Nucleosides for the treatment of respiratory RNA virus infections

Jordan, Paul C; Stevens, Sarah K; Deval, Jerome

The antiviral 6-fluoro-3-hydroxy-2-pyrazinecarboxamide (T-705, favipiravir, AVIGAN) has been approved in Japan for the treatment of influenza infection since 2014. T-705 is a nucleoside precursor inhibiting influenza virus with broad-strain coverage 137,139 ( Figure 5 ). It is often proposed that T-705 exerts its antiviral activity through its NTP form (T-705 RTP) by directly inhibiting the RdRp activity of influenza A virus polymerase, 140 but the exact mode of action and precise molecular interaction between the nucleotide and the viral polymerase has been elusive. In vitro, T-705 is efficiently converted to its ribofuranosyl 5 0 -triphosphate (T-705 RTP) form by cellular enzymes. 141 Treatment of influenza A virus-infected cells with T-705 results in a significant increase of lethal mutations within the viral genome, a phenomenon also described as error catastrophe. 142 The lethal mutagenesis hypothesis is supported by enzymatic assays showing that T-705 RTP is efficiently recognized by influenza A virus polymerase both as a guanosine and an adenosine analog. 143 In addition, single events of T-705 RMP incorporation into RNA by influenza A virus polymerase delayed but did not block the extension of the RNA primer strand. The antiviral potency of T-705 covers other virus families well beyond orthomyxoviruses. T-705 has been shown to inhibit a number of diverse RNA viruses unrelated to influenza, including representatives of noroviruses, bunyaviruses, arenaviruses, flaviviruses, and filoviruses. [144] [145] [146] [147] [148] [149] [150] [151] [152] It is interesting to point out that the mutagenic effect of T-705 has also been documented for HCV. 153 At the biochemical level, we showed that T-705 is recognized as substrate for RNA synthesis not only by viral polymerases, but also by human mitochondrial RNA polymerase. 154, 155 This host-based interaction did not result in any measurable in vitro mitochondrial toxicity, but it raised more questions about the mechanism of action of the compound. Recently, the possibility that T-705 exerts its main antiviral effect without converting to its triphosphate form came from the observation that T-705 ribonucleoside is chemically unstable under biological conditions. 156 Even though T-705 does not seem to potently inhibit the human IMPDH enzyme, 157 its very broad antiviral spectrum and its capacity to induce lethal mutagenesis are somewhat reminiscent of ribavirin, another nucleoside that inhibits HCV replication through host-based mechanisms. Therefore, the possibility that T-705 exerts its inhibition through interactions with host proteins cannot be ruled out and remains to be further explored. Considering its similarities with ribavirin in terms of antiviral spectrum and mode of action, it will be interesting to see if T-705 becomes more widely used in patients suffering from respiratory viral infections, or if it will remain limited to stockpiling for potential influenza pandemic in Japan.