Trisodium Phosphonoformate, a New Antiviral Compound

Helgstrand, Erik; Eriksson, Barbro; Johansson, NG; Lannero, B; Larsson, Anna‐Karin; Misiorny, Alfons; Noren, JO; Sjöberg, Berndt; Stenberg, K; Stening, G.; Stridh, S.; Öberg, Bo

doi:10.1126/science.210500

Cited by 220 publications

(103 citation statements)

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“…Eukaryotic DNA polymerase  is crucially involved in chromosome maintenance, DNA repair and recombination, transcriptional silencing, checkpoint activation, and telomere length maintenance [76]. Mammalian DNA polymerase  is potently inhibited by foscarnet [74,75]. Therefore, the low-affinity half-transamination of AMPA by AGT, the ratelimiting step leading to foscarnet, could negatively influence human chromosome maintenance, DNA damage repair, and telomere length preservation, mediated by the AMPA catabolite foscarnet inhibition of DNA polymerase .…”

Section: Discussionmentioning

confidence: 99%

“…Phosphonoformaldehyde, seen as an glyoxylate analogue, could be oxidized by glycolate oxidase (GO) and lactate dehydrogenase (LDH) [73]. Foscarnet is a potent inhibitor of eukaryotic DNA polymerase  [74,75], an enzyme crucially involved in maintaining chromosomal integrity and telomere length. [58] and Kuhn & Kuhn [59] [pK′a,HG = apparent acid dissociation constant (25 °C) of haploid H. sapiens genome B-DNA double helix; pKa,R-OH = 1.29 = theoretical pKa (25 °C) [86] of one isolated internucleotide phosphodiester (R-OH) proton; s = 1 = number of statistical subunits on thread molecule [59]; j = 6 = number of spacing atoms (at least distance) in one dsDNA repeating unit [59]; b = 0.334 × 10 -7 cm (0.334 ± 0.01 nm [87]) = length rise in cm of one B- [103,104], creating an apurinic site [103][104][105].…”

Section: Discussionmentioning

confidence: 99%

“…This latter result is of interest, since the product of the half-transamination of AMPA by AGT is phosphonoformaldehyde which can be oxidized (peroxisomal glycolate oxidase, cytoplasmic lactate dehydrogenase [73]) to phosphonoformic acid (phosphonoformate, forscarnet) ( Figure 11B). Foscarnet represents a well-known inhibitor of mammalian [74,75] and viral [74,75] DNA-dependent DNA polymerases. Eukaryotic DNA polymerase  is crucially involved in chromosome maintenance, DNA repair and recombination, transcriptional silencing, checkpoint activation, and telomere length maintenance [76].…”

Section: Discussionmentioning

confidence: 99%

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The Spermine Phosphate-Bound Cyclooctaoxygen Sodium Epigenetic Shell of Euchromatin DNA Is Destroyed by the Epigenetic Poison Glyphosate

Kesel¹,

Struys²,

Cellini³

2017

Preprint

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Oxygen exists in two gaseous and six solid allotropic modifications. An additional allotropic modification of oxygen, the cyclooctaoxygen, was predicted to exist in 1990. The first synthesis and characterization of cyclooctaoxygen as its sodium crown complex, isolated in the form of three cytosine nucleoside hydrochloride complexes, was reported in 2016. Cyclooctaoxygen sodium was synthesized from atmospheric oxygen, or catalase effect-generated oxygen, under catalysis of cytosine nucleosides and either ninhydrin or eukaryotic low-molecular weight RNA. The cationic cyclooctaoxygen sodium complex was shown to bind RNA and DNA, to associate with single-stranded DNA and spermine phosphate, and to be essentially non-toxic to cultured mammalian cells at 0.1-1.0 mM concentration. We postulated that cyclooctaoxygen is formed in most eukaryotic cells from dihydrogen peroxide in a catalase reaction catalysed by cytidine and RNA. A molecular biological model was deduced for a first epigenetic shell of eukaryotic euchromatin. This model incorporates an epigenetic explanation for the interactions of the essential micronutrient selenium (as selenite) with eukaryotic euchromatin. The sperminium phosphate/cyclooctaoxygen sodium complex is calculated to cover the actively transcribed regions (2.6%) of bovine lymphocyte interphase genome. Cyclooctaoxygen seems to be naturally absent in hypoxia-induced highly condensed chromatin, taken as a model for eukaryotic metaphase/anaphase/early telophase mitotic chromatin. We hence propose that the cyclooctaoxygen sodium-bridged spermine phosphate and selenite coverage serves as an epigenetic shell of actively transcribed gene regions in eukaryotic 'open' euchromatin DNA. The total herbicide glyphosate (ROUNDUP) and its metabolite (aminomethyl)phosphonic acid (AMPA) are proved to represent 'epigenetic poisons', since they both selectively destroy the cyclooctaoxygen sodium complex. This definition is of reason, since the destruction of cyclooctaoxygen is sufficient to bring the protection shield of human euchromatin into collateral epigenetic collapse.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The Spermine Phosphate-Bound Cyclooctaoxygen Sodium Epigenetic Shell of Euchromatin DNA Is Destroyed by the Epigenetic Poison Glyphosate

Kesel¹,

Struys²,

Cellini³

2017

Preprint

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“…The replication of this virus can be inhibited by a number of DNA synthesis inhibitors including cytosine arabinoside, bromodeoxyuridine and hydroxyurea (Kelly & Lescott, 1976. In this paper, we report the sensitivity of T. ni MNPV to other inhibitors of DNA virus replication, such as phosphonoformate, phosphonoacetate, 9-(2-hydroxyethoxymethyl)guanine (Acyclovir), and [E]-5-(2-bromovinyl)-2'-deoxyuridine (bromovinyldeoxyuridine; BVdU) (Mao et al, 1975;De Clercq et al, 1979;Helgstand et al, 1978 ;Schaeffer et al, 1978). All four drugs act by inhibiting virus-specified DNA polymerase, although both Acyclovir and BVdU must first be phosphorylated to their triphosphates by the successive action of virus-induced deoxythymidine (deoxycytidine) kinase or cellular kinases before they can interact with DNA polymerase.…”

Section: Introductionmentioning

confidence: 99%

Baculovirus Replication: Inhibition of Trichoplusia ni Multiple Nuclear Polyhedrosis Virus by [E]-5-(2-Bromovinyl)-2'-deoxyuridine

Wang

Lescott

Clercq

et al. 1983

Journal of General Virology

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SUMMARY[E]-5-(2-bromovinyl)-2'-deoxyuridine (BVdU) inhibits the replication of the baculovirus Trichoplusia ni multiple nucleocapsid nuclear polyhedrosis virus in Spodoptera frugiperda cells. Virus-specific DNA synthesis and late protein synthesis are suppressed by the drug. BVdU is phosphorylated by deoxythymidine (deoxycytidine) kinase present in both uninfected and virus-infected cells, and in its 5'-triphosphate form it inhibits DNA polymerase activity in virus-infected cells. The effect of the BVdU is not completely reversible. Phosphonoacetic acid, phosphonoformic acid and Acyclovir have no effect on baculovirus replication. Acyclovir fails to compete with deoxycytidine and thymidine as substrates for pyrimidine deoxynucleoside kinase in virus-infected and uninfected cells.

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“…The antiviral drug foscarnet (trisodium phosphonoformate) inhibits herpesvirus DNA polymerase activity [9,10] and was shown to suppress replication of both laboratory strains and clinical isolates ofCMV in vitro [11][12][13]. Clinical studies among transplant recipients and patients with AIDS who received foscarnet treatment for severe CMV disease have shown therapeutic effects and indicate that renal dysfunction is the main adverse experience associated with foscarnet, whereas neutrophil counts do not appear to be substantially affected [14].…”

mentioning

confidence: 99%

Phase I-II Trial of Foscarnet for Prevention of Cytomegalovirus Infection in Autologous and Allogeneic Marrow Transplant Recipients

Reusser

Gambertoglio

Lilleby

et al. 1992

Journal of Infectious Diseases

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The safety and efficacy of foscarnet for prevention of cytomegalovirus (CMV) infection was evaluated in 19 CMV-seropositive bone marrow transplant (BMT) recipients. All patients received intermittent intravenous (iv) foscarnet: 40 mg/kg every 8 h from 7 days before to day 30 after BMT, then 60 mg/kg once a day until day 75. The main toxicity was transient renal dysfunction, with a >50 pmol/L increase in serum creatinine above baseline in 5 of the 7 autograft recipients and in 6 of the 12 allograft recipients. Only 4 allograft recipients developed CMV infection during foscarnet prophylaxis, and no patient showed evidence ofCMV disease. Because 3 allograft recipients receiving concomitant iv amphotericin B showed rapid impairment of renal function, foscarnet prophylaxis should not be given to allograft recipients requiring amphotericin B; otherwise, foscarnet prophylaxis at this dose appears safe after BMT.Infection due to cytomegalovirus (CMV) causes significant morbidity and mortality among bone marrow transplant (BMT) recipients [1]. In two published series, the probability ofCMV infection within the first 100 days after BMT among patients who were CMV-seropositive before transplant was up to 80%and 60%for allograft and autograft recipients, respectively [2,3]. Mortality was primarily related to CMV pneumonia, which developed in 37% of allograft and in 22% of autograft recipients who had evidence of active CMV infection [2,3]. Thus, the prevention of CMV infection and disease after BMT is of foremost importance.Antiviral chemotherapy aimed at preventing reactivation of latent virus may be the most promising approach to CMV prophylaxis both among CMV-seropositive autograft and allograft recipients and among seronegative allograft recipients who have a seropositive marrow donor. CMV drug prophylaxis should cover the early period after BMT in which a deficiency in CMV-specific immunity can contribute to the risk of severe CMV disease [4].The antiviral agent acyclovir given intravenously at high doses was shown to be partially effective in preventing CMV infection and disease among seropositive BMT recipients [5].

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Trisodium Phosphonoformate, a New Antiviral Compound

Cited by 220 publications

References 24 publications

The Spermine Phosphate-Bound Cyclooctaoxygen Sodium Epigenetic Shell of Euchromatin DNA Is Destroyed by the Epigenetic Poison Glyphosate

The Spermine Phosphate-Bound Cyclooctaoxygen Sodium Epigenetic Shell of Euchromatin DNA Is Destroyed by the Epigenetic Poison Glyphosate

Baculovirus Replication: Inhibition of Trichoplusia ni Multiple Nuclear Polyhedrosis Virus by [E]-5-(2-Bromovinyl)-2'-deoxyuridine

Phase I-II Trial of Foscarnet for Prevention of Cytomegalovirus Infection in Autologous and Allogeneic Marrow Transplant Recipients

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