indexes up to 100,000, which makes them particularly promising drug candidates for the chemotherapy and -prophylaxis of HIV infections in vitro. These new candidate drugs for the treatment of AIDS fall into the following categories: (i) polyanions (polysulfates, polysulfonates, polycarboxylates and polyoxometalates), which interfere with virus attachment to the cell membrane; (ii) some plant lectins and modified (i.e. succinylated) albumins, which may directly interact with the fusion of the viral envelope with the cell membrane; (iii) bicyclam derivatives, which seem to be targeted at the uncoating (disassembly of the viral proteins from the viral RNA genome); and (iv) reverse transcriptase (RT) inhibitors which fall into two subcategories. The phosphonylmethoxyalkyl derivatives PMEA and FPMPA interact, as chain terminators, with the RT substrate binding site, as do azidothymidine (AZT) and the other dideoxynucleoside analogues. The TIBO derivatives and their congeners interact with a non-substrate binding site at the HIV-1 RT, and thus behave as allosteric inhibitors of the enzyme. The TIBO congeners have proved to be highly specific inhibitors of HIV-1 replication.
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PMID:New perspectives for the chemotherapy and chemoprophylaxis of AIDS (acquired immune deficiency syndrome). 163 22

The antiviral mechanism of action and intracellular metabolism of 2',3'-dideoxycytidine (ddCyd), 3'-azido-2',3'-dideoxythymidine (AZT) and 2',3'-didehydro-2',3'-dideoxythymidine (D4T) has been investigated. Marked differences in the affinity of these anti-HIV compounds for their activating (phosphorylating) enzymes, and the eventual intracellular levels of their active 5'-triphosphate metabolites were discovered. Moreover, new approaches were developed to manipulate the metabolism of these products in such a way that combination of ddCyd with thymidine, and 2',3'-dideoxynosine with ribavirin resulted in an enhanced antiretroviral effect of the test compounds in vitro and/or in vivo. Several metabolic and kinetic properties of AZT and D4T proved highly relevant to perform or modify the treatment modalities of AIDS patients with these chemotherapeutics. A novel class of acyclic purine nucleotide phosphonate derivatives endowed with potent and selective anti-HIV activity has been developed. The prototype compound is 9-(2-phosphonylmethoxyethyl)adenine (PMEA). PMEA proved to have a potent antiretroviral activity in a number of retrovirus models in vivo. Furthermore, a unique administration schedule of PMEA in retrovirus infections has been proposed, in which the antiretroviral properties of PMEA are clearly superior and distinguished from those of other chemotherapeutics such as AZT. The metabolic and kinetic properties of PMEA and its phosphorylated metabolites have been investigated. Our data provide a better and profound insight in the antiretroviral activity and the molecular and biochemical bases for the mechanism or action of the drug.
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PMID:[Anti-retroviral activity and molecular-biochemical action mechanism of 2',3'-dideoxynucleoside analogs and 9-(2-phosphonylmethoxyethyl) purine derivatives]. 164 85

A new class of compounds, 9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] [(RS)-FPMP] derivatives of purines, is described that has selective activity against a broad spectrum of retroviruses [including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2)] but not other RNA or DNA viruses. This activity spectrum is completely different from that of the parental compounds, 9-[(2S)-3-hydroxy-2-phosphonylmethoxypropyl] [(S)-HPMP] derivatives of purines, which are active against a broad range of DNA viruses. The racemic (RS)-FPMP derivatives of adenine and 2,6-diaminopurine, termed (RS)-FPMPA and (RS)-FPMPDAP, respectively, are markedly more selective as in vitro antiretroviral agents than their 9-(2-phosphonylmethoxyethyl) (PME) counterparts, PMEA and PMEDAP. Also, (RS)-FPMPA and (RS)-FPMPDAP have a substantially higher therapeutic index in mice in inhibiting Moloney murine sarcoma virus-induced tumor formation and associated death and are markedly less inhibitory to human bone marrow cells than PMEA and PMEDAP. The diphosphate derivative of (RS)-FPMPA [(RS)-FPMPApp] is a potent and selective inhibitor of HIV-1 reverse transcriptase but not of HSV-1 DNA polymerase or DNA polymerase alpha. (RS)-FPMPApp, akin to PMEA diphosphate (PMEApp), acts as a DNA chain terminator. The DNA chain-terminating properties of PMEApp and (RS)-FPMPApp seem to be a prerequisite for acyclic nucleoside phosphonates to exhibit antiretrovirus (i.e., anti-HIV) activity.
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PMID:9-[(2RS)-3-fluoro-2-phosphonylmethoxypropyl] derivatives of purines: a class of highly selective antiretroviral agents in vitro and in vivo. 171 Dec 14

In order to evaluate the influence of antiviral nucleoside analogues upon the natural immune system, we investigated the immunomodulatory activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a nucleotide analogue with potent anti-HIV and anti-herpes activity, in a murine system. C57BL/6 mice were inoculated intraperitoneally with 10, 25 and 50 mg PMEA/kg. Mononuclear cells were isolated from their spleens, and some natural immune functions were evaluated. The results show that PMEA significantly increases the levels of natural killer (NK)-cell cytotoxicity. We also found that alpha/beta IFN production was substantially increased in PMEA-treated mice, while both IL-1 and IL-2 production was decreased. Thus, PMEA can increase some natural immunity functions, such as NK activity and IFN production. These results suggest that PMEA might be active in vivo against HIV and herpes viruses both as an immunomodulator and as an antiviral compound.
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PMID:Immunomodulatory activity of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), a potent anti-HIV nucleotide analogue, on in vivo murine models. 172 64

Phosphonylmethoxyalkylpurines and -pyrimidines offer great promise for both topical and systemic treatment of various DNA virus and retrovirus infections: HPMPA for the treatment of adeno-, herpes- and poxvirus infections, HPMPC for the treatment of herpesvirus (in particular CMV) infections, and PMEA and PMEDAP for the treatment of retrovirus (i.e. HIV) infections. The efficacy of HPMPA, HPMPC, PMEA and PMEDAP has been demonstrated in various animal model infections, and the further pursuit of their clinical potential seems fully justified. The target for the antiviral action of these compounds appears to be viral DNA synthesis, which they inhibit at a concentration which is far below the concentration required to inhibit cellular DNA synthesis.
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PMID:Therapeutic potential of phosphonylmethoxyalkylpurines and -pyrimidines as antiviral agents. 196 99

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of the in vitro replication of a number of retroviruses, including HIV-1 and HIV-2, simian immunodeficiency virus (SIV), simian AIDS-related virus (SRV), feline immunodeficiency virus (FIV) and Moloney murine sarcoma virus (MSV). PMEA causes a dose-dependent suppression of the induction of anti-SIVmacgp120 antibodies in SIV mac-infected rhesus monkeys. Complete suppression of anti-SIVmacgp120 antibodies was achieved in SIV-infected animals treated with PMEA at 2 x 10 or 2 x 5 mg/kg per day for 29 days. No toxic side-effects were noted during this treatment period. Antibodies against SIVmac gp120 appeared 1-2 weeks after PMEA treatment was stopped, but the antibody titre reached in these animals was significantly lower than in the SIVmac-infected animals who had not been treated with PMEA. Our data strongly suggest that PMEA should be pursued for its potential in the treatment of AIDS and other retrovirus infections.
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PMID:9-(2-Phosphonylmethoxyethyl)adenine (PMEA) effectively inhibits retrovirus replication in vitro and simian immunodeficiency virus infection in rhesus monkeys. 205 58

A number of acyclic nucleoside phosphonate analogues, including 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and its 2,6-diaminopurine derivative PMEDAP, (R,S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine [(R,S)-FPMPA] and its 2,6-diaminopurine derivative (R,S)-FPMPDAP were evaluated for their inhibitory effects on HIV-1 replication in two natural human cell systems, i.e. peripheral blood lymphocytes (PBL) and freshly prepared monocyte/macrophages (M/M). All compounds were potent inhibitors of HIV-1 replication in PBL [50% effective concentration (EC50): 0.94-3.9 microM] and M/M (EC50: 0.022-0.95 microM). In particular, (R,S)-FPMPA and (R,S)-FPMPDAP showed a greater antiviral selectivity than PMEA and PMEDAP due to the virtual lack of toxicity of the former compounds in these cell systems. Also, the antiviral selectivity of the acyclic nucleoside phosphonate analogues was much higher in M/M than in the human T-cell lines MT-4, ATH8 and CEM.
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PMID:Activity of acyclic nucleoside phosphonate analogues against human immunodeficiency virus in monocyte/macrophages and peripheral blood lymphocytes. 206 72


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