tetano
Editor, Senior Moderator
Antiviral Res
. 2021 Jun 19;105115.
doi: 10.1016/j.antiviral.2021.105115. Online ahead of print.
Selinexor, a novel selective inhibitor of nuclear export, reduces SARS-CoV-2 infection and protects the respiratory system in vivo
Trinayan Kashyap[SUP] 1 [/SUP], Jackelyn Murray[SUP] 2 [/SUP], Christopher J Walker[SUP] 1 [/SUP], Hua Chang[SUP] 1 [/SUP], Sharon Tamir[SUP] 1 [/SUP], Bing Hou[SUP] 3 [/SUP], Sharon Shacham[SUP] 1 [/SUP], Michael G Kauffman[SUP] 1 [/SUP], Ralph A Tripp[SUP] 2 [/SUP], Yosef Landesman[SUP] 4 [/SUP]
Affiliations
Abstract
The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the recent global pandemic. The nuclear export protein (XPO1) has a direct role in the export of SARS-CoV proteins including ORF3b, ORF9b, and nucleocapsid. Inhibition of XPO1 induces anti-inflammatory, anti-viral, and antioxidant pathways. Selinexor is an FDA-approved XPO1 inhibitor. Through bioinformatics analysis, we predicted nuclear export sequences in the ACE-2 protein and confirmed by in vitro testing that inhibition of XPO1 with selinexor induces nuclear localization of ACE-2. Administration of selinexor inhibited viral infection prophylactically as well as therapeutically in vitro. In a ferret model of COVID-19, selinexor treatment reduced viral load in the lungs and protected against tissue damage in the nasal turbinates and lungs in vivo. Our studies demonstrated that selinexor downregulated the pro-inflammatory cytokines IL-1β, IL-6, IL-10, IFN-γ, TNF-α, and GMCSF, commonly associated with the cytokine storm observed in COVID-19 patients. Our findings indicate that nuclear export is critical for SARS-CoV-2 infection and for COVID-19 pathology and suggest that inhibition of XPO1 by selinexor could be a viable anti-viral treatment option.
Keywords: COVID19; CRM1; Exportin-1; SARS-CoV-2; SINE compound; Selinexor; XPO1.
. 2021 Jun 19;105115.
doi: 10.1016/j.antiviral.2021.105115. Online ahead of print.
Selinexor, a novel selective inhibitor of nuclear export, reduces SARS-CoV-2 infection and protects the respiratory system in vivo
Trinayan Kashyap[SUP] 1 [/SUP], Jackelyn Murray[SUP] 2 [/SUP], Christopher J Walker[SUP] 1 [/SUP], Hua Chang[SUP] 1 [/SUP], Sharon Tamir[SUP] 1 [/SUP], Bing Hou[SUP] 3 [/SUP], Sharon Shacham[SUP] 1 [/SUP], Michael G Kauffman[SUP] 1 [/SUP], Ralph A Tripp[SUP] 2 [/SUP], Yosef Landesman[SUP] 4 [/SUP]
Affiliations
- PMID: 34157321
- DOI: 10.1016/j.antiviral.2021.105115
Abstract
The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the recent global pandemic. The nuclear export protein (XPO1) has a direct role in the export of SARS-CoV proteins including ORF3b, ORF9b, and nucleocapsid. Inhibition of XPO1 induces anti-inflammatory, anti-viral, and antioxidant pathways. Selinexor is an FDA-approved XPO1 inhibitor. Through bioinformatics analysis, we predicted nuclear export sequences in the ACE-2 protein and confirmed by in vitro testing that inhibition of XPO1 with selinexor induces nuclear localization of ACE-2. Administration of selinexor inhibited viral infection prophylactically as well as therapeutically in vitro. In a ferret model of COVID-19, selinexor treatment reduced viral load in the lungs and protected against tissue damage in the nasal turbinates and lungs in vivo. Our studies demonstrated that selinexor downregulated the pro-inflammatory cytokines IL-1β, IL-6, IL-10, IFN-γ, TNF-α, and GMCSF, commonly associated with the cytokine storm observed in COVID-19 patients. Our findings indicate that nuclear export is critical for SARS-CoV-2 infection and for COVID-19 pathology and suggest that inhibition of XPO1 by selinexor could be a viable anti-viral treatment option.
Keywords: COVID19; CRM1; Exportin-1; SARS-CoV-2; SINE compound; Selinexor; XPO1.