Selinexor, a novel selective inhibitor of nuclear export, reduces SARS-CoV-2 infection and protects the respiratory system in vivo

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. A schematic model demonstrates how inhibition of nuclear export protects cells from SARS-CoV-2 infection by: reducing membranal presentation of ACE-2, blocking the cytoplasmic shuttling of the host protein GLTSCR2, (Wang et al., 2016), and sequestering the viral proteins ORF3b (Freundt et al., 2009; Konno et al., 2020), ORF9b (Moshynskyy et al., 2007; Sharma et al., 2011; Jiang et al., 2020), and the nucleocapsid protein (Timani et al., 2005; You et al., 2007; Li et al., 2020) in the nucleus. This allows for the activation of the innate immune response and the production of the type I interferons. [Display omitted] •Nuclear export inhibition by selinexor reduces membranal ACE-2 and induces nuclear ACE-2 accumulation, confirming our prediction that angiotensin-converting enzyme 2 (ACE-2) is an XPO1 cargo.•In vitro, prophylactic or therapeutic administration of selinexor reduced viral load and infection.•In vivo, treatment with selinexor reduced lung viral load and protected against lung and nasal turbinate injury.•Selinexor reduced several inflammatory cytokines in vitro.•Our findings support the development of selinexor as a potential treatment option for COVID-19.