Differential inhibition of various mammalian DNA polymerase activities by ammonium 21‐tungsto‐9‐antimoniate (HPA23)

Ono, Katsuhiko; Nakane, Hideo; Barré‐Sinoussi, Françoise; Chermann, Jean‐Claude

doi:10.1111/j.1432-1033.1988.tb14282.x

Cited by 23 publications

(9 citation statements)

References 22 publications

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“…HPA-23 (ammonium-21-tungsto-9-antimoniate) inhibits retrovirus replication by inhibiting RNA-dependent DNA polymerases and thus could be effective in the treatment of HIV-1 infections and AIDS. HPA-23 inhibits nucleic acid polymerases in vitro (1,4,7,10) and has antiviral activity both in vitro (14) and in vivo (8,9). Furthermore, HPA-23 inhibits HIV-1 reverse transcriptase in vitro (5).…”

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confidence: 99%

Clinical trial of tolerance of HPA-23 in patients with acquired immune deficiency syndrome

Moskovitz¹

1988

Antimicrob Agents Chemother

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An open-label, multicenter clinical trial assessed the tolerance of HPA-23 (ammonium-21-tungsto-9-antimoniate) in patients with acquired immune deficiency syndrome. Sixty-nine patients were sequentially assigned to receive 0.25, 0.5, 1.0, or 2.0 mg of HPA-23 per kg intravenously 5 days per week for 8 weeks. HPA-23 was fairly well tolerated at doses of 1.0 mg/kg or less; nearly 60% of patients given 2.0 mg/kg discontinued treatment. Twenty-six patients discontinued treatment because of adverse events or concurrent illness. HPA-23 produced dose-related decreases in platelet count and increases in serum glutamine oxalacetic transaminase. There were no changes in immune system function, as determined by total lymphocyte count, T4-cell count, T8-cell count, and T4/T8 ratio. The effects of HPA-23 seemed to be more closely related to the total dose than to the daily dose. No improvement in the clinical status of the patients was observed during the 8 weeks of treatment.Acquired immune deficiency syndrome (AIDS) is caused by a retrovirus, human immunodeficiency virus type 1 (HIV-1) (2, 6, 11, 13). HPA-23 (ammonium-21-tungsto-9-antimoniate) inhibits retrovirus replication by inhibiting RNA-dependent DNA polymerases and thus could be effective in the treatment of HIV-1 infections and AIDS. HPA-23 inhibits nucleic acid polymerases in vitro (1, 4, 7, 10) and has antiviral activity both in vitro (14) and in vivo (8, 9). Furthermore, HPA-23 inhibits HIV-1 reverse transcriptase in vitro (5). Preliminary observations in a limited number of AIDS patients suggest that HPA-23 inhibits HIV-1 replication (12). The goal of this study was to assess the tolerance of patients with AIDS to HPA-23.(Portions of this study were presented at the Third International Conference on Acquired Immunodeficiency Syndrome, 1-5 June 1987, Washington, D.C.) MATERIALS AND METHODSThis was an open-label, multicenter clinical trial. The Institutional Review Board at each institution approved the study protocol, and all patients gave informed consent. Patients were assigned nonrandomly to the treatment groups, and no placebo was used. patients was treated with the lowest dose of HPA-23 (0.25 mg/kg per day), and the preliminary data on adverse events in these patients were evaluated. After evaluation of the results from this group, additional groups of patients were treated with higher doses of HPA-23.Patients who had AIDS, as defined by the Centers for Disease Control (Atlanta, Ga.), and who were between 18 and 60 years old, clinically stable, and ambulatory were eligible for this clinical trial. Excluded were females of childbearing potential; patients who had hemophilia; lymphoma; visceral Kaposi's sarcoma (KS); neutropenia (leukocyte count, <1,000/mm3); thrombocytopenia (platelet count, <100,000/mm3); prolonged coagulation times (prothrombin time or partial thromboplastin time of more than 2 or 8 s longer than the control times, respectively); elevated serum glutamic oxalacetic transaminase (SGOT), serum glutamic pyruvic transaminase, or alkaline phospha...

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Clinical trial of tolerance of HPA-23 in patients with acquired immune deficiency syndrome

Moskovitz¹

1988

Antimicrob Agents Chemother

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“…However, ddTTP cannot be used for in vivo experiments, because it cannot penetrate the cells. Other compounds reported to inhibit the pol ␤ activity include long chain fatty acids (9,10,26), a bile acid such as lithocholic acid (35,63), terpenoids (12, 64 -67), nucleotide analogs (68,69), flavonoids (15,70,71), sulfate-or sialic acidcontaining glycolipids (11,72,73), and phospholipids (74,75), but these agents inhibited activities of both pol ␣ and pol ␤. As a result, we studied the antibiotic in more detail that was first reported 10 years ago and report here our findings on its unique properties (i.e.…”

Section: Discussionmentioning

confidence: 99%

A Plant Phytotoxin, Solanapyrone A, Is an Inhibitor of DNA Polymerase β and λ

Mizushina¹,

Kamisuki²,

Kasai³

et al. 2002

Journal of Biological Chemistry

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Eukaryotic cells reportedly contain three replicative DNAdirected DNA polymerases (EC 2.7.7.7) (pol ␣, ␦, and ⑀), 1 mitochondrial DNA polymerase (pol ␥), and at least nine repair types of DNA polymerase (pol ␤, ␦, ⑀, , , , , , and ) (1-8), and we have screened for natural compounds that selectively inhibit each of these eukaryotic DNA polymerases and found several inhibitors (9 -15). The purpose was to use the compounds as tools and molecular probes to distinguish DNA polymerases and to clarify their biological and in vivo functions. In this study, we found an interesting fungus-produced compound that selectively inhibits the activities of pol ␤ and pol . Interestingly, the compound was found to be a plant phytotoxin, solanapyrone A, isolated from the causal fungus of early blight disease in potato. To our knowledge, such specific natural compounds have not been reported with the exception of the pol ␤-inhibitor, prunasin, which we reported previously (13). The compound was a stronger pol ␤-inhibitor than prunasin, and no pol -inhibitors have been reported.Pol ␤ is the lowest molecular mass (39 kDa) DNA polymerase lacking such intrinsic accessory activities as 3Ј-or 5Ј-exonuclease, endonuclease, dNMP turnover, or pyrophosphorolysis (16). Pol ␤ consists of an independently folded N-terminal 8-kDa domain and C-terminal 31-kDa domain (17,18). The N-terminal domain was originally characterized as a single-stranded DNA (ssDNA)-binding domain. It was then found to possess binding specificity for the 5Ј-phosphate in gapped DNA (19 -21) and a helix-hairpin-helix motif found in several other DNA repair enzymes (22,23). Recently, Matsumoto and Kim (24) demonstrated that pol ␤ catalyzes the removal of dRP from the AP endonuclease-incised AP site via ␤-elimination as opposed to hydrolysis, and that this dRP lyase activity resides in the 8-kDa domain of pol ␤. According to recent studies (7, 25), moreover, pol ␤ is known to have another family polymerase, pol . Pol ␤ has been present in all tissues examined and is generally expressed at a low level as are a number of other so-called constitutive "house-keeping" enzymes. Although the in vivo function of the family enzyme, pol , is unclear as yet, pol appears to work in a similar manner to pol ␤ (7). As to why a plant phytotoxin is a pol ␤-family-specific inhibitor, we presently are analyzing the structure and function of pol ␤ and pol using the inhibitor from two different view-points to understand the precise role of each of the polymerases in vivo and to develop a drug design strategy for cancer chemotherapy agents. We previously reported the three-dimensional structure of pol ␤ and the N-terminal 8-kDa domain (the DNA template-binding domain) with or without long chain fatty acids to further clarify the structure and function of pol ␤ (26). Because at least pol ␤ is an essential enzyme for nucleotide excision repair (1, 2), the plant phytotoxin may lead to blockage of the DNA repair systems of rescue cancer cells under clinical radiation-therapy or chemotherapy. The plan...

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“…The antiviral drug HPA-23 has been tested in the DNA synthesis reactions catalyzed by DNAand RNA-dependent DNA polymerases [3,10,12,22].…”

Section: Discussionmentioning

confidence: 99%

“…HPA-23, a cryptate compound with a central cage in which metallic ions can be located [12], is an antiviral agent with signifcant activity in vitro against many DNA and RNA viruses [10,22]. In vivo, in mice, HPA-23 prevents or ameliorates infection by Friend leukemia virus, murine sarcoma virus [13], and murine scrapie [ 14].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the wheat germ DNA polymerase A activity by the antiviral drug HPA-23

et al. 1993

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Wheat germ DNA polymerase A, a gamma-like enzyme, recognized efficiently natural and synthetic RNA templates, resembling a retroviral reverse transcriptase (P. Laquel et al., Biochim Biophys Acta 1048 (1990): 139-148). Ammonium-21-tungsto-9-antimoniate (HPA-23), an antiviral drug, inhibited the DNA polymerase A activities, independently of the template primers used, i.e. activated DNA or polyriboadenylic acid oligodeoxythymidylate (poly(rA)-oligo(dT)). The inhibition observed in the poly(rA)-oligo(dT)-directed DNA polymerase A activity occurred in the presence of either Mg2+ or Mn2+ as divalent cation, and also with the 2'-fluoro analogue of poly(rA) as template. HPA-23 was a non-competitive inhibitor with respect to TTP, activated DNA, poly(rA)-oligo(dT), and poly(dAfl)-oligo(dT). A preincubation study showed a reversible HPA-23 binding to DNA polymerase A, in the presence of poly(rA)-oligo(dT) as the template primer.

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Differential inhibition of various mammalian DNA polymerase activities by ammonium 21‐tungsto‐9‐antimoniate (HPA23)

Cited by 23 publications

References 22 publications

Clinical trial of tolerance of HPA-23 in patients with acquired immune deficiency syndrome

Clinical trial of tolerance of HPA-23 in patients with acquired immune deficiency syndrome

A Plant Phytotoxin, Solanapyrone A, Is an Inhibitor of DNA Polymerase β and λ

Inhibition of the wheat germ DNA polymerase A activity by the antiviral drug HPA-23

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