Verdinexor Targeting of CRM1 is a Promising Therapeutic Approach against RSV and Influenza Viruses

Pickens, Jennifer A.; Tripp, Ralph A.

doi:10.3390/v10010048

Cited by 26 publications

(21 citation statements)

References 220 publications

(272 reference statements)

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“…In the nucleus, NF-B also induces the expression of the repressor IB, and the newly synthesized IB then reinhibits NF-B, forming an auto-feedback loop (41,42). XPO1 is required for the replenishment of cytoplasmic pools of NF-B/IB complexes and the subsequent regulation of NF-B activation (43). We show in this study that KPT-335 treatment of mock-or RSV-infected A549 cells results in the nuclear retention of NF-B subunit p65, thus likely leading to inactivation of NF-B signaling.…”

Section: Discussionmentioning

confidence: 99%

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

Jorquera

Mathew

Pickens

et al. 2019

J Virol

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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. IMPORTANCE RSV is an important cause of LRTI in infants and young children for which there are no suitable antiviral drugs offered. We evaluated the efficacy of KPT-335 as an anti-RSV drug and show that KPT-335 inhibits XPO1-mediated nuclear export, leading to nuclear accumulation of RSV M protein and reduction in RSV levels. KPT-335 treatment also resulted in inhibition of proinflammatory pathways, which has important implications for its effectiveness in vivo.

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Section: Discussionmentioning

confidence: 99%

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

Jorquera

Mathew

Pickens

et al. 2019

J Virol

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“…However, binding to other proteins like cysteine proteases could not be detected which has been discussed to be the reason for poor tolerance of LMB [ 100 ]. Although preliminary studies investigating SINE compounds have concentrated on their use as anti-cancer agents, recent studies suggest Verdinexor as a novel broad-spectrum antiviral against various influenza strains and respiratory syncytial virus [ 101 , 102 ]. The anti-viral activity of Verdinexor was underlined by Widman et al showing that Verdinexor efficiently inhibits infection by a panel of different viruses (Epstein-Barr virus, human cytomegalovirus, Kaposi’s sarcoma virus, adenoviruses, BK virus, John Cunningham virus, and human papillomavirus) in antiviral screens [ 103 ].…”

Section: Targeting Nucleocytoplasmic Transportmentioning

confidence: 99%

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Kosyna

Depping

2018

Cells

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Nuclear transport receptors of the karyopherin superfamily of proteins transport macromolecules from one compartment to the other and are critical for both cell physiology and pathophysiology. The nuclear transport machinery is tightly regulated and essential to a number of key cellular processes since the spatiotemporally expression of many proteins and the nuclear transporters themselves is crucial for cellular activities. Dysregulation of the nuclear transport machinery results in localization shifts of specific cargo proteins and associates with the pathogenesis of disease states such as cancer, inflammation, viral illness and neurodegenerative diseases. Therefore, inhibition of the nuclear transport system has future potential for therapeutic intervention and could contribute to the elucidation of disease mechanisms. In this review, we recapitulate clue findings in the pathophysiological significance of nuclear transport processes and describe the development of nuclear transport inhibitors. Finally, clinical implications and results of the first clinical trials are discussed for the most promising nuclear transport inhibitors.

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“…A more recent class of drugs under development are the selective inhibitors of nuclear export (SINE), which are primarily being investigated as anticancer agents and are involved in several clinical trials [189]. Of the several drugs in this class, Verdinexor (KPT-335) has been demonstrated to function as a potential antiviral [190]. In vitro evidence has shown the effectiveness of Verdinexor against RSV, VEEV, IAV, EBV, Kaposi’s sarcoma virus (KSHV), HAdV-5, and HPV-11 [191,192,193,194].…”

Section: Targeting Nuclear Transport To Control Viral Replicationmentioning

confidence: 99%

Viral Appropriation: Laying Claim to Host Nuclear Transport Machinery

Tessier

Dodge

Prusinkiewicz

et al. 2019

Cells

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Protein nuclear transport is an integral process to many cellular pathways and often plays a critical role during viral infection. To overcome the barrier presented by the nuclear membrane and gain access to the nucleus, virally encoded proteins have evolved ways to appropriate components of the nuclear transport machinery. By binding karyopherins, or the nuclear pore complex, viral proteins influence their own transport as well as the transport of key cellular regulatory proteins. This review covers how viral proteins can interact with different components of the nuclear import machinery and how this influences viral replicative cycles. We also highlight the effects that viral perturbation of nuclear transport has on the infected host and how we can exploit viruses as tools to study novel mechanisms of protein nuclear import. Finally, we discuss the possibility that drugs targeting these transport pathways could be repurposed for treating viral infections.

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Verdinexor Targeting of CRM1 is a Promising Therapeutic Approach against RSV and Influenza Viruses

Cited by 26 publications

References 220 publications

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

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

Controlling the Gatekeeper: Therapeutic Targeting of Nuclear Transport

Viral Appropriation: Laying Claim to Host Nuclear Transport Machinery

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