The Intracellular Formation of a Mononucleotide of the Anti-Influenza Agent 1,3,4-thiadiazol-2-ylcyanamide (LY217896)

Birch, G. M.; Colacino, Joseph M.; Ehlhardt, William J.; Balzarini, Jan

doi:10.1177/095632029500600301

Cited by 6 publications

(4 citation statements)

References 26 publications

(40 reference statements)

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“…Analogues of a nucleic acid have been known to exhibit antiviral activity through intracellular metabolism to the phosphates. 1,3,4-Thiadiazol-2-ylcyanamide (LY217896), which had anti-influenza virus activity in vitro and in a mouse model of infection (8), was metabolized in BS-C-1 cells to the monophosphate form and inhibited IMPDH (1). It has been reported that ribavirin as a pseudobase could equivalently pair with both cytosine and uracil due to rotation of the carboxamide moiety and that RNA viruses, such as poliovirus and hepatitis C virus, use ribavirin triphosphate as a substrate for the viral RNA polymerase, and ribavirin incorporation was also found to be mutagenic (4,12).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Action of T-705 against Influenza Virus

Furuta

Takahashi

Kuno-Maekawa

et al. 2005

Antimicrob Agents Chemother

498

483

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T-705, a substituted pyrazine compound, has been found to exhibit potent anti-influenza virus activity in vitro and in vivo. In a time-of-addition study, it was indicated that T-705 targeted an early to middle stage of the viral replication cycle but had no effect on the adsorption or release stage. The anti-influenza virus activity of T-705 was attenuated by addition of purines and purine nucleosides, including adenosine, guanosine, inosine, and hypoxanthine, whereas pyrimidines did not affect its activity. T-705-4-ribofuranosyl-5-triphosphate (T-705RTP) and T-705-4-ribofuranosyl-5-monophosphate (T-705RMP) were detected in MDCK cells treated with T-705. T-705RTP inhibited influenza virus RNA polymerase activity in a dose-dependent and a GTP-competitive manner. Unlike ribavirin, T-705 did not have an influence on cellular DNA or RNA synthesis. Inhibition of cellular IMP dehydrogenase by T-705RMP was about 150-fold weaker than that by ribavirin monophosphate, indicating the specificity of the anti-influenza virus activity and lower level of cytotoxicity of T-705. These results suggest that T-705RTP, which is generated in infected cells, may function as a specific inhibitor of influenza virus RNA polymerase and contributes to the selective anti-influenza virus activity of T-705.Influenza is responsible for much morbidity and mortality in the world (7), and effective treatment is required. We now have two classes of drugs for the treatment of influenza, the ion channel blockers and the neuraminidase inhibitors. The ion channel blockers amantadine and rimantadine are of limited use because of a lack of activity against influenza B virus, side effects, and the rapid emergence of resistant virus strains (9). Neuraminidase inhibitors are effective against both influenza A and B viruses, and their usefulness in clinical treatment has been reported (2, 11). Ribavirin is a guanosine analogue and inhibits various RNA and DNA viruses, including influenza viruses (19). Its clinical efficacy against influenza virus after aerosol treatment of infected individuals has been reported (5), but it has been approved for use in only a few countries. Influenza viruses are able to undergo rapid antigenic changes, especially in the surface glycoproteins, and novel influenza virus variants which have high levels of virulence may emerge in the human population and cause severe disease. Therefore, exploration for novel anti-influenza virus agents is of most importance.T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent inhibitory activity against RNA viruses in vitro, especially influenza A, B, and C viruses. The selectivity index (the ratio of the 50% cell-inhibitory concentration [CC 50 ]/50% influenza virus-inhibitory concentration [IC 50 ]) was more than 6,000 (Table 1) (6). T-705 showed therapeutic efficacy in mouse infection models and had a profile different from those of ribavirin and oseltamivir (16).The present study describes an experimental approach to clarifying the mode of action of T-705, and the ...

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Section: Discussionmentioning

confidence: 99%

Mechanism of Action of T-705 against Influenza Virus

Furuta

Takahashi

Kuno-Maekawa

et al. 2005

Antimicrob Agents Chemother

498

483

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“…94 All these are cytostatic molecules mainly explored as anticancer agents. 180 The substituted thiadiazole compound LY217896 was shown to display broad anti-influenza virus activity 95 via IMPDH inhibition, 181 but proved ineffective in a placebo-controlled clinical trial. 182…”

Section: Ribavirin and Structurally Related Carboxamide Analoguesmentioning

confidence: 99%

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Stevaert

Naesens

2016

Medicinal Research Reviews

136

151

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Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

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“…Along these lines, it was shown that the antiviral activity and cytotoxicity of LY217896 were correlated with the formation of an intracellular metabolite (Colacino et al, 1993). This metabolite was subsequently characterized as a mononucleotide, mesoionic species that was able to inhibit IMPDH (Ehlhardt et al, 1993;Birch et al, 1995). Thus the reversal of the biological activity of LY217896 by guanosine could be explained by the drop in GTP pools as a result of the inhibition of IMPDH by the metabolite of LY217896.…”

Section: Inhibition Of Transcription Translation and Replicationmentioning

confidence: 99%

Approaches and Strategies for the Treatment of Influenza Virus Infections

Colacino

Staschke

Laver

1999

Antivir Chem Chemother

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Influenza A and B viruses belong to theOrthomyxoviridae family of viruses. These viruses are responsible for severe morbidity and significant excess mortality each year. Infection with influenza viruses usually leads to respiratory involvement and can result in pneumonia and secondary bacterial infections. Vaccine approaches to the prophy-laxis of influenza virus infections have been problematic owing to the ability of these viruses to undergo antigenic shift by exchanging genomic segments or by undergoing antigenic drift, consisting of point mutations in the haemagglutinin (HA) and neuraminidase (NA) genes as a result of an error-prone viral polymerase. Historically, antiviral approaches for the therapy of both influenza A and B viruses have been largely unsuccessful until the elucidation of the X-ray crystallographic structure of the viral NA, which has permitted structure-based drug design of inhibitors of this enzyme. In addition, recent advances in the elucidation of the structure and complex function of influenza HA have resulted in the discovery of a number of diverse compounds that target this viral protein. This review article will focus largely on newer antiviral agents including those that inhibit the influenza virus NA and HA. Other novel approaches that have entered clinical trials or been considered for their clinical utility will be mentioned. Keywords: Influenza virus; haemagglutinin; neuraminidase; amantadine; ribavirin; zanamivir; GS 4104Infection with influenza viruses can result in an infectious disease for which there is no adequate control. Killed influenza vaccines against this virus have been available for nearly 70 years but, on a community-wide basis, the use of these vaccines has not resulted in a significant decrease in the morbidity or mortality of this disease and has not alleviated the severe financial loss which occurs as a result of hospitalizations and lost productivity. Currently, the only compounds approved by the US FDA for the treatment of influenza infections are amantadine and rimantadine, both of which target the M2 ion channel protein of the virus (Pinto et al., 1992). However, these compounds are not effective against influenza B virus, which does not have an M2 ion channel. Also, virus mutants resistant to amantadine or rimantadine can be isolated readily from individuals treated with these drugs Hayden et al., 1989). Recently, it has been suggested that resistance to amantadine can be overcome by mixing amantadine with other amantadine derivatives that interfere with the ion channel function of M2 from amantadine-resistant viruses (Scholtissek et al., 1998). Ribavirin, a broad-spectrum antiviral agent Witkowski et al., 1972;Huffman et al., 1973;Oxford, 1975) has been considered for use against influenza A and B viruses, but the clinical trials of this compound have not been encouraging (Cohen et al., 1976;Togo & McCracken, 1976;Magnussen et al., 1977;Smith et al., 1980;Stein et al., 1987) and it has not been approved for the treatment of influenza virus infection.Hist...

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The Intracellular Formation of a Mononucleotide of the Anti-Influenza Agent 1,3,4-thiadiazol-2-ylcyanamide (LY217896)

Cited by 6 publications

References 26 publications

Mechanism of Action of T-705 against Influenza Virus

Mechanism of Action of T-705 against Influenza Virus

The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

Approaches and Strategies for the Treatment of Influenza Virus Infections

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