Modulation of leukocyte genetic expression by novel purine nucleoside analogs. A new approach to antitumor and antiviral agents

Bonnet, Pierre-Antoine; Robins, Roland K.

doi:10.1021/jm00058a001

Cited by 55 publications

(22 citation statements)

References 68 publications

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“…Surprisingly, no direct in vitro antiviral activity in virus-infected cells was observed with these compounds (5). Therefore, the in vivo antiviral activity of 7-thia-8-oxoguanosine was attributed to immunomodulatory effects, especially interferon induction (27,29 (Fig.…”

Section: Discussionmentioning

confidence: 98%

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

Lewis

Drach

Fennewald

et al. 1994

Antimicrob Agents Chemother

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A series of alkyl and alkenyl guanine analogs containing a thiazolo [4,5-d]pyrimidine ring system were prepared by reaction of the appropriate alkyl halide with the sodium salt of the heterocycle. In preliminary antiviral efficacy evaluations against laboratory strains of both human cytomegalovirus (HCMV) and herpes simplex virus types 1 and 2, it was determined that two of the compounds (T70072 and T01132) were more active and less toxic in stationary-phase cell monolayers than were the other derivatives tested. T01132 and T70072, which have 2-pentenyl and 3-methyl-2-butenyl moieties attached to position 3 of the 5-aminothiazolo[4,5-dlpyrimidine-2,7-dione, respectively, were then more extensively evaluated for anti-HCMV activity.The concentrations of T01132 and T70072 required to inhibit HCMV by 50%o in plaque reduction assays were -0.5 and 6.8 ,iM, respectively. These two compounds inhibited the growth of KB, or Vero cells at concentrations of 75 to 150 ,uM, depending upon the cell line. In bone marrow progenitor cells T01132 was slightly less toxic than ganciclovir (DHPG). The 50%o inhibitory concentrations of T01132 against clinical isolates and DHPG-resistant strains of HCMV were approximately the same as those obtained for laboratory strains of HCMV (-0.5 jiM). When tested in combination with DHPG, the resultant antiviral activity was determined to be additive but not synergistic. Experiments performed using variations of the viral multiplicity of infection (MOI) demonstrated that T01132 was more active than DHPG at a low MOI (0.002 or 0.02). However, when a higher MOI (0.2 or 2.0) was used, DHPG was more efficacious than T01132. In experiments in which drug was added at various times post-viral infection, T01132 was most effective when added within the first 24 h post-HCMV infection while DHPG was able to protect cells in this assay system when added up to 48 h postinfection, indicating that T01132 is exerting its antiviral effect on events leading up to and possibly including viral DNA synthesis. The data presented in this report suggest that the antiviral activity of alkenyl-substituted thiazolopyrimidine derivatives may represent a mechanism of action against herpesviruses alternative to that of classical nucleoside analogs such as acyclovir or DHPG.

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Section: Discussionmentioning

confidence: 98%

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

Lewis

Drach

Fennewald

et al. 1994

Antimicrob Agents Chemother

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“…Differences in enzymatic phosphorylation have been reported for enantiomeric guanosine nucleoside analogs (28). The mechanism(s) for immunomodulation by purine nucleoside analogs may not require phosphorylation (5,14), and thus differences in phosphorylation may account for at least some of the distinguishing properties we report here for ribavirin and ICN 17261. However, additional work is needed to confirm this hypothesis.…”

Section: Downloaded Frommentioning

confidence: 87%

The Ribavirin Analog ICN 17261 Demonstrates Reduced Toxicity and Antiviral Effects with Retention of both Immunomodulatory Activity and Reduction of Hepatitis-Induced Serum Alanine Aminotransferase Levels

Tam¹,

Ramasamy²,

Bard³

et al. 2000

Antimicrob Agents Chemother

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The demonstrated utility of the nucleoside analog ribavirin in the treatment of certain viral diseases can be ascribed to its multiple distinct properties. These properties may vary in relative importance in differing viral disease conditions and include the direct inhibition of viral replication, the promotion of T-cell-mediated immune responses via an enhanced type 1 cytokine response, and a reduction of circulating alanine aminotransferase (ALT) levels associated with hepatic injury. Ribavirin also has certain known toxicities, including the induction of anemia upon chronic administration. To determine if all these properties are linked, we compared the D-nucleoside ribavirin to its L-enantiomer (ICN 17261) with regard to these properties. Strong similarities were seen for these two compounds with respect to induction of type 1 cytokine bias in vitro, enhancement of type 1 cytokine responses in vivo, and the reduction of serum ALT levels in a murine hepatitis model. In contrast, ICN 17261 had no in vitro antiviral activity against a panel of RNA and DNA viruses, while ribavirin exhibited its characteristic activity profile. Importantly, the preliminary in vivo toxicology profile of ICN 17261 is significantly more favorable than that of ribavirin. Administration of 180 mg of ICN 17261 per kg of body weight to rats by oral gavage for 4 weeks generated substantial serum levels of drug but no observable clinical pathology, whereas equivalent doses of ribavirin induced a significant anemia and leukopenia. Thus, structural modification of ribavirin can dissociate its immunomodulatory properties from its antiviral and toxicologic properties, resulting in a compound (ICN 17261) with interesting therapeutic potential.Ribavirin (1-␤-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) is a nucleoside analog that has demonstrated efficacy in treating viral disease as monotherapy (respiratory syncytial virus [RSV] [15]) and in combination with alpha interferon (IFN-␣) (hepatitis C virus [HCV] [27,36]). Ribavirin has multiple biologic properties that are favorable for treating viral diseases. It can directly inhibit the replication of many DNA and RNA viruses (38). More recently, studies have shown that it can also act as an immunomodulator and thus promote T-cell-mediated immunity against viral infection (18,25,30,39,40). The central focus of this effect of ribavirin is the augmentation of antiviral type 1 cytokine expression (interleukin-2 [IL-2], gamma interferon [IFN-␥], and tumor necrosis factor alpha [TNF-␣]) and concomitant suppression of type 2 cytokine levels by activated T cells in both human and murine systems. Finally, ribavirin, alone or in combination with IFN-␣, can lower serum alanine aminotransferase (ALT) levels during the course of treatment of HCV infection (11). Elevated serum ALT levels are a marker for liver damage and progressive hepatitis, and hence the ribavirin-mediated lowering of ALT levels is a distinct liver-specific effect of this nucleoside analog.The therapeutic use of ribavirin is restric...

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“…The activation effects of 8Brguo are not directly dependent on metabolism through purine salvage routes or the protein kinase C pathway [19,20], but there is evidence of protein G involvement as a signal transducer in macrophages [5]. Also, it has been documented that guanosine analogues activate a broad range of immunological functions including increased cytokine production such as tumor necrosis factor, interferons ·, ß and Á and interleukin 1 [3,4,21,22], and both the respiratory burst and cytotoxicity of macrophages [5,21].…”

Section: Discussionmentioning

confidence: 99%

“…The substitution of guanine ribonucleosides at the carbon 8 position produced a class of immunostimulatory compounds among which the best studied are 8-bromoguanosine (8Brguo) and 7-ally-8-oxoguanosine [3,4]. These nucleosides activate a broad range of immunological functions, such as differentiation of B cells, natural killer cell-mediated cytotoxicity, increase in cytokine pro-duction and both the respiratory burst and cytotoxicity of macrophages [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

“…These nucleosides activate a broad range of immunological functions, such as differentiation of B cells, natural killer cell-mediated cytotoxicity, increase in cytokine pro-duction and both the respiratory burst and cytotoxicity of macrophages [3][4][5]. Consistent with this profile of immune stimulation, these nucleosides have been found to be active in mouse models for the treatment of viral infections and as cancer chemotherapeutic agents [4]. The clinical application of the nucleosides as anti-tumor and immunostimulant agents is presently underway and offers an alternative to chemotherapy with highly cytotoxic drugs [6].…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of 8-Bromoguanosine against Murine Cutaneous Leishmaniasis Induced with <i>Leishmania amazonensis</i>

Barão

Giorgio²

2003

Chemotherapy

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Background and Methods: In this study, we investigated the effect of 8-bromoguanosine (8Brguo), an immunostimulatory compound, in a murine model of experimental cutaneous leishmaniasis. Results: The results indicated that treatment by intraperitoneal administration of 8Brguo (150 mg/kg once daily for 1 week and thereafter once weekly for 1 month) diluted in Tween-80 produces an effect similar to that of treatment with the classical antimonial drug, Glucantime, in Leishmania amazonensis-infected CBA/J mice. While complete cure did not occur, animals treated with the nucleoside had small lesions in the infected footpad and delayed surface ulceration. Studies involving examination of serum glutamic pyruvic transaminase activity, concentration of urea, blood pathology and histology of the spleen, kidney and liver showed no apparent toxicity of the nucleoside in treated mice. Conclusion: The protective in vivo effect during murine leishmaniasis as well as the lack of apparent toxicity of 8Brguo as attested by blood/serum pathology and histology from treated mice encourage further studies of C8-substituted guanine ribonucleosides, such as 8Brguo, as new leishmanial drugs and as modifiers of the immunological response to combat infections with intracellular pathogens.

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Modulation of leukocyte genetic expression by novel purine nucleoside analogs. A new approach to antitumor and antiviral agents

Cited by 55 publications

References 68 publications

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

Inhibition of human cytomegalovirus in culture by alkenyl guanine analogs of the thiazolo[4,5-d]pyrimidine ring system

The Ribavirin Analog ICN 17261 Demonstrates Reduced Toxicity and Antiviral Effects with Retention of both Immunomodulatory Activity and Reduction of Hepatitis-Induced Serum Alanine Aminotransferase Levels

Efficacy of 8-Bromoguanosine against Murine Cutaneous Leishmaniasis Induced with <i>Leishmania amazonensis</i>

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