Enzyme Inhibitors XXIV: Bridging Hydrophobic and Hydrophilic Regions on Adenosine Deaminase

Schaeffer, Howard J.; Schwender, Charles F.

doi:10.1002/jps.2600600818

Cited by 42 publications

(40 citation statements)

References 12 publications

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“…This finding implied that extracellular adenosine in the culture medium was not converted to adenine by parasite nucleoside hydrolase activities but, rather, that adenosine was being deaminated to inosine by mammalian adenosine deaminase, a component of the serum-based medium (45) in which promastigotes are propagated, prior to being taken up by the parasite. To test this conjecture, the ability of all strains to salvage adenosine was also evaluated in the presence of EHNA, a specific inhibitor of mammalian adenosine deaminase (44). Wild type, ⌬adss[pADSS], ⌬aah, and ⌬aah/⌬adss promastigotes, but not ⌬adss cells, grew in adenosine plus EHNA (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The ability of these lines to grow in either adenine or adenosine was also determined in the presence of dCF. In addition, the adenosine growth profile of the ⌬aah/ ⌬adss double knock-outs was also assessed in the presence of 20 M erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) (44) to inhibit the adenosine deaminase activity found in FBS (45), thereby preserving the nucleoside. After 7-10 days, parasites were enumerated visually by hemocytometer.…”

Section: Materials Chemicals and Reagents-[8-mentioning

confidence: 99%

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Adenylosuccinate Synthetase and Adenylosuccinate Lyase Deficiencies Trigger Growth and Infectivity Deficits in Leishmania donovani

Boitz

Strasser

Yates

et al. 2013

Journal of Biological Chemistry

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Section: Resultsmentioning

confidence: 99%

Section: Materials Chemicals and Reagents-[8-mentioning

confidence: 99%

Adenylosuccinate Synthetase and Adenylosuccinate Lyase Deficiencies Trigger Growth and Infectivity Deficits in Leishmania donovani

Boitz

Strasser

Yates

et al. 2013

Journal of Biological Chemistry

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“…The most potent inhibitor was ara-A, followed by ara-H, ara-M, and 6-ethoxypurine arabinoside. Since ara-A is known to be converted to ara-H in the presence of adenosine deaminase (Brink and LePage, 1964), the BFU-E assays were repeated in the presence of EHNA, a potent and selective inhibitor of this enzyme (Schaeffer and Schwender, 1974). Under these conditions, ara-A was thirty-fold more potent (Fig.…”

Section: Resultsmentioning

confidence: 99%

Purine Arabinosides as Inhibitors of Human Haemopoietic Progenitor Cells

Averett

Steinberg

Koszalka

et al. 1992

Antivir Chem Chemother

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SummaryFour purine arabinosides that inhibit varicella-zoster virus (VZV)replication in vitro were tested as inhibitors of colony formation by progenitor cells from normal human bone marrow. In general, erythroid burst forming cells (BFU-E) were more sensitive to inhibition by . these compounds than were either erythroid colony forming cells (CFU-E) or granulocyte/macrophage colony forming cells (CFU-GM). A 50% reduction in colony formation (IC so ) was observed for BFU-E in the presence of 8 fLM 6-methoxypurine arabinoside. Adenine arabinoside and hypoxanthine arabinoside had IC sa values of 1 fLM and 4 fLM respectively, whereas 6-ethoxypurine arabinoside was not inhibitory (IC so > 50 fLM). Enzyme studies showed that both 6-methoxypurine arabinoside and adenine arabinoside were converted to hypoxanthine arabinoside by adenosine deaminase. 6-Ethoxypurine arabinoside was a much less efficient substrate. When the BFU-E assays were performed in the presence of an inhibitor of adenosine deaminase, 6-methoxypurine arabinoside became non-inhibitory. In contrast, adenine arabinoside became much more inhibitory (IC sa = 0.03 fLM). The potency of hypoxanthine arabinoside was unaffected. Thus, incubation of 6-methoxypurine arabinoside and adenine arabinoside under conditions appropriate for the BFU-E assay resulted in the in situ conversion of these compounds to hypoxanthine arabinoside. Biotransformation of compounds must be considered in the assessment of toxicity in vitro.

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“…nucleoside analog is rapidly deaminated in biological systems by the enzyme adenosine deamninase to yield a considerably less potent antiviral agent, 9-,3-D-arabinofuranosylhypoxanthine (16). Attempts to circumvent the loss of activity of ara-A through deamination to 9-,3-D-arabinofuranosylhypoxanthine have involved the use of potent adenosine deaminase inhibitors, such as 2'-deoxycoformycin (39) and erythro-9-(2-hydroxy-3-nonyl)adenine (18), in combination with ara-A or ara-AMP (3,15,20,21,23,28). These studies have provided experimental data which indicate that the antiviral potency of ara-A can be greatly increased by the simultaneous administration of either of these potent enzyme inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Comparison of the efficacy of vidarabine, its carbocyclic analog (cyclaradine), and cyclaradine-5'-methoxyacetate in the treatment of herpes simplex virus type 1 encephalitis in mice

Shannon¹,

Westbrook²,

Arnett³

et al. 1983

Antimicrob Agents Chemother

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The relative therapeutic effects of vidarabine (9-,-D-arabinofuranosyladenine), cyclaradine (the adenosine deaminase-resistant carbocyclic analog of vidarabine), and cyclaradine-5'-methoxyacetate in the parenteral treatment of systemic herpes simplex virus type 1 infections in Swiss mice were determined. Among control mice inoculated intraperitoneally with virus, a mortality rate of 95% was observed. The intraperitoneal administration of nontoxic doses of vidarabine (125 to 250 mg/kg per day) or cyclaradine (113 to 450 mg/kg per day), by daily injections for 7 days beginning 4 h after virus inoculation, reduced mortality to 0 to 10%, Amnong control animals inoculated intracerebrally with 32 50% lethal doses of virus, 100%to mortality was observed, with a mean survival time of 4.6 days.Treatment with either drug at equimolar dose levels ranging from ca. 32 to 750 mg/kg per day produced significant (P < 0.0005), dose-dependent increases in the mean survival time of animals dying of herpesvirus encephalitis. Mice inoculated intracerebraily with 10 50o lethal doses of virus exhibited 97% mortality and a mean survival time of 5.5 to 6.4 days. Treatment with vidarabine, cyclaradine, or cyclaradine-5'-methoxyacetate significantly increased the mean survival time of dying animals and, at doses ranging from 250 to 750 mg/kg per day, produced significant increases in survival. The three drugs displayed equivalent antiviral efficacy in vivo. Drug toxicity (measured by weight loss) was not detected in mice treated with cyclaradine or cyclaradine-5'-methoxyacetate at 750 mg/kg per day, whereas severe toxicity (weight loss of -3 g) was observed in mice treated with vidarabine at an equivalent dose level. Thus, cyclaradine or its 5'-methoxyacetic acid ester may possess some advantage over vidarabine in the treatment of severe herpesvirus infections and should therefore be considered for clinical trials in humans.

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Enzyme Inhibitors XXIV: Bridging Hydrophobic and Hydrophilic Regions on Adenosine Deaminase

Cited by 42 publications

References 12 publications

Adenylosuccinate Synthetase and Adenylosuccinate Lyase Deficiencies Trigger Growth and Infectivity Deficits in Leishmania donovani

Adenylosuccinate Synthetase and Adenylosuccinate Lyase Deficiencies Trigger Growth and Infectivity Deficits in Leishmania donovani

Purine Arabinosides as Inhibitors of Human Haemopoietic Progenitor Cells

Comparison of the efficacy of vidarabine, its carbocyclic analog (cyclaradine), and cyclaradine-5'-methoxyacetate in the treatment of herpes simplex virus type 1 encephalitis in mice

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