T-705 (favipiravir) inhibition of arenavirus replication in cell culture.
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.
Institute for Antiviral Research and Department of Animal, Dairy, and Veterinary Sciences, Utah State University, Logan, UT 84322-5600, USA.
Michelle
M
Mendenhall
Andrew
A
Russell
Terry
T
Juelich
Emily L
EL
Messina
Donald F
DF
Smee
Alexander N
AN
Freiberg
Michael R
MR
Holbrook
Yousuke
Y
Furuta
Juan-Carlos
JC
de la Torre
Jack H
JH
Nunberg
Brian B
BB
Gowen
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D006477:Arenaviruses, New World / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D002522:Chlorocebus aethiops; D006801:Humans; D018051:Junin virus / Q000187:drug effects / Q000502:physiology; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects / Q000502:physiology; D008826:Microbial Sensitivity Tests / Q000379:methods; D011719:Pyrazines / Q000494:pharmacology*; D012254:Ribavirin / Q000494:pharmacology; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects*
D000577:Amides; D000998:Antiviral Agents; D011719:Pyrazines; D012254:Ribavirin; C462182:favipiravir