T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections

Abstract

A series of pyrazinecarboxamide derivatives T-705 (favipiravir), T-1105 and T-1106 were discovered to be candidate antiviral drugs. These compounds have demonstrated good activity in treating viral infections in laboratory animals caused by various RNA viruses, including influenza virus, arenaviruses, bunyaviruses, West Nile virus (WNV), yellow fever virus (YFV), and foot-and-mouth disease virus (FMDV). Treatment has in some cases been effective when initiated up to 5-7 days after virus infection, when the animals already showed signs of illness. Studies on the mechanism of action of T-705 have shown that this compound is converted to the ribofuranosyltriphosphate derivative by host enzymes, and this metabolite selectively inhibits the influenza viral RNA-dependent RNA polymerase without cytotoxicity to mammalian cells. Interestingly, these compounds do not inhibit host DNA and RNA synthesis and inosine 5'-monophosphate dehydrogenase (IMPDH) activity. From in vivo studies using several animal models, the pyrazinecarboxamide derivatives were found to be effective in protecting animals from death, reducing viral burden, and limiting disease manifestations, even when treatment was initiated after virus inoculation. Importantly, T-705 imparts its beneficial antiviral effects without significant toxicity to the host. Prompt development of these compounds is expected to provide effective countermeasures against pandemic influenza virus and several bioweapon threats, all of which are of great global public health concern given the current paucity of highly effective broad-spectrum drugs.

Fig. 1

Chemical structure of T-705, T-1105 and T-1106.

Fig. 2

Mode of action of T-705 and other anti-influenza drugs. T-705 is converted to the ribofuranosyl triphosphate form and inhibits influenza virus RNA polymerase in the host cells. Amantadine inhibits virus M2 proteins, and oseltamivir inhibits the release of virus.

Fig. 3

Survival of Pichinde virus-infected hamsters treated with T-705 or placebo beginning on day 6 or 7 post-infection. T-705 was given twice daily at 320 mg/kg/day on the first day and 100 mg/kg/day thereafter. ***P < 0.001 compared to respective placebo-treated hamsters by log-rank test (Gowen et al., 2007).

Fig. 4

Survival of YFV-infected hamsters treated i.p. with 100 mg/kg/day of T-1106 starting at various times after virus challenge. beg, beginning of treatment. ***P < 0.001, **P < 0.01 compared to placebo-treated animals (Julander et al., 2007).

Fig. 5

(A) Effect of twice-daily oral treatment with 200 mg/kg of T-705 beginning on day 1, 2 or 3 post-infection on the survival of WNV-infected C57Bl/6 mice. *P ≤ 0.05, **P ≤ 0.01 compared to placebo controls. (B) Immunohistochemical detection of WNV envelope glycoprotein on day 7 of infection in the brains of Syrian golden hamsters treated twice daily with 200 mg/kg of T-705 or with a placebo beginning on the day of infection. Scale bar: 50 μm (Morrey et al., 2008).