Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro

Patricia A. Jorquera, Cynthia Mathew, Jennifer Pickens, Colin Williams, Jasmina M. Luczo, Sharon Tamir, Reena Ghildyal, Ralph A. Tripp

Research output: Contribution to journalArticle

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-B signaling pathway.

Original languageEnglish
Article numbere0168418
Pages (from-to)1-17
Number of pages17
JournalJournal of Virology
Volume93
Issue number4
DOIs
Publication statusPublished - 1 Feb 2019

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Respiratory Syncytial Viruses
Cell Nucleus Active Transport
Virus Replication
virus replication
viruses
respiratory system
proteins
therapeutics
In Vitro Techniques
verdinexor
antiviral agents
Respiratory System
bronchitis
Antiviral Agents
Hospitalization
drug resistance
asthma
Virus Release
respiratory tract diseases
Virus Assembly

Cite this

Jorquera, P. A., Mathew, C., Pickens, J., Williams, C., Luczo, J. M., Tamir, S., ... Tripp, R. A. (2019). Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro. Journal of Virology, 93(4), 1-17. [e0168418]. https://doi.org/10.1128/JVI.01684-18
Jorquera, Patricia A. ; Mathew, Cynthia ; Pickens, Jennifer ; Williams, Colin ; Luczo, Jasmina M. ; Tamir, Sharon ; Ghildyal, Reena ; Tripp, Ralph A. / Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro. In: Journal of Virology. 2019 ; Vol. 93, No. 4. pp. 1-17.
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Jorquera, PA, Mathew, C, Pickens, J, Williams, C, Luczo, JM, Tamir, S, Ghildyal, R & Tripp, RA 2019, 'Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro', Journal of Virology, vol. 93, no. 4, e0168418, pp. 1-17. https://doi.org/10.1128/JVI.01684-18

Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro. / Jorquera, Patricia A.; Mathew, Cynthia; Pickens, Jennifer; Williams, Colin; Luczo, Jasmina M.; Tamir, Sharon; Ghildyal, Reena; Tripp, Ralph A.

In: Journal of Virology, Vol. 93, No. 4, e0168418, 01.02.2019, p. 1-17.

Research output: Contribution to journalArticle

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T1 - Verdinexor (KPT-335), a Selective Inhibitor of Nuclear Export, Reduces Respiratory Syncytial Virus Replication In Vitro

AU - Jorquera, Patricia A.

AU - Mathew, Cynthia

AU - Pickens, Jennifer

AU - Williams, Colin

AU - Luczo, Jasmina M.

AU - Tamir, Sharon

AU - Ghildyal, Reena

AU - Tripp, Ralph A.

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Y1 - 2019/2/1

N2 - 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-B signaling pathway.

AB - 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-B signaling pathway.

KW - Exportin 1

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KW - M protein

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KW - Respiratory syncytial virus

KW - RSV

KW - Verdinexor

KW - XPO1

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