title: Antiviral Activity of Favipiravir (T-705) against a Broad Range of Paramyxoviruses In Vitro and against Human Metapneumovirus in Hamsters.
abstract: The clinical impact of infections with respiratory viruses belonging to the family Paramyxoviridae argues for the development of antiviral therapies with broad-spectrum activity. Favipiravir (T-705) has demonstrated potent antiviral activity against multiple RNA virus families and is presently in clinical evaluation for the treatment of influenza. Here we demonstrate in vitro activity of T-705 against the paramyxoviruses human metapneumovirus (HMPV), respiratory syncytial virus, human parainfluenza virus, measles virus, Newcastle disease virus, and avian metapneumovirus. In addition, we demonstrate activity against HMPV in hamsters. T-705 treatment inhibited replication of all paramyxoviruses tested in vitro, with 90% effective concentration (EC90) values of 8 to 40 μM. Treatment of HMPV-challenged hamsters with T-705 at 200 mg/kg of body weight/day resulted in 100% protection from infection of the lungs. In all treated and challenged animals, viral RNA remained detectable in the respiratory tract. The observation that T-705 treatment had a significant effect on infectious viral titers, with a limited effect on viral genome titers, is in agreement with its proposed mode of action of viral mutagenesis. However, next-generation sequencing of viral genomes isolated from treated and challenged hamsters did not reveal (hyper)mutation. Polymerase activity assays revealed a specific effect of T-705 on the activity of the HMPV polymerase. With the reported antiviral activity of T-705 against a broad range of RNA virus families, this small molecule is a promising broad-range antiviral drug candidate for limiting the viral burden of paramyxoviruses and for evaluation for treatment of infections with (re)emerging viruses, such as the henipaviruses.
authors.affiliation: Rega Institute for Medical Research, University of Leuven (KU Leuven), Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Jochmans
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: van Nieuwkoop
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: S L
authors.initials: SL
authors.lastname: Smits
authors.affiliation: Rega Institute for Medical Research, University of Leuven (KU Leuven), Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, the Netherlands.
authors.forename: R A M
authors.initials: RA
authors.lastname: Fouchier
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, the Netherlands b.vandenhoogen@erasmusmc.nl.
authors.forename: B G
authors.initials: BG
authors.lastname: van den Hoogen
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D006224:Cricetinae; D057809:HEK293 Cells; D006801:Humans; D008168:Lung / Q000821:virology; D008647:Mesocricetus; D029121:Metapneumovirus / Q000187:drug effects*; D018184:Paramyxoviridae Infections / Q000188:drug therapy*; D011719:Pyrazines / Q000494:pharmacology*; D012136:Respiratory Syncytial Viruses / Q000187:drug effects; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000577:Amides; D000914:Antibodies, Viral; D000998:Antiviral Agents; D011719:Pyrazines; C462182:favipiravir