The compound 2',3'-dideoxycytidine (ddC) is a potent inhibitor of human immunodeficiency virus replication in vitro and currently clinical trials for treatment acquired syndrome. was found to exert delayed cytotoxicity against Molt-4F cells, T lymphoblastic cell line. At concentration as low 0.1 microM, the doubling time cells increased after 8 days ddC treatment. This 5-fold lower than plasma levels reached trials. finally died 2-week exposure or 0.2 microM ddC. not due greater accumulation...

A guanosine analog, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG), was found to inhibit herpes simplex virus type 1 (HSV-1), 2, cytomegalovirus, and Epstein-Barr replication by greater than 50% at concentrations that do not cell growth in culture. The potency of the drug against all these viruses is 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir). DHPG active HSV-1 during early phase had no activity when added a later time after infection. Its antiviral irreversible. Thymidine partially...

Using affinity purified human immunodeficiency virus (HIV) reverse transcriptase the reaction assay conditions were determined.The optimum incorporation of dTMP into (rA),(dT)lo template with HIV required 6 mM MgClz and 80 m M KCl.The specificity is quite different from those ypolymerase-associated or avian transcriptase.The preferential inhibition as compared to y-reverse was observed several nucleoside analog triphosphates.The Ki values for thymidine triphosphate analogs ranged 5 13 nM...

A novel anti-hepatitis B virus (anti-HBV) agent, 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil (L-FMAU), was synthesized and found to be a potent anti-HBV anti-Epstein-Barr agent. Its in vitro potency evaluated 2.2.15 H1 cells for activities, respectively. In cytotoxicity MT2, CEM, 2.2.15, also assessed, the results indicated high antiviral selectivities of L-FMAU these cells.

2',3'-Dideoxy-3'-thiacytidine (+/-)-SddC) was found to have potent activity against human hepatitis B virus as well immunodeficiency viruses in culture. The (-)form ((-)-SddC) which is resistant deoxycytidine deaminase be the more active antiviral stereoisomer than (+)-form ((+)-SddC). (+)-SddC susceptible deamination by and 25- 12-fold toxic (-)-SddC CEM cells terms of anti-cell growth anti-mitochondrial DNA synthesis, respectively. Similar results were obtained using a mixture their...

The nucleoside analog 2',3'-dideoxycytidine (ddcyd) has been shown to inhibit the infectivity and cytopathic effect of human immunodeficiency virus on OKT4+ lymphocytes in vitro (1).Metabolism ddCyd by T-lymphoblastic cells (Molt 4) negative for OKT4 was examined.Molt 4 accumulated its phosphorylated derivatives into acid-soluble acid-insoluble material a dose-dependent manner.For each concentration tested, triphosphate represented 40% total pool metabolites.Uptake 5 PM linear h after...

We studied the effect of a novel purine acyclic nucleoside, 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), on human cytomegalovirus (HCMV) replication. The susceptibility HCMV to this drug was monitored in cell culture by plaque reduction assay. replication various strains inhibited extent 50% 1 5 microM DHPG. DHPG highly specific its anti-HCMV activity, since at concentrations as high 100 it did not exert any detectable inhibitory uninfected macromolecular synthesis and growth. At 2 4...

2',3'-Dideoxy-3'-thiacytidine (cis-(+/-)-SddC) was found to have potent activity against hepatitis B virus and human immunodeficiency viruses in culture. Recent studies by us identified (-)-SddC as the stereoisomer responsible for antiviral effect showed that cytotoxicity mainly caused (+)-SddC. Metabolism these drugs were converted their monophosphates, diphosphates, triphosphates. The enzyme formation of monophosphates be cytoplasmic deoxycytidine kinase CEM cells. Uptake intracellular...

Herpes simplex virus (HSV) encodes a DNA polymerase that is similar in several respects to the replicative mammalian alpha. Recently, these and other polymerases have been shown share regions of protein sequence similarity. Despite similarities, antiviral drugs mimic natural substrates specifically inhibit herpesvirus polymerases. To study amino acids involved substrate drug recognition, we characterized mapped altered sensitivity markers nine HSV pol mutants sequenced relevant portions...

Abstract The inhibition of highly purified herpes simplex virus (HSV)-induced and host cell DNA polymerases by the triphosphate form 9-(2-hydroxyethoxymethyl)guanine (acyclovir; acycloguanosine) was examined. Acyclovir (acyclo-GTP) competitively inhibited incorporation dGMP into DNA, catalyzed HSV polymerase; apparent Km Ki values dGTP acyclo-GTP were 0.15 microM 0.003 microM, respectively. HeLa polymerase alpha also inhibited; 1.2 0.18 In contrast, beta insensitive to analogue. limited...

Two forms of deoxythymidine kinase from blast cells acute myelocytic leukemia were identified by electrophoresis. One was associated mainly with the cytoplasm and other mitochondria. Both isozymes separated purified differential affinity column chromatography which resulted in 2416- 1634-fold purification cytoplasmic mitochondrial enzymes, respectively. Affinity gel prepared linkage through position 3' deoxythymidine. Each enzyme had same electrophoretic mobility state as it did derived...

The metabolism of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), one the most promising new anti-herpes virus compounds, in HeLa cells infected with herpes simplex type 1 was compared that uninfected cells. In virus-infected cells, uptake DHPG enhanced and major metabolites were found to be mono-, di-, triphosphate derivatives. formation these dependent on extracellular concentration (0.5 5.0 microM). Virus-induced thymidine kinase capable phosphorylating its monophosphate which could...

Deoxythymidine kinase activities were induced in HeLa TK- (deoxythymidine kinase-deficient) cells infected with either herpes simplex virus type I or II. The I-induced enzyme was found the cytoplasmic and nuclear fractions of cells, whereas II-induced deoxythymidine could only be cytoplasm. Herpes II specific kinases purified by affinity column chromatography. Both retained deoxycytidine activity present crude preparation. had a different mobility on electrophoresis, but same sedimentation...

Recently, 2-halogenated deoxyadenosine analogs (F, Cl, and Br) have been shown to antitumor activity. These are phosphorylated by cells believed exert their cytotoxic action at the nucleoside triphosphate level. In this work interaction of these with potential targets, such as DNA polymerase alpha, beta, gamma, primase, ribonucleotide reductase was examined in detail. All compounds competitively inhibited incorporation dAMP into or gamma. F-dATP able completely substitute for dATP using...

Potential antiviral nucleoside analogs 1-beta-D-arabinofuranosylthymine, the 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-nucleosides of -5-methyluracil, -5-iodouracil, -5-methylcytosine, -5-iodocytosine, and -E-5-(2-bromovinyl)uracil, E-5-(2-bromovinyl)-2'-deoxyuridine, E-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil, 9-(2-hydroxyethyoxymethyl)guanine were studied to compare their phosphorylation rates relative thymidine by purified kinases from human herpes simplex virus sources. Most...

The inhibition constants (Ki) of a series 5-(2-halogenovinyl)-29-deoxyuridines, including E-5-(2-chlorovinyl)-dUrd, E-5-(2-bromovinyl)-dUrd, E-5-(2-iodovinyl)-dUrd, and Z-5-(2-bromovinyl)-dUrd, have been determined for the dThd kinases human cytosol or mitochondria, herpes simplex virus type 1 (HSV-1) 2 (HSV-2), varicella-zoster (VZV). E-5-(2-halogenovinyl)-29-deoxyuridines had much higher affinity HSV-1 (or VZV) kinase than HSV-2 kinase, E-5-(2-bromovinyl)-dUrd was also that its...

9-beta-D-Arabinofuranosyl-2-fluoroadenine (2-F-araA) inhibited the growth in vitro of HeLa cells by 50% at a concentration 0.25 microM and depressed replication herpes simplex virus Types 1 2 99% 25 microM. The analogue served as substrate for cytoplasmic but not mitochondrial deoxycytidine (dCyd) kinase partially purified from human peripheral chronic lymphocytic leukemic blast cells. Km values dCyd 2-F-araA enzyme were 5 213 microM, respectively. However, concentrations 0.4 mM, was...

The pharmacokinetics of high-dose cytosine arabinoside (HiDAC) given as a three-hour intravenous infusion at 3 g/m2 were studied in five patients with acute leukemia during relapse and/or remission their disease. Apparent steady state plasma levels ara-C 13 infusions averaged 115 +/- 32 microM. Upon cessation the infusion, (ara-C) was rapidly cleared from plasma. apparent postinfusion kinetics triexponential distribution half-life 16 minutes and elimination half-lives 1.8 hours six hours....

The triphosphates of 9-(2-hydroxyethoxymethyl)guanine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine were examined for their inhibitory effect on highly purified cellular DNA polymerase alpha human cytomegalovirus (Towne strain)-induced polymerase. These two nucleoside competitively inhibited the incorporation dGMP into catalyzed by polymerases. virus-induced had greater binding affinity triphosphate (Ki, 8 nM) than 22 nM), although latter compound was strikingly more effective against...