Broad Spectrum Antiviral Activity of Favipiravir (T-705): Protection from Highly Lethal Inhalational Rift Valley Fever

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Abstract

Background

Development of antiviral drugs that have broad-spectrum activity against a number of viral infections would be of significant benefit. Due to the evolution of resistance to currently licensed antiviral drugs, development of novel anti-influenza drugs is in progress, including Favipiravir (T-705), which is currently in human clinical trials. T-705 displays broad-spectrum in vitro activity against a number of viruses, including Rift Valley Fever virus (RVFV). RVF is an important neglected tropical disease that causes human, agricultural, and economic losses in endemic regions. RVF has the capacity to emerge in new locations and also presents a potential bioterrorism threat. In the current study, the in vivo efficacy of T-705 was evaluated in Wistar-Furth rats infected with the virulent ZH501 strain of RVFV by the aerosol route.

Methodology/Principal Findings

Wistar-Furth rats are highly susceptible to a rapidly lethal disease after parenteral or inhalational exposure to the pathogenic ZH501 strain of RVFV. In the current study, two experiments were performed: a dose-determination study and a delayed-treatment study. In both experiments, all untreated control rats succumbed to disease. Out of 72 total rats infected with RVFV and treated with T-705, only 6 succumbed to disease. The remaining 66 rats (92%) survived lethal infection with no significant weight loss or fever. The 6 treated rats that succumbed survived significantly longer before succumbing to encephalitic disease.

Conclusions/Significance

Currently, there are no licensed antiviral drugs for treating RVF. Here, T-705 showed remarkable efficacy in a highly lethal rat model of Rift Valley Fever, even when given up to 48 hours post-infection. This is the first study to show protection of rats infected with the pathogenic ZH501 strain of RVFV. Our data suggest that T-705 has potential to be a broad-spectrum antiviral drug.

Author Summary

Broad-spectrum antiviral drugs are preferred because they have the capacity to treat a range of viral illnesses rather than just one. Food and Drug Administration (FDA) approval of antiviral drugs to treat neglected tropical diseases is difficult to obtain due to ethical and logistical considerations when conducting human clinical trials. Rift Valley Fever (RVF) is an endemic tropical disease that causes human morbidity and mortality, as well as economic damage to the livestock industry. There are no licensed antiviral drugs to treat RVF. In this study, we found that a novel anti-influenza drug, Favipiravir (T-705), is able to prevent lethal RVF in rats, and therefore shows promise as a broad-spectrum antiviral treatment.

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Most cited references 43

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Mechanism of action of T-705 against influenza virus.

Yousuke Furuta, Kazumi Takahashi, Masako Kuno-Maekawa … (2005)

T-705, a substituted pyrazine compound, has been found to exhibit potent anti-influenza virus activity in vitro and in vivo. In a time-of-addition study, it was indicated that T-705 targeted an early to middle stage of the viral replication cycle but had no effect on the adsorption or release stage. The anti-influenza virus activity of T-705 was attenuated by addition of purines and purine nucleosides, including adenosine, guanosine, inosine, and hypoxanthine, whereas pyrimidines did not affect its activity. T-705-4-ribofuranosyl-5'-triphosphate (T-705RTP) and T-705-4-ribofuranosyl-5'-monophosphate (T-705RMP) were detected in MDCK cells treated with T-705. T-705RTP inhibited influenza virus RNA polymerase activity in a dose-dependent and a GTP-competitive manner. Unlike ribavirin, T-705 did not have an influence on cellular DNA or RNA synthesis. Inhibition of cellular IMP dehydrogenase by T-705RMP was about 150-fold weaker than that by ribavirin monophosphate, indicating the specificity of the anti-influenza virus activity and lower level of cytotoxicity of T-705. These results suggest that T-705RTP, which is generated in infected cells, may function as a specific inhibitor of influenza virus RNA polymerase and contributes to the selective anti-influenza virus activity of T-705.

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T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections

Yousuke Furuta, Kazumi Takahashi, Kimiyasu Shiraki … (2009)

A series of pyrazinecarboxamide derivatives T-705 (favipiravir), T-1105 and T-1106 were discovered to be candidate antiviral drugs. These compounds have demonstrated good activity in treating viral infections in laboratory animals caused by various RNA viruses, including influenza virus, arenaviruses, bunyaviruses, West Nile virus (WNV), yellow fever virus (YFV), and foot-and-mouth disease virus (FMDV). Treatment has in some cases been effective when initiated up to 5–7 days after virus infection, when the animals already showed signs of illness. Studies on the mechanism of action of T-705 have shown that this compound is converted to the ribofuranosyltriphosphate derivative by host enzymes, and this metabolite selectively inhibits the influenza viral RNA-dependent RNA polymerase without cytotoxicity to mammalian cells. Interestingly, these compounds do not inhibit host DNA and RNA synthesis and inosine 5′-monophosphate dehydrogenase (IMPDH) activity. From in vivo studies using several animal models, the pyrazinecarboxamide derivatives were found to be effective in protecting animals from death, reducing viral burden, and limiting disease manifestations, even when treatment was initiated after virus inoculation. Importantly, T-705 imparts its beneficial antiviral effects without significant toxicity to the host. Prompt development of these compounds is expected to provide effective countermeasures against pandemic influenza virus and several bioweapon threats, all of which are of great global public health concern given the current paucity of highly effective broad-spectrum drugs.

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Hemorrhagic fever viruses as biological weapons: medical and public health management.

Jonas T Johnson, Tara O'Toole, K Tonat … (2002)

To develop consensus-based recommendations for measures to be taken by medical and public health professionals if hemorrhagic fever viruses (HFVs) are used as biological weapons against a civilian population. The Working Group on Civilian Biodefense included 26 representatives from academic medical centers, public health, military services, governmental agencies, and other emergency management institutions. MEDLINE was searched from January 1966 to January 2002. Retrieved references, relevant material published prior to 1966, and additional sources identified by participants were reviewed. Three formal drafts of the statement that synthesized information obtained in the evidence-gathering process were reviewed by the working group. Each draft incorporated comments and judgments of the members. All members approved the final draft. Weapons disseminating a number of HFVs could cause an outbreak of an undifferentiated febrile illness 2 to 21 days later, associated with clinical manifestations that could include rash, hemorrhagic diathesis, and shock. The mode of transmission and clinical course would vary depending on the specific pathogen. Diagnosis may be delayed given clinicians' unfamiliarity with these diseases, heterogeneous clinical presentation within an infected cohort, and lack of widely available diagnostic tests. Initiation of ribavirin therapy in the early phases of illness may be useful in treatment of some of these viruses, although extensive experience is lacking. There are no licensed vaccines to treat the diseases caused by HFVs.

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Author and article information

Contributors

Maya Williams: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Negl Trop Dis

Journal ID (iso-abbrev): PLoS Negl Trop Dis

Journal ID (publisher-id): plos

Journal ID (pmc): plosntds

Title: PLoS Neglected Tropical Diseases

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Print): 1935-2727

ISSN (Electronic): 1935-2735

Publication date Collection: April 2014

Publication date (Electronic): 10 April 2014

Volume: 8

Issue: 4

Electronic Location Identifier: e2790

Affiliations

[1 ]Regional Biocontainment Laboratory, Center for Vaccine Research, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America

[2 ]Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America

[3 ]Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America

[4 ]Department of Infectious Diseases and Microbiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, United States of America

U.S. Naval Medical Research Unit No. 2, Indonesia

Author notes

* E-mail: hartman2@ 123456pitt.edu

The authors have declared that no competing interests exist.

Conceived and designed the experiments: ALH DSR. Performed the experiments: DSP LMB ALC DSR. Analyzed the data: ALH TDO DSR. Wrote the paper: ALH.

Article

Publisher ID: PNTD-D-13-02019

DOI: 10.1371/journal.pntd.0002790

PMC ID: 3983105

PubMed ID: 24722586

SO-VID: 758d8e10-8f26-4d8e-8648-e92156518dfb

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 20 December 2013

Date accepted : 2 March 2014

Page count

Pages: 8

Funding

This work is being conducted under contract with the U.S. Department of Defense Joint Project Manager Medical Countermeasure Systems (JPM-MCS) contract #HDTRA1-10-C-0066. The views expressed here are those of the authors and do not necessarily represent the views or official position of JPM-MCS. The funding agency approved the study design and reviewed the final draft of this manuscript. The funders did not have a role in data collection and analysis, decision to publish, or preparation of the manuscript.

Broad Spectrum Antiviral Activity of Favipiravir (T-705): Protection from Highly Lethal Inhalational Rift Valley Fever

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Abstract

Background

Methodology/Principal Findings

Conclusions/Significance

Author Summary

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Animal Welfare

Most cited references 43

Mechanism of action of T-705 against influenza virus.

T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections

Hemorrhagic fever viruses as biological weapons: medical and public health management.

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