1. Low-dose ribavirin potentiates the antiviral activity of favipiravir against hemorrhagic fever viruses
Jonna B. Westover, Eric J. Seﬁng, Kevin W. Bailey, Brian B. Gowen*. Antiviral Research 126 (2016) 62-68
Favipiravir (T-705) is a nucleoside analog that was recently approved as an anti-inﬂuenza drug in Japan, and is in Phase 3 clinical trials in the USA for the same indication. It is active against a growing list of virulent RNA viruses including Ebola virus, and the author studies show that it is highly protective in rodent models of Argentine hemorrhagic fever (AHF), caused by Junin virus (JUNV). Favipiravir appears to act by directly inhibiting the viral RNA-dependent RNA polymerase (RdRP), with minimal effect on cellular nucleoside metabolism or intracellular nucleic acid pools. There is little evidence that resistant viruses are selected during the course of therapy, indicating that the drug's target site is essential for efficient virus replication.
2. Favipiravir (T-705) inhibits in vitro norovirus replication
J. Rocha-Pereira, D. Jochmans, J. Neyts*. Biochemical and Biophysical Research Communications 424 (2012) 777-780
T-705 (favipiravir) is an antiviral molecule that is being developed for the treatment of inﬂuenza virus infections but that exerts also activity against a number of unrelated RNA viruses, including bunyaviruses, arenaviruses and ﬂaviviruses. T-705 is converted to its active form T-705 ribofuranosyl 5’-tri-phosphate by cellular enzymes . This metabolite inhibits the inﬂuenza polymerase without affecting the synthesis of cellular RNA and DNA. The exact mechanism and precise molecular interaction of the T-705 metabolite with the viral polymerase of either inﬂuenza, or the other viruses has not yet been reported. The aim of the present work was to evaluate whether the relative broad-spectrum anti-RNA virus activity of T-705 extends to noroviruses. To this end, we employed the cultivable MNV as a surrogate for human norovirus.
3. Drugs in Development for Influenza
David A. Boltz, Jerry R. Aldridge Jr, Robert G. Webster, Elena A. Govorkova. Drugs 2010; 70 (11): 1349-1362
Presently, ribavirin is the only polymerase inhibitor available to treat influenza infection; however, its approved use is limited to a few countries. In 2002, Furuta et al. reported that a novel pyrazine molecule, favipiravir (T-705), inhibited influenza virus infections in cell culture and in mice. Favipiravir inhibits replication of both influenza A and B viruses. Similar to ribavirin, favipiravir is an inhibitor of the influenza RNA polymerase; however, unlike ribavirin, favipiravir does not interfere with host DNA or RNA synthesis and is only weakly inhibitory to the host inosine monophosphate dehydrogenase, thus rendering favipiravir less cytotoxic. These properties make favipiravir an attractive candidate for the treatment of influenza virus infections in humans. High doses of favipiravir resulted in little or no cytotoxicity, and repeated passage of influenza virus in cell culture in the presence of the drug did not result in the development of resistance. Influenza viruses resistant to ribavirin have yet to be described; however, the generation in cell culture of ribavirin-resistant polio virus and ribavirin-resistant hepatitis C virus replicon-containing cell lines has been described. Ribavirin resistance has not been identified in the clinical setting; therefore, it is possible to hypothesize that the possibility of emergence of influenza viruses resistant to favipiravir is low.