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.

Mycophenolic acid, an immunomodulator, has potent and broad-spectrum in vitro antiviral activity against pandemic, seasonal and avian influenza viruses affecting humans

“…Secondly, since the C max of MPA in humans [25 µg ml À1 (78 µM) after 1000 mg single oral dose of MMF, 26 µg ml À1 (81 µM) after 720 mg single oral dose of mycophenolate sodium] is much higher (>50 times) than the IC 50 demonstrated in our in vitro assays, the concentration of MPA in humans should be sufficient to inhibit viral replication (Anonymous). In fact, the IC 50 of MPA is comparable with that of nitazoxanide (0.9-3.2 µM) and favipiravir (0.19-22.5 µM), which have undergone human clinical trials in the treatment of influenza virus infection (Belardo et al, 2015;Furuta et al, 2013). Thirdly, since this drug targets the viral replication by depleting the host guanosine pool, it is unlikely that the virus can develop resistance against it.…”

Post-exposure treatments for Ebola and Marburg virus infections

“…Favipiravir, also known as T-705 or Avigan (6-fluoro-3-hydroxy-2-pyrazinecarboxamide), is a pyrazine derivative prodrug that has broad-spectrum antiviral activity against a number of RNA viruses 166 .…”

In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells

“…Currently, there are only few approved therapeutic options with limited efficacies in the treatment of acute influenza virus infections, including administration of M2 ion channel blockers or neuraminidase inhibitors 21 . Very recently, the pyrazinecarboxamide RNA polymerase inhibitor, favipiravir was approved in Japan against influenza 22 .…”