Prophylactic and therapeutic activities of 7-thia-8-oxoguanosine against Punta Toro virus infections in mice

Smee, Donald F.; Huffman, John H.; Gessaman, Ann C.; Huggins, John W.; Sidwell, Robert W.

doi:10.1016/0166-3542(91)90069-4

Cited by 26 publications

(20 citation statements)

References 19 publications

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“…This association indicates that isatoribine must induce an immune response to achieve an anti-HCV effect, consistent with preclinical data. [18][19][20][21] Although OAS and viral concentrations showed little or no change after a single dose of 800 mg isatoribine, these biological markers were substantially changed both immediately before and 24 hours after the 7th daily dose. Circulating neopterin and IP10 were elevated after 6 days of once-daily administration of 800 mg isatoribine, providing additional evidence of immunological activation that is consistent with a TLR7 agonist mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…14 In preclinical studies, isatoribine does not exhibit direct antiviral activity or significant cytotoxicity in vitro; however, through stimulation of innate immunity, isatoribine does prevent or reverse otherwise lethal viral infections in various acute infection models in mice. [18][19][20][21] Based on this preclinical profile, and in view of the need for new anti-HCV therapies, we performed a clinical proof-of-concept study with isatoribine to determine whether treatment with a TLR7 agonist can achieve a demonstrable antiviral effect at a well-tolerated dose in patients chronically infected with HCV.…”

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confidence: 99%

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Isatoribine, an Agonist of TLR7, Reduces Plasma Virus Concentration in Chronic Hepatitis C Infection *

et al. 2005

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Immune-based therapy is the mainstay treatment for chronic hepatitis C virus (HCV) infection but causes multiple side effects and achieves durable viral clearance in only approximately 50% of patients. Most new investigational anti-HCV compounds are direct-acting antivirals for which durability of response and risk of viral mutations and resistance are not yet known. Therefore, continuing discovery and development of new immune-based treatments is desirable. Toll-like receptors (TLRs) are pathogen recognition receptors that initiate the innate immune response. The responsiveness of HCV or other ongoing chronic systemic infections to treatment with a selective TLR agonist has not been reported. Isatoribine is a selective agonist of TLR7. In a proof-of-concept study, we found that once-daily 7-day treatment with intravenous isatoribine 800 mg caused a significant (P ‫؍‬ .001) reduction of plasma HCV RNA (mean, ؊0.76; range, ؊2.85 to ؉0.21 log 10 units) in otherwise untreated patients (n ‫؍‬ 12) who were chronically infected with HCV. Viral load reduction occurred in patients infected with genotype 1 as well as non-genotype 1 HCV. The reduction of viral load was correlated with induction of markers of a heightened immune antiviral state, including 2-, 5-oligoadenylate synthetase levels in whole blood. This treatment was well tolerated, with a low frequency of mild to moderate adverse events. In conclusion, systemic administration of the selective TLR7 agonist isatoribine resulted in dose-dependent changes in immunologic biomarkers and a statistically significant antiviral effect with relatively few and mild side effects. ( C hronic infection with hepatitis C virus (HCV) is a major cause of morbidity and mortality, affecting 170 million persons worldwide. 1,2 Although chronic HCV infection is largely asymptomatic, persistent infection over many years significantly increases the risk of cirrhosis, hepatocellular carcinoma, and end-stage liver disease. [1][2][3][4] The current standard-of-care treatment for HCV infection is immune based, consisting of an injectable interferon-alpha product (a type 1 cytokine) in combination with the orally administered nucleoside analog ribavirin. 1,5,6 This treatment can durably clear HCV from approximately 50% of treated patients but has multiple side effects that often result in early abandonment of treatment. Thus, a need remains for novel anti-HCV therapies to improve response rates and reduce adverse effects.A variety of investigational anti-HCV compounds are approaching or undergoing clinical studies. 7 Aside from modified versions of interferon-alpha and ribavirin, most investigational compounds are direct-acting antivirals that bind to virally encoded targets. Whether durable virological responses can be achieved with direct-acting anti-HCV agents is unknown. Moreover, the high rate and low fidelity of HCV replication may lead to rapid emergence of resistance to direct-acting antivirals. 8,9 In light of these uncertainties, continuing to explore immune stimulation as an appro...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Isatoribine, an Agonist of TLR7, Reduces Plasma Virus Concentration in Chronic Hepatitis C Infection *

et al. 2005

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“…Both agents induced a rapid (within 1 h of treatment) production of interferon. Recent work has shown that interferon induction is of major importance in the antiviral activity of TOGuo against Semliki Forest (16) and Punta Toro (17) virus infection in mice. In both models, antibody to alpha/beta interferon completely abrogated the protective effect of treatment.…”

Section: Discussionmentioning

confidence: 99%

“…TOGuo has no in vitro antiviral activity against a large number of DNA and RNA viruses, however. The effects in animals are primarily due to interferon induction (16,17), although natural killer (NK) cells (6,16), lymphocytes (6), and macrophages (3,7) are also activated. The role of interferon in combating acute virus infections has been well documented (5,8), whereas activated cells of the immune system, although necessary in the overall fight against virus infections, seem to play a lesser role (1,21).…”

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confidence: 99%

Immunoenhancing properties and antiviral activity of 7-deazaguanosine in mice

Smee

Alaghamandan

Gilbert

et al. 1991

Antimicrob Agents Chemother

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The nucleotide analog 7-deazaguanosine has not previously been reported to possess biological (antiviral or antitumor) properties in cell culture or in vivo. Up to 10(5) U of interferon per ml was detected in mouse sera 1 to 4 h following oral (200-mg/kg of body weight) and intraperitoneal (50-mg/kg) doses of the compound. 7-Deazaguanosine also caused significant activation of natural killer and phagocytic cells but did not augment T- and B-cell blastogenesis. Intraperitoneal treatments of 50, 100, and 200 mg/kg/day administered 24 and 18 h before virus inoculation were highly protective in mice inoculated with lethal doses of Semliki Forest or San Angelo viruses. Less but still significant survivor increases were evident in treated mice infected with banzi or encephalomyocarditis viruses. In most cases, the degree of antiviral activity was similar to that exhibited by the biological response modifier 7-thia-8-oxoguanosine. 7-Thia-8-oxoguanosine was more potent than 7-deazaguanosine against encephalomyocarditis virus in mice, however. Oral efficacy was achieved with 7-deazaguanosine treatments of greater than or equal to 100 mg/kg against all virus infections, whereas 7-thia-8-oxoguanosine is reported to be devoid of oral activity in rodents. Thus, 7-deazaguanosine represents the first reported orally active nucleoside biological response modifier exhibiting broad-spectrum antiviral activity against particular types of RNA viruses.

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“…The availability of these rodent models makes PTV a viable alternative to the use of Rift Valley fever virus for antiviral studies because the latter is highly restricted and requires high-level containment facilities. To that end, numerous evaluations of promising antivirals have been conducted using the PTV models of acute phlebovirus-induced disease (5)(6)(7)(8)(9)(10)(11)(12). Moreover, several large studies have involved the evaluation of immune modulators and have demonstrated that the PTV is acutely sensitive to IFN inducers (5,10).…”

Section: P Unta Toro Virus (Ptv)mentioning

confidence: 99%

TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules

Gowen

Wong

Jung

et al. 2007

The Journal of Immunology

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104

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In the wake of RNA virus infections, dsRNA intermediates are often generated. These viral pathogen-associated molecular patterns can be sensed by a growing number of host cell cytosolic proteins and TLR3, which contribute to the induction of antiviral defenses. Recent evidence indicates that melanoma differentiation-associated gene-5 is the prominent host component mediating IFN production after exposure to the dsRNA analog, poly(I:C). We have previously reported that Punta Toro virus (PTV) infection in mice is exquisitely sensitive to treatment with poly(I:C12U), a dsRNA analog that has a superior safety profile while maintaining the beneficial activity of the parental poly(I:C) in the induction of innate immune responses. The precise host factor(s) mediating protective immunity following its administration remain to be elucidated. To assess the role of TLR3 in this process, mice lacking the receptor were used to investigate the induction of protective immunity, type I IFNs, and IL-6 following treatment. Unlike wild-type mice, those lacking TLR3 were not protected against PTV infection following poly(I:C12U) therapy and failed to produce IFN-α, IFN-β, and IL-6. In contrast, poly(I:C) treatment significantly protected TLR3−/− mice from lethal challenge despite some deficiencies in cytokine induction. There was no indication that the lack of protection was due to the fact that TLR3-deficient mice had a reduced capacity to fight infection because they were not found to be more susceptible to PTV. We conclude that TLR3 is essential to the induction of antiviral activity elicited by poly(I:C12U), which does not appear to be recognized by the cytosolic sensor of poly(I:C), melanoma differentiation-associated gene-5.

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Prophylactic and therapeutic activities of 7-thia-8-oxoguanosine against Punta Toro virus infections in mice

Cited by 26 publications

References 19 publications

Isatoribine, an Agonist of TLR7, Reduces Plasma Virus Concentration in Chronic Hepatitis C Infection *

Isatoribine, an Agonist of TLR7, Reduces Plasma Virus Concentration in Chronic Hepatitis C Infection *

Immunoenhancing properties and antiviral activity of 7-deazaguanosine in mice

TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules

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