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In vitro and in vivo activities of anti-influenza virus compound T-705
Y Furuta1, K Takahashi, Y Fukuda
1Research Laboratories, Toyama Chemical Co., Ltd., 2-4-1 Shimookui, Toyama, Japan. YOUSUKE_FURUTA@toyama-chemical.co.jp
Abstract:
T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) has been found to have potent and selective inhibitory activity against influenza virus. In an in vitro plaque reduction assay, T-705 showed potent inhibitory activity against influenza A, B, and C viruses, with 50% inhibitory concentrations (IC(50)s) of 0.013 to 0.48 microg/ml, while it showed no cytotoxicity at concentrations up to 1,000 microg/ml in Madin-Darby canine kidney cells. The selectivity index for influenza virus was more than 2,000. It was also active against a neuraminidase inhibitor-resistant virus and some amantadine-resistant viruses. T-705 showed weak activity against non-influenza virus RNA viruses, with the IC(50)s being higher for non-influenza virus RNA viruses than for influenza virus, and it had no activity against DNA viruses. Orally administered T-705 at 100 mg/kg of body weight/day (four times a day) for 5 days significantly reduced the mean pulmonary virus yields and the rate of mortality in mice infected with influenza virus A/PR/8/34 (3 x 10(2) PFU). These results suggest that T-705 may be a compound that is useful and highly selective against influenza virus infections and that has a mode of action different from those of commercially available drugs, such as amantadine, rimantadine, and neuraminidase inhibitors.
Insights
T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is a potent antiviral agent effective against influenza A, B, and C viruses. This novel compound demonstrates high selectivity and a unique mechanism of action, offering promise for treating influenza infections.
Area of Science:
- Virology
- Antiviral Drug Discovery
- Infectious Diseases
Background:
- Influenza viruses pose a significant global health threat.
- Existing antiviral drugs face challenges with resistance and varying efficacy.
- Novel therapeutic agents with distinct mechanisms are needed.
Purpose of the Study:
- To evaluate the antiviral activity and selectivity of T-705 against influenza viruses.
- To assess the efficacy of T-705 in a preclinical mouse model of influenza infection.
- To explore the potential of T-705 as a new treatment for influenza.
Main Methods:
- In vitro plaque reduction assays were used to determine 50% inhibitory concentrations (IC50s) against various influenza strains.
- Cytotoxicity assays were performed on Madin-Darby canine kidney cells.
- In vivo studies involved oral administration of T-705 to influenza A virus-infected mice.
Main Results:
- T-705 exhibited potent activity against influenza A, B, and C viruses with low IC50 values and no observed cytotoxicity.
- The compound demonstrated a high selectivity index (>2,000) for influenza viruses.
- T-705 was effective against resistant strains and reduced viral load and mortality in infected mice.
Conclusions:
- T-705 is a highly selective and potent inhibitor of influenza virus replication.
- Its distinct mechanism of action differentiates it from current influenza therapeutics.
- T-705 shows significant promise as a novel antiviral agent for influenza treatment.