Targeting human respiratory syncytial virus transcription anti-termination factor M2-1 to inhibit in vivo viral replication

View/ Open
Author(s)
Bailly, B
Richard, C-A
Sharma, G
Wang, L
Johansen, L
Cao, J
Pendharkar, V
Sharma, D-C
Galloux, M
Wang, Y
Cui, R
Zou, G
Guillon, P
von Itzstein, M
Eleouet, J-F
Altmeyer, R
Griffith University Author(s)
Year published
2016
Metadata
Show full item recordAbstract
Human respiratory syncytial virus (hRSV) is a leading cause of acute lower respiratory tract infection
in infants, elderly and immunocompromised individuals. To date, no specific antiviral drug is available
to treat or prevent this disease. Here, we report that the Smoothened receptor (Smo) antagonist
cyclopamine acts as a potent and selective inhibitor of in vitro and in vivo hRSV replication. Cyclopamine
inhibits hRSV through a novel, Smo-independent mechanism. It specifically impairs the function of the
hRSV RNA-dependent RNA polymerase complex notably by reducing expression levels of the viral antitermination
factor M2-1. ...
View more >Human respiratory syncytial virus (hRSV) is a leading cause of acute lower respiratory tract infection in infants, elderly and immunocompromised individuals. To date, no specific antiviral drug is available to treat or prevent this disease. Here, we report that the Smoothened receptor (Smo) antagonist cyclopamine acts as a potent and selective inhibitor of in vitro and in vivo hRSV replication. Cyclopamine inhibits hRSV through a novel, Smo-independent mechanism. It specifically impairs the function of the hRSV RNA-dependent RNA polymerase complex notably by reducing expression levels of the viral antitermination factor M2-1. The relevance of these findings is corroborated by the demonstration that a single R151K mutation in M2-1 is sufficient to confer virus resistance to cyclopamine in vitro and that cyclopamine is able to reduce virus titers in a mouse model of hRSV infection. The results of our study open a novel avenue for the development of future therapies against hRSV infection.
View less >
View more >Human respiratory syncytial virus (hRSV) is a leading cause of acute lower respiratory tract infection in infants, elderly and immunocompromised individuals. To date, no specific antiviral drug is available to treat or prevent this disease. Here, we report that the Smoothened receptor (Smo) antagonist cyclopamine acts as a potent and selective inhibitor of in vitro and in vivo hRSV replication. Cyclopamine inhibits hRSV through a novel, Smo-independent mechanism. It specifically impairs the function of the hRSV RNA-dependent RNA polymerase complex notably by reducing expression levels of the viral antitermination factor M2-1. The relevance of these findings is corroborated by the demonstration that a single R151K mutation in M2-1 is sufficient to confer virus resistance to cyclopamine in vitro and that cyclopamine is able to reduce virus titers in a mouse model of hRSV infection. The results of our study open a novel avenue for the development of future therapies against hRSV infection.
View less >
Journal Title
Scientific Reports
Volume
6
Copyright Statement
© The Author(s). 2016. This work is licensed under a Creative Commons Attribution 4.0 International License. The images
or other third party material in this article are included in the article’s Creative Commons license,
unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license,
users will need to obtain permission from the license holder to reproduce the material. To view a copy of this
license, visit http://creativecommons.org/licenses/by/4.0/
Subject
Biochemistry and Cell Biology not elsewhere classified