tetano
Editor, Senior Moderator
The NF-κB inhibitor SC75741 efficiently blocks influenza virus propagation and confers a high barrier for development of viral resistance
Christina Ehrhardt1,?,
Andrea R?ckle1,?,
Eike R. Hrincius1,
Emanuel Haasbach2,
Darisuren Anhlan1,
Katharina Ahmann1,
Carina Banning1,
Sarah J. Reiling5,
Joachim K?hn3,
Stefan Strobl4,
Daniel Vitt4,
Johann Leban4,
Oliver Planz2,
Stephan Ludwig1,*
DOI: 10.1111/cmi.12108
Abstract
Ongoing human infections with highly pathogenic avian H5N1 viruses and the emergence of the pandemic swine-origin influenza viruses (IV) highlight the permanent threat elicited by these pathogens. Occurrence of resistant seasonal and pandemic strains against the currently licensed antiviral medications points to the urgent need for new and amply available anti-influenza drugs. The recently identified virus-supportive function of the cellular IKK/NF-κB signaling pathway suggests this signaling module as a potential target for antiviral intervention. We characterised the NF-κB inhibitor SC75741 as a broad and efficient blocker of IV replication in non-toxic concentrations. The underlying molecular mechanism of SC75741 action involves impaired DNA-binding of the NF-κB subunit p65, resulting in reduced expression of cytokines, chemokines, and pro-apoptotic factors, subsequent inhibition of caspase activation and block of caspase-mediated nuclear export of viral ribonucleoproteins. SC75741 reduces viral replication and H5N1-induced IL6 and IP-10 expression in the lung of infected mice. Besides its virusstatic effect the drug suppresses virus-induced overproduction of cytokines and chemokines, suggesting that it might prevent hypercytokinemia that is discussed to be an important pathogenicity determinant of highly pathogenic IV. Importantly the drug exhibits a high barrier for development of resistant virus variants. Thus, SC75741-derived drugs may serve as broadly non-toxic anti-influenza agents.
http://onlinelibrary.wiley.com/doi/...ionid=4A976CBA3F4002BF5228759736243B01.d04t01
Christina Ehrhardt1,?,
Andrea R?ckle1,?,
Eike R. Hrincius1,
Emanuel Haasbach2,
Darisuren Anhlan1,
Katharina Ahmann1,
Carina Banning1,
Sarah J. Reiling5,
Joachim K?hn3,
Stefan Strobl4,
Daniel Vitt4,
Johann Leban4,
Oliver Planz2,
Stephan Ludwig1,*
DOI: 10.1111/cmi.12108
Abstract
Ongoing human infections with highly pathogenic avian H5N1 viruses and the emergence of the pandemic swine-origin influenza viruses (IV) highlight the permanent threat elicited by these pathogens. Occurrence of resistant seasonal and pandemic strains against the currently licensed antiviral medications points to the urgent need for new and amply available anti-influenza drugs. The recently identified virus-supportive function of the cellular IKK/NF-κB signaling pathway suggests this signaling module as a potential target for antiviral intervention. We characterised the NF-κB inhibitor SC75741 as a broad and efficient blocker of IV replication in non-toxic concentrations. The underlying molecular mechanism of SC75741 action involves impaired DNA-binding of the NF-κB subunit p65, resulting in reduced expression of cytokines, chemokines, and pro-apoptotic factors, subsequent inhibition of caspase activation and block of caspase-mediated nuclear export of viral ribonucleoproteins. SC75741 reduces viral replication and H5N1-induced IL6 and IP-10 expression in the lung of infected mice. Besides its virusstatic effect the drug suppresses virus-induced overproduction of cytokines and chemokines, suggesting that it might prevent hypercytokinemia that is discussed to be an important pathogenicity determinant of highly pathogenic IV. Importantly the drug exhibits a high barrier for development of resistant virus variants. Thus, SC75741-derived drugs may serve as broadly non-toxic anti-influenza agents.
http://onlinelibrary.wiley.com/doi/...ionid=4A976CBA3F4002BF5228759736243B01.d04t01