Favipiravir (T-705), a novel viral RNA polymerase inhibitor

Abstract

Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an antiviral drug that selectively inhibits the RNA-dependent RNA polymerase of influenza virus. It is phosphoribosylated by cellular enzymes to its active form, favipiravir-ribofuranosyl-5'-triphosphate (RTP). Its antiviral effect is attenuated by the addition of purine nucleic acids, indicating the viral RNA polymerase mistakenly recognizes favipiravir-RTP as a purine nucleotide. Favipiravir is active against a broad range of influenza viruses, including A(H1N1)pdm09, A(H5N1) and the recently emerged A(H7N9) avian virus. It also inhibits influenza strains resistant to current antiviral drugs, and shows a synergistic effect in combination with oseltamivir, thereby expanding influenza treatment options. A Phase III clinical evaluation of favipiravir for influenza therapy has been completed in Japan and two Phase II studies have been completed in the United States. In addition to its anti-influenza activity, favipiravir blocks the replication of many other RNA viruses, including arenaviruses (Junin, Machupo and Pichinde); phleboviruses (Rift Valley fever, sandfly fever and Punta Toro); hantaviruses (Maporal, Dobrava, and Prospect Hill); flaviviruses (yellow fever and West Nile); enteroviruses (polio- and rhinoviruses); an alphavirus, Western equine encephalitis virus; a paramyxovirus, respiratory syncytial virus; and noroviruses. With its unique mechanism of action and broad range of antiviral activity, favipiravir is a promising drug candidate for influenza and many other RNA viral diseases for which there are no approved therapies.

Keywords: Favipiravir; Influenza; RNA viruses; RNA-dependent RNA polymerase; T-705.

Figure 1

Chemical structure of Favipiravir (T-705), T-1105 and T-1106.

Figure 2

Favipiravir time-of-addition analysis. MDCK cells were inoculated with influenza A/PR/8/34 virus at a multiplicity of infection of 0.001. Favipiravir was added at the indicated periods. Viral yields were determined at 10 h post-infection by plaque assays. The columns show the mean of viral yield in cells treated with favipiravir (10 μg/ml). Vertical lines represent standard deviations (n=3). Two independent experiments were done, and representative data are shown. * P < 0.05, ** P < 0.01, compared to respective control groups (Student’s t test). (Based on Furuta et al., 2005)

Figure 3

Competetive inhibition of favipiravir activity by addition of excess nucleic acids and nucleosides. The number of plaque was counted and is given as a percentage of the number of plaques for the nontreated control. All nucleosides and bases were added at 10-fold molarity of the 50% effective concentration (EC₅₀) of favipiravir. * P < 0.01 compared to favipiravir alone treated group (Dunnett’s test). (Based on Furuta et al., 2005)

Figure 4

Incorporation and inhibition of T-705RTP against influenza virus RdRP. (A) Incorporation of GTP and T-705RTP at the position of G11+2. The 32P-labeled pGEM-7zf (+) DNA run-off transcript with a 5′Cap1 structure (Cap1-pGEM-mRNA), crude influenza virus RdRp containing a viral genome, and nucleotides including T-705RTP were incubated. Reaction products were then electrophoresed. Lane 1–5: Cap1-pGEM-mRNA and crude enzyme solution + 50 μM CTP; Lane 2, 3: Conditions of lane 1 + 100 and 1,000 μM GTP; Lane 4, 5: Conditions of lane 2 + 100 and 1,000 μM T-705RTP. (B) Inhibition of T-705RTP against influenza virus RdRp The 32P-labeled pGEM-7zf (+) DNA run-off transcript with a 5′Cap1 structure (Cap1-pGEM-mRNA), crude influenza virus RdRp containing a viral genome, and nucleotides including T-705RTP were incubated. Reaction products were then electrophoresed. Lane 1: Cap1-pGEM-mRNA; Lane 2–6: Cap1-pGEM-mRNA + crude enzyme solution; Lane 3–6: Conditions of lane 2 + 50 μM CTP, 100 μM ATP, 50 μM GTP; Lanes 4–6: Conditions of lane 3 + 10, 100, and 1,000 μM T-705RTP * Elongated RNA was detected when GTP, ATP, and CTP were added to the reaction mixture.

Figure 5

Mechanism of action of favipiravir. Favipiravir is converted to Favipiravir-RTP by host cell enzymes and selectively inhibits the activity of the influenza viral RNA polymerase. (Furuta et al., 2009)

Figure 6

Favipiravir treatment of advanced PICV infection in guinea pigs. Guinea pigs (n = 7–8/group) challenged with 500 PFU of p19 PICV were treated with the indicated dosages of favipiravir, ribavirin, or placebo beginning on day 7 of infection. The 150-mg/kg/d group received a loading dose of 300 mg/kg/d on the first day of treatment. Drugs were administered twice daily for 14 days (capped hashed line) and (A) survival, (B) body weights, and (C) temperatures were monitored for 36 days. Serum was collected on day 10 for analysis of (D) AST and (E) viremia. *P < 0.05 compared to placebo-treated animals. (Mendenhall et al., 2011)