Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.7 (DNA polymerase)
 17,007 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our recent efforts have been directed at the development of selective inhibitors of different classes of viruses, including adeno, pox, and herpesviruses [herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2), varicella-zoster (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV)], (+/-)RNA viruses (reo- and rotavirus), (-)RNA viruses (influenza, parainfluenza, measles, respiratory syncytial, vesicular stomatitis and rabies virus) and retroviruses [i.e. human immunodeficiency virus (HIV), the causative agent of AIDS]. In this search, the following molecular targets were envisaged: for DNA viruses in general, the viral DNA polymerase; for herpes simplex virus and varicella-zoster virus, the viral DNA polymerase via a specific phosphorylation by the viral 2'-deoxythymidine (dThd) kinase; for (+/-)RNA and (-)RNA viruses, S-adenosylhomocysteine (SAH) hydrolase, a key enzyme in transmethylation reactions required for the maturation of viral mRNA; for retroviruses, reverse transcriptase as initiator of virus replication and/or cell transformation; and for several enveloped viruses (i.e. retro-, herpes- and rhabdoviruses), virus adsorption to the outer cell membrane. Several new compounds have been developed that appear to act at these targets: i.e. (E)-5-(2-bromovinyl)-2'-deoxyuridine [bromovinyldeoxyuridine (BVDU)] and derivatives thereof [i.e. carbocyclic BVDU (C-BVDU)] as well as derivatives of acyclovir (i.e. 8-substituted acyclovir derivatives) as inhibitors of herpesviruses; (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and other phosphonylmethoxyalkylpurines and -pyrimidines as inhibitors of DNA viruses and retroviruses; acyclic and carbocyclic analogues of adenosine [such as (S)-9-(2,3-dihydroxypropyl)adenine [S)-DHPA), carbocyclic 3-deazaadenosine (C-c3Ado), (RS)-3-adenin-9-yl-2-hydroxypropanoic acid (AHPA) alkyl esters, neplanocin A, 3-deazaneplanocin A and the 5'-nor derivatives of neplanocin A and 3-deazaneplanocin A] as inhibitors of (+/-)RNA and (-)RNA viruses; 2',3'-dideoxynucleoside analogues as inhibitors of retroviruses; and sulfated polysaccharides (i.e. heparin, dextran sulfate, pentosan polysulfate, mannan sulfate), sulfated polyvinylalcohol and co-polymers of sulfated polyvinylalcohol with acrylic acid as inhibitors of retro-, herpes- and rhabdoviruses.
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PMID:Selective virus inhibitors. 169 49

Several N-(S)-(3-hydroxy-2-phosphonylmethoxypropyl) (HPMP) and N-(2-phosphonylmethoxyethyl) (PME) derivatives of purine bases (adenine, guanine, 2-aminoadenine, 3-deazaadenine) and cytosine inhibit the growth of various DNA viruses. PME-derivatives (PMEA, PMEG and PMEDAP) are also active against retroviruses. Both types of nucleotide analogues undergo phosphorylation by cellular nucleotide kinases to their mono- and diphosphates. The phosphorylation with crude extracts of L-1210 cells is potentiated by an ATP-regenerating system. HPMPA is phosphorylated faster than PMEA with or without the ATP-regenerating system. The HPMP and PME analogues inhibit several virus-encoded target enzymes and their cellular counterparts: (1) HSV-1 DNA polymerase is inhibited by the diphosphates of the PME series; the virus-encoded enzyme is more sensitive than HeLa DNA pol alpha and beta. PMEApp terminates the growing DNA chain; it specifically replaces dATP. HPMPApp also acts as an alternative substrate of dATP, but, in contrast with PMEApp, it permits limited chain growth. (2) Diphosphates of both series inhibit HSV-1 ribonucleotide reductase; the greatest inhibition of CDP reduction to dCDP is exhibited by HPMPApp and PMEApp. The enzyme isolated from a PMEA-resistant HSV-1 mutant proved less sensitive to PMEApp, hydroxyurea and HPMPApp. (3) Diphosphates of PME derivatives efficiently inhibit AMV(MAV) reverse transcriptase. (4) The purine HPMP and PME analogues and, even more so, their monophosphate derivatives inhibit purine nucleoside phosphorylase from L-1210 cells.
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PMID:Acyclic nucleotide analogues: synthesis, antiviral activity and inhibitory effects on some cellular and virus-encoded enzymes in vitro. 169 93

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a potent and selective inhibitor of retrovirus (i.e., human immunodeficiency virus) replication in vitro and in vivo. Uptake of PMEA by human MT-4 cells and subsequent conversion to the mono- and diphosphorylated metabolites (PMEAp and PMEApp) are dose-dependent and occur proportionally with the initial extracellular PMEA concentrations. Adenylate kinase is unable to phosphorylate PMEA. However, 5-phosphoribosyl-1-pyrophosphate synthetase directly converts PMEA to PMEApp with a Km of 1.47 mM and a Vmax that is 150-fold lower than the Vmax for AMP. ATPase, 5'-phosphodiesterase, and nucleoside diphosphate kinase are able to dephosphorylate PMEApp to PMEAp, albeit to a much lower extent than the dephosphorylation of ATP. PMEApp has a relatively long intracellular half-life (16-18 hr) and has a much higher affinity for the human immunodeficiency virus-specified reverse transcriptase than for the cellular DNA polymerase alpha (Ki/Km: 0.01 and 0.60, respectively). PMEApp is at least as potent an inhibitor of human immunodeficiency virus reverse transcriptase as 2',3'-dideoxyadenosine 5'-triphosphate. Being an alternative substrate to dATP, PMEApp acts as a potent DNA chain terminator, and this may explain its anti-retrovirus activity.
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PMID:Intracellular metabolism and mechanism of anti-retrovirus action of 9-(2-phosphonylmethoxyethyl)adenine, a potent anti-human immunodeficiency virus compound. 170 39

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

The acyclic nucleoside phosphonate analogues (HPMPA, HPMPC, PMEA, FPMPA) show great promise for the treatment of infections with such important human pathogens as adeno, pox (vaccinia) and hepadna (hepatitis B) viruses (HPMPA), herpes (herpes simplex, varicella-zoster, cytomegalo, Epstein-Barr) viruses (HPMPC), and retro (human immunodeficiency) viruses (PMEA, FPMPA). All these compounds seem to be targeted at the viral DNA polymerase, with which they interact, as either competitive inhibitors or alternative substrates (or chain terminators), following their intracellular phosphorylation to the diphosphoryl derivatives. Of particular interest is the prolonged anti-viral action, lasting for several days or even weeks, that has been noted both in vitro and in vivo after a single administration of the acyclic nucleoside phosphonates.
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PMID:Chemotherapy of the acquired immune deficiency syndrome (AIDS): acyclic nucleoside phosphonate analogues. 182 10

9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a new antiviral compound with activity against herpes simplex virus (HSV) and retroviruses including human immunodeficiency virus. Although it has been suggested that the anti-HSV action of PMEA is through inhibition of the viral DNA polymerase via the diphosphorylated metabolite of PMEA (PMEApp), no conclusive evidence for this has been presented. We report that in cross-resistance studies, a PMEA-resistant HSV variant (PMEAr-1) was resistant to phosphonoformic acid, a compound which directly inhibits the HSV DNA polymerase. In addition, phosphonoformic acid-resistant HSV variants with defined drug resistance mutations within the HSV DNA polymerase gene were resistant to PMEA. Furthermore, the HSV DNA polymerase purified from PMEAr-1 was resistant to PMEApp in comparison with the enzyme from the parental virus. Moreover, PMEA inhibited HSV DNA synthesis in cell culture. These results provide strong evidence that HSV DNA polymerase is the major target for the anti-viral action of PMEA. Further studies showed that HSV DNA polymerase incorporated PMEApp into DNA in vitro, while the HSV polymerase-associated 3'-5' exonuclease was able to remove the incorporated PMEA. Thus, the inhibition of HSV DNA polymerase by PMEApp appears to involve chain termination after its incorporation into DNA.
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PMID:Herpes simplex virus-specified DNA polymerase is the target for the antiviral action of 9-(2-phosphonylmethoxyethyl)adenine. 184 64

Foremost among the acyclic nucleoside phosphonates currently pursued for their potential in the treatment of herpes and retrovirus infections are (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA). These compounds are as such taken up by the cells and then phosphorylated by cellular enzymes to their diphosphoryl derivatives HPMPCpp and PMEApp. The main target for the antiviral action of HPMPCpp and PMEApp is the viral DNA polymerase. Whereas PMEApp has been shown to interact as a DNA chain terminator with both retro- and herpes viruses, the mechanism by which HPMPCpp inhibits herpes viral DNA synthesis remains the subject of further study.
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PMID:Mechanism of action of acyclic nucleoside phosphonates against herpes virus replication. 831 44

9-(2-phosphonylmethoxyethyl)-2,6-diaminopurine (PMEDAP), a potent inhibitor of human immunodeficiency virus (HIV) replication, was evaluated for its activity against human cytomegalovirus (HCMV) in vitro, and murine cytomegalovirus (MCMV) and rat CMV (RCMV) in vivo. PMEDAP strongly inhibited HCMV-induced cytopathicity in human embryonic lung (HEL) cell cultures (EC50 11 microM) and caused a concentration-dependent suppression of viral DNA synthesis (IC50 20 microM) [corrected]. PMEDAP had no effect on the expression of HCMV-specific immediate early antigens (IEA) as measured on day 1 post-infection, but inhibited the expression of HCMV late antigens as measured on day 6 post-infection (EC50 20 microM) [corrected]. The diphosphate derivative of PMEDAP (PMEDAPpp) selectively inhibited HCMV-induced DNA polymerase (IC50 0.1 microM). PMEDAP proved markedly effective in reducing the mortality rate of NMRI mice that had been infected intraperitoneally or intracerebrally with a lethal dose of MCMV. PMEDAP exhibited greater anti-MCMV activity when administered as a single dose immediately after infection than when this dose was divided over repeated administrations. 9-(2-phosphonylmethoxyethyl)-adenine (PMEA) also prevented MCMV-induced mortality, but only at a dose ten-fold higher than that of PMEDAP. PMEDAP also delayed death in severe combined immune deficiency (SCID) mice that had been infected with MCMV. The effect of PMEDAP on RCMV infections in rats was less pronounced.
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PMID:Activity of the anti-HIV agent 9-(2-phosphonyl-methoxyethyl)-2,6-diaminopurine against cytomegalovirus in vitro and in vivo. 839 82

The efficacy of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) against the replication of human immunodeficiency virus (HIV) and herpes simplex virus type 1 (HSV-1) and its cellular metabolism were investigated in human primary macrophages from seronegative donors. PMEA potently inhibited the replication of both HIV and HSV-1 in macrophages, with similar EC50 values (0.025 and 0.032 microM, respectively), whereas the EC50 values of PMEA in lymphocytic C8166 cells and fibroblastoid Vero cells were 150-200-fold higher (3.5 and 7.9 microM, respectively). Granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor, two cytokine enhancers of the replication of HIV (and HSV-1), decreased the activity of PMEA against both viruses, yet EC50 values were still lower than in lymphocytes and fibroblasts. Thus, the selectivity index of PMEA in macrophages was > 2 orders of magnitude higher than that in lymphocytes and fibroblasts and still > 1 log higher under conditions of enhancement of virus replication in macrophages. The intracellular levels of 2'-deoxyadenosine-5'-triphosphate, the natural competitor of PMEA-diphosphate at the level of viral DNA polymerase (either RNA or DNA dependent), were 5-12-fold lower in macrophages than in other cells. Furthermore, intracellular concentrations of PMEA-diphosphate (the active metabolite of PMEA) were unusually much higher in macrophages (with or without cytokines) than in lymphocytes and fibroblasts. Consequently, the ratio of PMEA-diphosphate to 2'-deoxyadenosine-5'-triphosphate in monocytes/macrophages was approximately 2 orders of magnitude higher in macrophages than in the other cells and correlated closely with the pronounced antiviral potency of PMEA. The dual potent activity of PMEA against HIV and HSV-1 stresses the importance of clinical trials to assess the role of this drug in the therapy of HIV-related disease.
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PMID:Potent inhibition of human immunodeficiency virus and herpes simplex virus type 1 by 9-(2-phosphonylmethoxyethyl)adenine in primary macrophages is determined by drug metabolism, nucleotide pools, and cytokines. 870 Jan 44

Acyclovir is an effective drug for the treatment of HSV and VZV infections, which after phosphorylation to the triphosphate, inhibits viral DNA polymerase. Acyclovir has low oral bioavailability, therefore prodrugs have been developed, and the L-valyl ester, valaciclovir, recently has been licensed for the treatment of shingles. Ganciclovir is used against CMV, and famciclovir, a lipophilic prodrug of penciclovir, is marketed for shingles. The acyclic nucleoside phosphonates are active against thymidine kinase-resistant viral strains. Promising analogs are PMEA (in clinical trial for the treatment of AIDS) and (S)-HPMPC (good in vivo activity against HSV, VZV, CMV, and EBV). Oligonucleotides incorporating acyclic nucleosides at the 3'-and 5'-ends, or constituted of amino acyclic nucleosides, are resistant to cleavage by nucleases and may be useful in antisense and/or antigene therapy. HEPT is active against HIV-1: It binds in a hydrophic pocket on reverse transcriptase, rather than in the polymerase active site. Some acyclic nucleosides are potent inhibitors of purine and pyrimidine nucleoside phosphorylase. These compounds may have a therapeutic niche in combination therapy with antiviral and anticancer nucleosides, and in the treatment of diseases involving the T-cell.
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PMID:Acyclic nucleosides as antiviral compounds. 873 25


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