tetano
Editor, Senior Moderator
J Virol. 2014 Jun 25. pii: JVI.01774-14. [Epub ahead of print]
Verdinexor, a novel Selective Inhibitor of Nuclear Export (SINE), reduces Influenza A virus replication in vitro and in vivo.
Perwitasari O1, Johnson S1, Yan X1, Howerth E2, Shacham S3, Landesman Y3, Baloglu E3, McCauley D3, Tamir S3, Tompkins SM1, Tripp RA4.
Author information
Abstract
Influenza is a global health concern causing mortality, morbidity, and economic losses. Chemotherapeutics that target influenza are available; however, rapid emergence of drug resistant strains is common. Therapeutic targeting of host proteins hijacked by influenza virus to facilitate replication is an antiviral strategy to reduce the development of drug resistance. Nuclear export of influenza ribonucleoprotein (vRNP) from infected cells has been shown to be mediated by Exportin 1 (XPO1) interaction with nuclear export signal proteins tethered to vRNP. RNA interference (RNAi) screening has identified XPO1 as a host pro-influenza factor where XPO1 silencing results in reduced influenza replication. The Streptomyces metabolite XPO1 inhibitor, Leptomycin B (LMB), has been shown to limit influenza replication in vitro; however, LMB is toxic in vivo which makes it unsuitable for therapeutic use. In this study, we tested the anti-influenza activity of a new class of orally available small molecule Selective Inhibitors of Nuclear Export (SINE), specifically the XPO1 antagonist, KPT-335 (verdinexor). Verdinexor was shown to potently and selectively inhibit vRNP export, and effectively inhibited replication of various influenza A and B strains in vitro including pandemic H1N1, highly pathogenic H5N1 avian influenza virus, and the recently emerged H7N9 strain. In vivo, prophylactic and therapeutic administration of verdinexor protected mice against disease pathology following challenge with influenza A/California/04/09 or A/Philippines/2/82-X79, as well as reduced lung viral load and pro-inflammatory cytokine expression having minimal toxicity. These studies show that verdinexor acts as a novel anti-influenza therapeutic agent.
IMPORTANCE:
Anti-viral drugs represent important means for influenza virus control. However, substantial drug resistance has developed with currently approved influenza therapeutics. New anti-viral approaches are required to address drug resistance, and reduce the burden of influenza-related disease. This study addressed critical pre-clinical studies for the development of verdinexor (KPT-335) as a novel anti-viral drug. Verdinexor blocks nuclear export of progeny influenza virus genome, thus effectively inhibits virus replication. Verdinexor was found to limit replication of various strains of influenza A and B viruses including a pandemic H1N1 influenza virus, a highly pathogenic H5N1 avian influenza virus, and a recently emerging H7N9 influenza virus strains. Importantly, oral verdinexor treatments, given prophylactically or therapeutically, were efficacious to limit lung virus burden in influenza-infected mice, in addition to limiting lung pro-inflammatory cytokines expression, pathology, and mortality. Thus, this study demonstrated that verdinexor is efficacious against influenza virus infection in vitro and in vivo.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
24965445
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24965445
Verdinexor, a novel Selective Inhibitor of Nuclear Export (SINE), reduces Influenza A virus replication in vitro and in vivo.
Perwitasari O1, Johnson S1, Yan X1, Howerth E2, Shacham S3, Landesman Y3, Baloglu E3, McCauley D3, Tamir S3, Tompkins SM1, Tripp RA4.
Author information
Abstract
Influenza is a global health concern causing mortality, morbidity, and economic losses. Chemotherapeutics that target influenza are available; however, rapid emergence of drug resistant strains is common. Therapeutic targeting of host proteins hijacked by influenza virus to facilitate replication is an antiviral strategy to reduce the development of drug resistance. Nuclear export of influenza ribonucleoprotein (vRNP) from infected cells has been shown to be mediated by Exportin 1 (XPO1) interaction with nuclear export signal proteins tethered to vRNP. RNA interference (RNAi) screening has identified XPO1 as a host pro-influenza factor where XPO1 silencing results in reduced influenza replication. The Streptomyces metabolite XPO1 inhibitor, Leptomycin B (LMB), has been shown to limit influenza replication in vitro; however, LMB is toxic in vivo which makes it unsuitable for therapeutic use. In this study, we tested the anti-influenza activity of a new class of orally available small molecule Selective Inhibitors of Nuclear Export (SINE), specifically the XPO1 antagonist, KPT-335 (verdinexor). Verdinexor was shown to potently and selectively inhibit vRNP export, and effectively inhibited replication of various influenza A and B strains in vitro including pandemic H1N1, highly pathogenic H5N1 avian influenza virus, and the recently emerged H7N9 strain. In vivo, prophylactic and therapeutic administration of verdinexor protected mice against disease pathology following challenge with influenza A/California/04/09 or A/Philippines/2/82-X79, as well as reduced lung viral load and pro-inflammatory cytokine expression having minimal toxicity. These studies show that verdinexor acts as a novel anti-influenza therapeutic agent.
IMPORTANCE:
Anti-viral drugs represent important means for influenza virus control. However, substantial drug resistance has developed with currently approved influenza therapeutics. New anti-viral approaches are required to address drug resistance, and reduce the burden of influenza-related disease. This study addressed critical pre-clinical studies for the development of verdinexor (KPT-335) as a novel anti-viral drug. Verdinexor blocks nuclear export of progeny influenza virus genome, thus effectively inhibits virus replication. Verdinexor was found to limit replication of various strains of influenza A and B viruses including a pandemic H1N1 influenza virus, a highly pathogenic H5N1 avian influenza virus, and a recently emerging H7N9 influenza virus strains. Importantly, oral verdinexor treatments, given prophylactically or therapeutically, were efficacious to limit lung virus burden in influenza-infected mice, in addition to limiting lung pro-inflammatory cytokines expression, pathology, and mortality. Thus, this study demonstrated that verdinexor is efficacious against influenza virus infection in vitro and in vivo.
Copyright ? 2014, American Society for Microbiology. All Rights Reserved.
PMID:
24965445
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/24965445