Favipiravir (T-705), a broad spectrum inhibitor of viral RNA polymerase

Abstract

Favipiravir (T-705; 6-fluoro-3-hydroxy-2-pyrazinecarboxamide) is an anti-viral agent that selectively and potently inhibits the RNA-dependent RNA polymerase (RdRp) of RNA viruses. Favipiravir was discovered through screening chemical library for anti-viral activity against the influenza virus by Toyama Chemical Co., Ltd. Favipiravir undergoes an intracellular phosphoribosylation to be an active form, favipiravir-RTP (favipiravir ribofuranosyl-5′-triphosphate), which is recognized as a substrate by RdRp, and inhibits the RNA polymerase activity. Since the catalytic domain of RdRp is conserved among various types of RNA viruses, this mechanism of action underpins a broader spectrum of anti-viral activities of favipiravir. Favipiravir is effective against a wide range of types and subtypes of influenza viruses, including strains resistant to existing anti-influenza drugs. Of note is that favipiravir shows anti-viral activities against other RNA viruses such as arenaviruses, bunyaviruses and filoviruses, all of which are known to cause fatal hemorrhagic fever. These unique anti-viral profiles will make favipiravir a potentially promising drug for specifically untreatable RNA viral infections.

T‐705‐modified ssRNA in complex with Lassa virus nucleoprotein exhibits nucleotide splaying and increased water influx into the RNA‐binding pocket

“…T‐705 is a prodrug and only activated by phospho‐ribosylation reaction catalyzed by host enzymes (Sangawa et al., ). T‐705‐ribosyl‐monophosphate inhibits inosine monophosphate dehydrogenase, while T‐705‐ribosyl‐triphosphate both inhibits RNA‐dependent RNA polymerase (RdRp) of RNA viruses (Furuta, Komeno, & Nakamura, ) and incorporates into nascent RNA (Baranovich et al., ), thus resulting in reduced viral replication (Sangawa et al., ) and mutation in viral genome (Vanderlinden et al., ).…”

Antivirals in medical biodefense

“…Remdesivir (GS-5734;1-cyano-substituted adenosine nucleotide analogue), a nucleoside-analogue prodrug and lead compound of the small-molecule antivirals class, has been shown to inhibit EBOV in cell culture and in non-human primates likely by chain termination [144], but showed lower efficacy in the clinical trial compared to monoclonal antibody-based therapeutics. A good alternative, albeit not tested in the DRC clinical trial, may be T705 (favipiravir; [48]), a repurposed drug synthesized by FUJIFILM-Toyam Chemical Co., licensed for use against influenza virus in Japan, and since found to be a broad-spectrum inhibitor of viral RNA polymerases [34,49]. T705 and the related pyrazinecarboxamide compounds T-1105 and T-1106 have similar antiviral properties-see also section "Alphaviridae."…”

“…Among the most promising novel compounds is the broad-spectrum antiviral candidate favipiravir (T-705), initially developed to treat human influenza, which shows a potent antiviral effect in small animal models. The drug is licensed in Japan, while FDA approval is pending [49]. An in vitro comparison between ribavirin and favipiravir revealed that efficacy is cell-type dependent [45].…”

Repurposing approved drugs on the pathway to novel therapies

“…The inexpensive, orally available nucleotide analogs, ribavirin, and favipiravir (developed for influenza), when used at high concentrations, inhibit many viral RNA polymerases by different mechanisms . Favipiravir inhibits Congo hemorrhagic fever virus (CCHF) and Ebola in mice and Ebola and Lassa fever in primate models.…”