Journal article
Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro
Journal of virology, Vol.93(4), pp.1-17
15/02/2019
PMCID: PMC6364025
PMID: 30541831
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Source: InCites
Abstract
Respiratory syncytial virus (RSV) is a leading cause of hospitalization of infants and young children, causing considerable respiratory disease and repeat infections that may lead to chronic respiratory conditions such as asthma, wheezing, and bronchitis. RSV causes ∼34 million new episodes of lower respiratory tract illness (LRTI) in children younger than 5 years of age, with >3 million hospitalizations due to severe RSV-associated LRTI. The standard of care is limited to symptomatic relief as there are no approved vaccines and few effective antiviral drugs; thus, a safe and efficacious RSV therapeutic is needed. Therapeutic targeting of host proteins hijacked by RSV to facilitate replication is a promising antiviral strategy as targeting the host reduces the likelihood of developing drug resistance. The nuclear export of the RSV M protein, mediated by the nuclear export protein exportin 1 (XPO1), is crucial for RSV assembly and budding. Inhibition of RSV M protein export by leptomycin B correlated with reduced RSV replication in vitro. In this study, we evaluated the anti-RSV efficacy of Verdinexor (KPT-335), a small molecule designed to reversibly inhibit XPO1-mediated nuclear export. KPT-335 inhibited XPO1-mediated transport and reduced RSV replication in vitro. KPT-335 was effective against RSV A and B strains and reduced viral replication following prophylactic or therapeutic administration. Inhibition of RSV replication by KPT-335 was due to a combined effect of reduced XPO1 expression, disruption of the nuclear export of RSV M protein, and inactivation of the NF-κB signaling pathway.
Details
- Title
- Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro
- Creators
- Patricia A Jorquera - University of GeorgiaCynthia Mathew - University of CanberraJennifer Pickens - University of GeorgiaColin Williams - University of GeorgiaJasmina M Luczo - University of GeorgiaSharon Tamir - Karyopharm TherapeuticsReena Ghildyal - University of CanberraRalph A Tripp - University of Georgia
- Publication Details
- Journal of virology, Vol.93(4), pp.1-17
- Publisher
- American Society for Microbiology
- Grant note
- R21 AI119903 / NIAID NIH HHS
- Identifiers
- 991013036339402368
- Academic Unit
- National Centre for Naturopathic Medicine
- Language
- English
- Resource Type
- Journal article