Incorporation and metabolism of 2′-fluoro-5-substituted arabinosyl pyrimidines and their selective inhibition of viral DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and mock-infected Vero cells

Kong, Xiangbin; Scheck, Adrienne C.; Price, Richard W.; Vidal, Pedro; Fanucchi, Michael; Watanabe, Kyoichi A.; Fox, Jack J.; Chou, Ting‐Chao

doi:10.1016/0166-3542(88)90028-9

Cited by 18 publications

(8 citation statements)

References 10 publications

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“…Interestingly, one of the patients from the Michigan cluster of human infections with B virus was given ganciclovir (5 mg/kg of body weight intravenously) twice daily, following a lack of success with ACV used at 15 mg/kg for 3 days, resulting in abatement of neurological symptoms and stabilization of cerebrospinal fluid antibody levels (12). In four other human cases, however, GCV was unable to reverse the fatal progression of disease (9,17,20), substantiating the need for more-efficacious antivirals for late-stage infection.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of B Virus (Macacine herpesvirus1) by Conventional and Experimental Antiviral Compounds

Krug

Schinazi

Hilliard

2010

Antimicrob Agents Chemother

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B virus infection of humans results in high morbidity and mortality in as many as 80% of identified cases.The main objective of this study was to conduct a comparative analysis of conventional and experimental antiviral drug susceptibilities of B virus isolates from multiple macaque species and zoonotically infected humans. We used a plaque reduction assay to establish the effective inhibitory doses of acyclovir, ganciclovir, and vidarabine, as well as those of a group of experimental nucleoside analogs with known anti-herpes simplex virus activity. Four of the experimental drugs tested were 10-to 100-fold more potent inhibitors of B virus replication than conventional antiviral agents. Drug efficacies were similar for multiple B virus isolates tested, with variations within 2-fold of the median effective concentration (EC 50 ) for each drug, and each EC 50 was considerably lower than those for B virus thymidine kinase (TK) mutants. We observed no differences in the viral TK amino acid sequence between B virus isolates from rhesus monkeys and those from human zoonoses. Differences in the TK protein sequence between cynomolgus and pigtail macaque B virus isolates did not affect drug sensitivity except in the case of one compound. Taken together, these data suggest that future B virus zoonoses will respond consistently to conventional antiviral treatment. Further, the considerably higher potency of FEAU (2-fluoro-5-ethyl-Ara-U) than of conventional antiviral drugs argues for its compassionate use in advanced human B virus infections.In its natural host, macaque monkeys, B virus (Macacine herpesvirus 1; Simplexvirus, Herpesviridae) causes lesions on epithelial surfaces (2, 33) and establishes reactivatable latent infection in sensory neurons (30, 37), like herpes simplex virus (HSV) in humans. B virus often results in severe pathogenesis, including paralysis, encephalitis, and in many cases, rapid death, following infection of humans (reviewed in reference 22). Nearly all reported cases of B virus zoonosis have been associated with individuals handling macaques during the course of research or technology development (33). Five fatalities, along with at least 23 cases in which the patient survived, have occurred in the past 20 years, underscoring that zoonotic infections remain a problem in the laboratory animal environment (7-9).The CDC's B Virus Working Group currently recommends treatment of confirmed zoonotic infections with herpesvirusspecific antiviral drugs, including acyclovir (ACV) and ganciclovir (GCV) (10). Both agents in this class of compounds are phosphorylated to active form by virus-encoded thymidine kinase (TK). The resulting nucleoside triphosphate analog inhibits viral DNA replication by termination of chain elongation and by direct inhibition of herpesvirus DNA polymerase (24). While ACV is effective against B virus both in cell culture and in animal models (6), the dose required for 50% plaque reduction is more than 10-fold higher for B virus than for HSV type 1 (HSV-1) (38). GCV is twice as pot...

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Section: Discussionmentioning

confidence: 99%

Inhibition of B Virus (Macacine herpesvirus1) by Conventional and Experimental Antiviral Compounds

Krug

Schinazi

Hilliard

2010

Antimicrob Agents Chemother

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“…These concentrations are in the range of the effective in vitro antiviral concentration for FEAU. (9), is metabolically stable (8). FEAU is eliminated rapidly in the mouse, with total clearance values approximating hepatic (0.05 ml/min/g) and renal (0.04 ml/min/g) blood flow rates (6 The study of tissue distribution in the rat showed that 6 h after a 10-mg/kg dose by the i.v.…”

Section: Preparationmentioning

confidence: 99%

“…FEAU has a higher affinity for HSV type 1 (HSV-1) and HSV-2 thymidine kinase than for host cell thymidine kinase (1). In vitro metabolic studies using HSV-1-infected and mock-infected Vero cells showed that 84% of FEAU is incorporated into the DNA of HSV-1-infected cells (8). FEAU is also highly effective in the treatment of simian varicella virus infection in vivo (10).…”

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confidence: 99%

“…Following intravenous (i.v.) Our earlier studies of structure-activity relationships for a series of 2'-fluoro-5-substituted 1-3-D-arabinofuranosyl pyrimidine analogs showed that 2'-fluoro-5-ethyl-1-0-D-arabinofuranosyluracil (FEAU) is a potent agent against herpes simplex virus with high selectivity in vitro (1, 3,5,8,12). FEAU has a higher affinity for HSV type 1 (HSV-1) and HSV-2 thymidine kinase than for host cell thymidine kinase (1).…”

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confidence: 99%

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Preclinical pharmacology and pharmacokinetics of the anti-hepatitis virus agent 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil in mice and rats

Kong

Vidal

Tong

et al. 1992

Antimicrob Agents Chemother

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The preclinical pharmacology and pharmacokinetics of 2'-fluoro-5-ethyl-1-13-D-arabinofuranosyluracil (FEAU), a selective inhibitor of herpesvirus and hepatitis virus replication, were investigated in the mouse and rat. Following intravenous (i.v.) Our earlier studies of structure-activity relationships for a series of 2'-fluoro-5-substituted 1-3-D-arabinofuranosyl pyrimidine analogs showed that 2'-fluoro-5-ethyl-1-0-D-arabinofuranosyluracil (FEAU) is a potent agent against herpes simplex virus with high selectivity in vitro (1, 3,5,8,12). FEAU has a higher affinity for HSV type 1 (HSV-1) and HSV-2 thymidine kinase than for host cell thymidine kinase (1). In vitro metabolic studies using HSV-1-infected and mock-infected Vero cells showed that 84% of FEAU is incorporated into the DNA of HSV-1-infected cells (8). FEAU is also highly effective in the treatment of simian varicella virus infection in vivo (10). In addition, recent studies have demonstrated that FEAU given either intraperitoneally or orally (p.o.) selectively inhibits the virusencoded DNA polymerase of woodchuck hepatitis virus found in the serum of chronically infected woodchucks. This inhibitory effect was immediate, nontoxic, and long lasting compared with the effects of 2'-fluoro-5-methyl-1-P-D-arabinofuranosyluracil (FMAU), 6-deoxyacyclovir(9-(2-hydroxethoxymethyl)-2-aminopurine), 9-(1,3-dihydroxy-2-* Corresponding author.

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“…ddC is a potent anti-HIV deoxycytidine analog that is also phosphorylated in cells (Balzarini et al, 1988). FMAU was found to have potent activities against herpes viruses and HBV (Kong et al, 1988;Fourel et al, 1992). The clinical studies were discontinued because of toxicity (Abbruzzese et al, 1989).…”

mentioning

confidence: 99%

Assessment of the Effect of Phosphorylated Metabolites of Anti-Human Immunodeficiency Virus and Anti-Hepatitis B Virus Pyrimidine Analogs on the Behavior of Human Deoxycytidylate Deaminase

et al. 2003

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Deoxycytidylate deaminase, catalyzing the conversion of dCMP to dUMP, is an important enzyme in the de novo synthesis of thymidine nucleotides. It also may be involved in the action, as well as the metabolism of anticancer agents. Recently, several L-and D-configuration pyrimidine deoxynucleoside analogs were found to be potent antiviral and antitumor agents. Their interaction with dCMP deaminase as a monophosphate or a triphosphate metabolite is not clear. These include D-nucleoside analogs such as-fluorocytidine, and L-FMAU. None of the L-deoxycytidine analog monophosphates act as substrates or inhibitors. Among these pyrimidine deoxynucleoside analog monophosphates, D-FMAU monophosphate (MP) is the most potent competitive inhibitor, whereas L-FMAUMP has no inhibitory activity. Interestingly, AZTMP and D4TMP also have potent inhibitory activities on dCMP deaminase. Among the dCTP and TTP analogs examined, D-and L-FMAUTP were the most potent inhibitors and had the same extent of inhibitory effect. These results suggest that a chiral specificity for the substrate-binding site may exist, but there is no chiral specificity for the regulator-binding site. This is also supported by the observation that L-OddC and L-FSddC have inhibitory activities as triphosphates but not as monophosphates. None of the D-and L-dCTP analogs activated dCMP deaminase as dCTP. The biological activities of AZT and D4T could be partially attributable to their inhibitory activity against dCMP deaminase by their phosphorylated metabolites, whereas that of ddC and the L-deoxycytidine analogs may not involve dCMP deaminase directly.

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Incorporation and metabolism of 2′-fluoro-5-substituted arabinosyl pyrimidines and their selective inhibition of viral DNA synthesis in herpes simplex virus type 1 (HSV-1)-infected and mock-infected Vero cells

Cited by 18 publications

References 10 publications

Inhibition of B Virus (Macacine herpesvirus1) by Conventional and Experimental Antiviral Compounds

Inhibition of B Virus (Macacine herpesvirus1) by Conventional and Experimental Antiviral Compounds

Preclinical pharmacology and pharmacokinetics of the anti-hepatitis virus agent 2'-fluoro-5-ethyl-1-beta-D-arabinofuranosyluracil in mice and rats

Assessment of the Effect of Phosphorylated Metabolites of Anti-Human Immunodeficiency Virus and Anti-Hepatitis B Virus Pyrimidine Analogs on the Behavior of Human Deoxycytidylate Deaminase

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