T-705 (favipiravir) inhibition of arenavirus replication in cell culture

Michelle Mendenhall, Andrew Russell, Terry Juelich, Emily L. Messina, Donald F. Smee, Alexander Freiberg, Michael R. Holbrook, Yousuke Furuta, Juan Carlos De La Torre, Jack H. Nunberg, Brian B. Gowen

Research output: Contribution to journalArticle

57 Citations (Scopus)

Abstract

A number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.

Original languageEnglish (US)
Pages (from-to)782-787
Number of pages6
JournalAntimicrobial Agents and Chemotherapy
Volume55
Issue number2
DOIs
StatePublished - Feb 2011

Fingerprint

Arenavirus
New World Arenaviruses
Cell Culture Techniques
Antiviral Agents
Arenaviridae Infections
Lymphocytic Choriomeningitis
Fever
Lassa Fever
Lassa virus
Security Measures
Purine Nucleosides
Viruses
Pyrazines
RNA Replicase
Pyrimidines
Replicon
Ribavirin
RNA Viruses
Viral RNA
Virus Diseases

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Mendenhall, M., Russell, A., Juelich, T., Messina, E. L., Smee, D. F., Freiberg, A., ... Gowen, B. B. (2011). T-705 (favipiravir) inhibition of arenavirus replication in cell culture. Antimicrobial Agents and Chemotherapy, 55(2), 782-787. https://doi.org/10.1128/AAC.01219-10

T-705 (favipiravir) inhibition of arenavirus replication in cell culture. / Mendenhall, Michelle; Russell, Andrew; Juelich, Terry; Messina, Emily L.; Smee, Donald F.; Freiberg, Alexander; Holbrook, Michael R.; Furuta, Yousuke; De La Torre, Juan Carlos; Nunberg, Jack H.; Gowen, Brian B.

In: Antimicrobial Agents and Chemotherapy, Vol. 55, No. 2, 02.2011, p. 782-787.

Research output: Contribution to journalArticle

Mendenhall, M, Russell, A, Juelich, T, Messina, EL, Smee, DF, Freiberg, A, Holbrook, MR, Furuta, Y, De La Torre, JC, Nunberg, JH & Gowen, BB 2011, 'T-705 (favipiravir) inhibition of arenavirus replication in cell culture', Antimicrobial Agents and Chemotherapy, vol. 55, no. 2, pp. 782-787. https://doi.org/10.1128/AAC.01219-10
Mendenhall, Michelle ; Russell, Andrew ; Juelich, Terry ; Messina, Emily L. ; Smee, Donald F. ; Freiberg, Alexander ; Holbrook, Michael R. ; Furuta, Yousuke ; De La Torre, Juan Carlos ; Nunberg, Jack H. ; Gowen, Brian B. / T-705 (favipiravir) inhibition of arenavirus replication in cell culture. In: Antimicrobial Agents and Chemotherapy. 2011 ; Vol. 55, No. 2. pp. 782-787.
@article{1c84c77e31c042b8bb309062d34b83af,
title = "T-705 (favipiravir) inhibition of arenavirus replication in cell culture",
abstract = "A number of New World arenaviruses (Jun{\'i}n [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.",
author = "Michelle Mendenhall and Andrew Russell and Terry Juelich and Messina, {Emily L.} and Smee, {Donald F.} and Alexander Freiberg and Holbrook, {Michael R.} and Yousuke Furuta and {De La Torre}, {Juan Carlos} and Nunberg, {Jack H.} and Gowen, {Brian B.}",
year = "2011",
month = "2",
doi = "10.1128/AAC.01219-10",
language = "English (US)",
volume = "55",
pages = "782--787",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "2",

}

TY - JOUR

T1 - T-705 (favipiravir) inhibition of arenavirus replication in cell culture

AU - Mendenhall, Michelle

AU - Russell, Andrew

AU - Juelich, Terry

AU - Messina, Emily L.

AU - Smee, Donald F.

AU - Freiberg, Alexander

AU - Holbrook, Michael R.

AU - Furuta, Yousuke

AU - De La Torre, Juan Carlos

AU - Nunberg, Jack H.

AU - Gowen, Brian B.

PY - 2011/2

Y1 - 2011/2

N2 - A number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.

AB - A number of New World arenaviruses (Junín [JUNV], Machupo [MACV], and Guanarito [GTOV] viruses) can cause human disease ranging from mild febrile illness to a severe and often fatal hemorrhagic fever syndrome. These highly pathogenic viruses and the Old World Lassa fever virus pose a significant threat to public health and national security. The only licensed antiviral agent with activity against these viruses, ribavirin, has had mixed success in treating severe arenaviral disease and is associated with significant toxicities. A novel pyrazine derivative currently in clinical trials for the treatment of influenza virus infections, T-705 (favipiravir), has demonstrated broad-spectrum activity against a number of RNA viruses, including arenaviruses. T-705 has also been shown to be effective against Pichinde arenavirus infection in a hamster model. Here, we demonstrate the robust antiviral activity of T-705 against authentic highly pathogenic arenaviruses in cell culture. We show that T-705 disrupts an early or intermediate stage in viral replication, distinct from absorption or release, and that its antiviral activity in cell culture is reversed by the addition of purine bases and nucleosides, but not with pyrimidines. Specific inhibition of viral replication/transcription by T-705 was demonstrated using a lymphocytic choriomeningitis arenavirus replicon system. Our findings indicate that T-705 acts to inhibit arenavirus replication/transcription and may directly target the viral RNA-dependent RNA polymerase.

UR - http://www.scopus.com/inward/record.url?scp=78751692774&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78751692774&partnerID=8YFLogxK

U2 - 10.1128/AAC.01219-10

DO - 10.1128/AAC.01219-10

M3 - Article

C2 - 21115797

AN - SCOPUS:78751692774

VL - 55

SP - 782

EP - 787

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 2

ER -