-
The Journal of Biological Chemistry Sep 1982Five independently derived variants of a herpes simplex virus type I (HSV-1) strain were plaque purified from a virus population passaged in 1 mM phosphonoformic acid...
Five independently derived variants of a herpes simplex virus type I (HSV-1) strain were plaque purified from a virus population passaged in 1 mM phosphonoformic acid (PFA). The DNA polymerase induced by the parent and PFA-resistant viruses were purified and characterized. No differences were observed among the enzymes with respect to their chromatographic properties, specific activities, or polypeptides resolved by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The variant enzymes exhibited levels of PFA resistance which ranged from 15- to 25-fold. Resistance to PFA was always associated with a similar degree of resistance to its congener phosphonoacetic acid, but cross-resistance to beta-phenylphosphonoacetic acid was only seen with two of the five variant enzymes. PFA and pyrophosphate were mutually competitive in PPi exchange reactions, but in DNA synthetic reactions the levels of resistance to PFA and PPi were not equal. The apparent affinities of the enzymes for Mg2+ did parallel their affinities for PFA. Km values of dNTPs were about 2-fold higher than the parent virus enzyme for all of the variant enzymes except one which was 4-fold higher. The processivity of polymerization was apparently unaffected by the enzyme changes related to PFA resistance although one variant enzyme had a lower value. Resistance among the variant enzymes to the triphosphates of 9-(2-hydroxyethoxymethyl)guanine and 2',3'-dideoxyguanosine was directly related to the level of resistance to PFA. The data presented here indicated that (i) PFA resistance may result from several types of active site alterations, since the PFA-resistant enzymes were of three kinetically distinct types. Also, additional enzyme alterations, probably unrelated to PFA resistance, were detected in one enzyme. (ii) PFA and PPi possess some different binding determinants within the active center of herpes simplex virus type I DNA polymerase. (iii) PFA and the triphosphates of 9-(2-hydroxyethoxymethyl)guanine and 2',3'-dideoxyguanosine may have a common ultimate inhibitory mechanism.
Topics: Antiviral Agents; DNA Replication; DNA-Directed DNA Polymerase; Foscarnet; Genetic Variation; Kinetics; Magnesium; Organophosphorus Compounds; Phosphonoacetic Acid; Simplexvirus
PubMed: 6286645
DOI: No ID Found -
The Journal of Infectious Diseases Oct 1991Investigations of mutants of human cytomegalovirus (CMV) that are resistant to foscarnet could shed light on mechanisms of selective drug action and features of drug...
Investigations of mutants of human cytomegalovirus (CMV) that are resistant to foscarnet could shed light on mechanisms of selective drug action and features of drug resistance that may be clinically important. Preexisting foscarnet-resistant mutants could not be detected in a stock of wild-type strain AD169 at frequencies greater than 0.0025%. However, foscarnet-resistant mutants could be isolated by passage in increasing drug concentrations. Two independent mutants were shown by plaque reduction and dot-blot hybridization assays to be resistant to phosphonoacetic acid and acyclovir, sensitive to ganciclovir, vidarabine, 2'fluoro-5-iodoarabinosylcytosine, and (S)-1-(3-hydroxy-2- phosphonylmethoxypropyl)cytosine; and hypersensitive to aphidicolin and (S)-1-(3-hydroxy-2-phosphonylmethoxypropyl)adenine. These results have implications for the mutation frequency of CMV, for the possibility that clinically important foscarnet- and acyclovir-resistant CMV infections could emerge, for possible therapies of drug-resistant virus infections, and for the role of viral DNA polymerase in mechanisms of selective action of anti-CMV drugs.
Topics: Antiviral Agents; Cells, Cultured; Cytomegalovirus; Drug Resistance, Microbial; Fibroblasts; Foscarnet; Humans; Mutation; Neutralization Tests; Nucleic Acid Hybridization; Phosphonoacetic Acid; Serial Passage
PubMed: 1654362
DOI: 10.1093/infdis/164.4.781 -
Pharmacotherapy 1991Licensed in 1987, zidovudine remains the only medication with proved efficacy for the treatment of disease caused by the human immunodeficiency virus (HIV). New... (Review)
Review
Licensed in 1987, zidovudine remains the only medication with proved efficacy for the treatment of disease caused by the human immunodeficiency virus (HIV). New information on the pharmacology (adults and children), effects of kidney and liver dysfunction on the disposition of the drug, and drug-drug interactions have improved the way we use and monitor this agent. The serious toxicity associated with zidovudine has led researchers to develop safer dosage regimens. Also, recognition that zidovudine slows but does not halt progression of disease has increased the search for effective alternatives. The best-studied agents are didanosine (2',3'-dideoxyinosine, ddl), zalcitabine (2',3'-dideoxycytidine, ddC), and foscarnet.
Topics: Acquired Immunodeficiency Syndrome; Adult; Antiviral Agents; Child; Didanosine; Female; Foscarnet; HIV Infections; Humans; Phosphonoacetic Acid; Pregnancy; Reverse Transcriptase Inhibitors; Zalcitabine; Zidovudine
PubMed: 1722897
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Sep 1978When applied topically, trisodium phosphonoformate (PFA) displayed activity against established cutaneous herpesvirus infections in guinea pigs similar to that exhibited... (Comparative Study)
Comparative Study
When applied topically, trisodium phosphonoformate (PFA) displayed activity against established cutaneous herpesvirus infections in guinea pigs similar to that exhibited by the closely related phosphonoacetic acid (PAA); however, unlike PAA, PFA was not locally skin irritating. The therapeutic benefits of topical application of PFA were clearly evident when application was delayed for 48 h after virus inoculation, at which time lesions were well developed. The therapeutic effect was dependent on the concentration of PFA and the duration of treatment. PFA exhibited significant activity against established infections when administered intraperitoneally, although it was less effective via this systemic route than when applied topically.
Topics: Animals; Antiviral Agents; Formates; Guinea Pigs; Herpesviridae Infections; Male; Organophosphorus Compounds; Phosphonoacetic Acid; Skin Diseases, Infectious
PubMed: 213015
DOI: 10.1128/AAC.14.3.408 -
American Journal of Nephrology 1989Foscarnet is a pyrophosphate analogue that has been successfully used in severe cytomegalovirus (CMV) infections. Little is known of the incidence and mechanisms of... (Comparative Study)
Comparative Study
Foscarnet is a pyrophosphate analogue that has been successfully used in severe cytomegalovirus (CMV) infections. Little is known of the incidence and mechanisms of foscarnet-induced nephrotoxicity as most data comes from recipients of renal allografts or from patients with severe underlying disease or with other nephrotoxic drugs. We have retrospectively analyzed the evolution of renal function after 56 courses of foscarnet. In addition, we have prospectively studied the protective effects of hydration on foscarnet nephrotoxicity (2.5 liters of saline/day during the night before the foscarnet therapy and throughout the course of treatment). Foscarnet-induced acute renal failure was defined as a rise in serum creatinine of at least 25% from the basal value. An increase in serum creatinine occurred in 37 cases out of the 56 courses of foscarnet (66%). The mean serum creatinine prior to foscarnet was 80.5 +/- 3.3 mumol/l and the mean increase was 190 +/- 28.3 mumol/l (range 80-1,000). Peak serum creatinine was higher than 200 and 300 mumol/l in 16 and 13 patients, respectively. Kidney obtained at autopsy from a 30-year-old male with AIDS, CMV pneumonitis and acute renal failure secondary to foscarnet administration showed an extensive tubular necrosis. In the group which was prospectively hydrated only 1 patient had an acute renal failure. The mean serum creatinine at the peak (96 +/- 4 mumol/l) and at the end of the treatment (83 +/- 4 mumol/l) was significantly lower (p less than 0.05) than in non hydrated patients. In conclusion, foscarnet is a highly nephrotoxic drug which induces acute tubular necrosis.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Acute Kidney Injury; Adult; Aged; Cohort Studies; Creatinine; Cytomegalovirus Infections; Fluid Therapy; Foscarnet; Humans; Male; Middle Aged; Phosphonoacetic Acid; Retrospective Studies
PubMed: 2554731
DOI: 10.1159/000167987 -
The American Journal of Medicine Feb 1992The use of ganciclovir in the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) is limited by marrow toxicity and... (Review)
Review
The use of ganciclovir in the treatment of cytomegalovirus (CMV) retinitis in patients with acquired immunodeficiency syndrome (AIDS) is limited by marrow toxicity and by the development of resistance to this agent in CMV strains capable of causing progressive disease. Foscarnet retains activity against ganciclovir-resistant CMV and has an adverse effect profile different from that of ganciclovir. Preliminary data from studies conducted under the AIDS Clinical Trials Group (ACTG) program indicate that intravenous foscarnet maintenance therapy at 60, 90, and 120 mg/kg/day in AIDS patients with CMV retinitis successfully completing foscarnet induction therapy is associated with median times to retinitis progression of 90, 95, and greater than 123 days, respectively. An ACTG trial of foscarnet in patients failing ganciclovir therapy has been initiated, as has a trial jointly sponsored by the National Eye Institute and the National Institute of Allergy and Infectious Diseases comparing the safety and efficacy of foscarnet and ganciclovir. Also underway is a trial evaluating the effects of combination and alternating regimens of these two agents.
Topics: Antiviral Agents; Cytomegalovirus Infections; Drug Therapy, Combination; Eye Infections, Viral; Foscarnet; Ganciclovir; Humans; Phosphonoacetic Acid; Retinitis
PubMed: 1310573
DOI: 10.1016/0002-9343(92)90334-8 -
Nucleosides, Nucleotides & Nucleic Acids 2007Oligodeoxynucleotides containing internucleotide phosphonoacetate esters are taken up irreversibly by cells in culture in the absence of cationic lipids. These...
Oligodeoxynucleotides containing internucleotide phosphonoacetate esters are taken up irreversibly by cells in culture in the absence of cationic lipids. These oligonucleotides also are active in stimulating RNase H and are stable toward nucleases.
Topics: DNA; Esterification; Flow Cytometry; HeLa Cells; Humans; Jurkat Cells; Lipids; Nucleic Acid Heteroduplexes; Oligonucleotides; Phosphonoacetic Acid; RNA; Transfection
PubMed: 18066852
DOI: 10.1080/15257770701489896 -
Journal of Medical Virology 1983This paper describes an assay for hepatitis B DNA polymerase which is based on the use of phosphonoformic acid (PFA), a known inhibitor of the viral enzyme, with...
This paper describes an assay for hepatitis B DNA polymerase which is based on the use of phosphonoformic acid (PFA), a known inhibitor of the viral enzyme, with particulate fractions prepared from blood plasma or serum. The assay makes possible the measurement of the viral enzyme activity in the presence of DNA polymerases unrelated to hepatitis B. The activities of the latter were largely but incompletely suppressed in the presence of 0.4 M KCl, and they were altogether excluded from nucleotide incorporation which was inhibited by PFA. Thus, particulate fractions obtained from HBsAg-negative blood had mean DNA polymerase activities of 1 +/- 1 (SD) pmol/liter/hr with a lower 90th percentile range of 0-3 pmol/liter/hr. Particulate fractions prepared from blood that was positive for both HBsAg and HBeAg had polymerase activities of 58 +/- 66 pmol/liter/hr with an upper 90th percentile range of 4-322 pmol/liter/hr. PFA concentration was optimized using a commercial preparation of the inhibitor, in which the degree of purity was determined. The method utilizes 3H-labeled deoxyribonucleoside triphosphates and is performed on 6 ml of plasma or serum. The effects of precursor concentration and specific activities on the rate of nucleotide incorporation were studied, and the optimal combinations were indicated. Other parameters of the proposed assay were also studied.
Topics: Antiviral Agents; Biological Assay; Blood; Foscarnet; Hepatitis B virus; Humans; Nucleic Acid Synthesis Inhibitors; Nucleotides; Organophosphorus Compounds; Phosphonoacetic Acid; Virion
PubMed: 6225836
DOI: 10.1002/jmv.1890120107 -
Journal of Medicinal Chemistry Jul 1994The synthesis of potential "combined prodrugs" where phosphonoformic acid (PFA) or phosphonoacetic acid (PAA) was attached to the 5'-O or N4 position of...
The synthesis of potential "combined prodrugs" where phosphonoformic acid (PFA) or phosphonoacetic acid (PAA) was attached to the 5'-O or N4 position of 2',3'-dideoxy-3'-thiacytidine (BCH-189) is described. The anti-HIV-1 activity of 11 analogues which included carboxylic ester or phosphoric ester linkages of PFA or PAA to BCH-189 was determined in MT-4 cells. Of these compounds, the IC50 of analogues 3, 4, 6, and 7 ranged from 0.2 to 100 microM, while IC50 for BCH-189 in this system was 0.1 microM. In vitro hydrolysis of the various esters or amides in human plasma indicated that these agents were relatively stable in the presence of plasma esterases with t1/2 values of up to 120 min. Moreover, lipophilicity of these compounds (partition coefficient) was determined in order to establish correlation between lipophilicity and diffusion of BCH-189 analogues into the cells. The active compounds may exert their effects by extracellular or intracellular hydrolysis to the corresponding antiviral agent BCH-189, but intrinsic anti-HIV-1 activity of some of PAA and PFA adducts, themselves, may also be involved.
Topics: Antiviral Agents; Foscarnet; HIV-1; Lamivudine; Phosphonoacetic Acid; Prodrugs; Structure-Activity Relationship; Virus Replication; Zalcitabine
PubMed: 8035429
DOI: 10.1021/jm00040a014 -
Voprosy Virusologii 1986A comparative study of cytotoxicity and antiherpes activity of acycloguanosine (Acg) of the Soviet and American manufacture and a Soviet preparation of phosphonoacetic... (Comparative Study)
Comparative Study
A comparative study of cytotoxicity and antiherpes activity of acycloguanosine (Acg) of the Soviet and American manufacture and a Soviet preparation of phosphonoacetic acid (PAA) for herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) was carried out in primary and continuous cell cultures. The Acg preparation was shown not to be inferior in maximal tolerated concentration, minimal inhibiting concentration, and chemotherapeutic index (CTI) to American drug. Zovirax (Zvr), in relation to both herpes simplex virus types in primary and continuous cell lines. The CTI of Acg and Zvr was 25-30-fold higher than that of PAA for HSV-1 (Vero cells) and 80-fold higher in chick embryo fibroblast cultures (CEF), and 25-fold higher for HSV-2 in CEF.
Topics: Acyclovir; Animals; Chick Embryo; Drug Evaluation, Preclinical; Herpes Simplex; Organophosphorus Compounds; Phosphonoacetic Acid; Simplexvirus; Virus Cultivation
PubMed: 3014751
DOI: No ID Found