SARS-CoV-2 is the viral pathogen that caused the global COVID-19 pandemic in 2019. The results of this study and other existing evidence showed that XPO1 has a direct role in replication and pathogenesis SARS-CoV, and is responsible for the export of certain SARS-CoV proteins, including ORF3b, ORF9b and the core, which help the virus escape innate immunity. In addition, similar activity has also been reported for the candidate host nuclear protein glioma tumor suppressor region gene 2 (GLTSCR2), as infection with the coronavirus induces an XPO1-dependent cytoplasmic translocation of GLTSCR2, leading to an attenuated induction of IFN-β and supporting viral replication. Therefore, XPO1 inhibitions may play a positive role in blocking viral replication and transmission, as well as in the prevention and treatment of COVID-19.
Selinexor inhibits the spread and viral shedding of SARS-CoV-2 in vitro
Vero E6 cells infected with SARS-CoV-2 were incubated with varying concentrations of selinexor from 6 hours before viral infection (preventive), at the time of viral infection (therapeutic), or at 0, 24, 36 and 48 hours post-infection. The test results showed that selinexor has potent anti-SARS-CoV-2 activity in vitro, with 50% inhibition of SARS-CoV-2 replication at 10 nM and 90% inhibition at 100 nM in Vero E6 cells. These tests also demonstrated that selinexor inhibited the viral spread of SARS-CoV-2 in vitro even when added up to 48 hours after infection.
Selinexor has been shown to be effective against SARS-CoV-2 in ferrets
In the in vivo analysis in models of infected ferrets, animals were infected intranasally with SARS-CoV-2, then treated with either selinexor (5 mg / kg) or placebo (vehicle only) for 3 days from 4 hours after infection. 3 days after infection with SARS-CoV-2, animals treated with selinexor had a significantly lower mean viral RNA than animals treated with placebo. Compared to the placebo group, selinexor also significantly reduced inflammation of the respiratory system.
Selinexor inhibits the expression of inflammatory cytokines by human peripheral blood mononuclear cells (PBMC) stimulated by lipopolysaccharides (LPS)
A high level of inflammatory cytokine is a key etiologic feature and a cause of death in patients infected with SARS-CoV-2. This study showed that selinexor can significantly reduce the ex vivo release of inflammatory cytokines from human PBMCs stimulated by LPS.
Antengene Corporation Limited (“Antengene”, SEHK: 6996.HK) is a leading R&D-driven biopharmaceutical company focused on innovative drugs for oncology and other life-threatening diseases. Antengene aims to provide the most advanced anticancer drugs to patients in the Asia-Pacific region and around the world. Since its inception in 2017, Antengene has built a large and expanding pipeline of clinical and preclinical stage assets through partnerships as well as in-house drug discovery, and has secured 15 Investigational New Drug Approvals (IND) and submitted 6 new drug applications (NDAs) in several markets in Asia Pacific. Antengene’s vision is to “Treat Patients Across Borders”. Antengene is focused on and committed to meeting significant unmet medical needs by discovering, developing and commercializing world-class therapeutic products.
About Selinexor (XPOVIO®)
Selinexor is to date the first and only oral SINE compound approved by the FDA and the first drug approved for the treatment of MM and DLBCL. Selinexor is also being evaluated in several other mid-phase and later clinical trials in multiple indications of solid tumors, including liposarcoma and endometrial cancer. Antengene is currently conducting five advanced clinical trials of selinexor for the treatment of MM, DLBCL, endometrial cancer, non-small cell lung cancer, and peripheral T and NK / T lymphomas.
Kashyap T, Murray J, Walker CJ, Chang H, Tamir S, Hou B, Shacham S, Kauffman MG, Tripp RA, Landesman Y. Selinexor, a novel selective nuclear export inhibitor, reduces SARS infection- CoV-2 and protects the respiratory system in vivo. Antiviral Res. June 19, 2021; 192: 105115.
SOURCE Antengene Corporation Limited