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SHANGHAI and HONG KONG, July 26, 2021 /PRNewswire/ -- In June 2021, results from a preclinical study jointly conducted by Antengene, American biopharmaceutical company Karyopharm Therapeutics and University of Georgia College of Veterinary Medicine has been published in a paper titled "selinexor, a novel selective inhibitor of nuclear export, reduces SARS-CoV-2 infection and protects the respiratory system in vivo", in Antiviral Research (192(2021)，105-115), a leading scientific journal in the field of virology. Results from the study showed that the nuclear export protein exportin-1 (XPO1) plays a direct role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections and the pathogenesis of coronavirus disease 19 (COVID-19); and the selective oral inhibitor of XPO1, selinexor, has potent anti-SARS-CoV-2 activity both in vitro and in vivo. These results demonstrated selinexor as a potential therapeutic strategy for COVID-19.
SARS-CoV-2 is the viral pathogen that caused the COVID-19 global pandemic in 2019. Results from this study and other existing evidence have shown that XPO1 has a direct role in SARS-CoV replication and pathogenesis, and is responsible for the nuclear export of certain SARS-CoV proteins including ORF3b, ORF9b, and nucleocapsid, which help the virus evade innate immunity. Moreover, similar activity was also reported for the host nuclear protein glioma tumor suppressor candidate region gene 2 (GLTSCR2), as coronavirus infection induces XPO1-dependent cytoplasmic translocation of GLTSCR2, leading to attenuated IFN-β induction and supporting viral replication. Therefore, XPO1 inhibitions may play a positive role in blockading viral replications and transmission, as well as in the prevention and treatment of COVID-19.
Selinexor inhibits SARS-CoV-2 viral propagation and shedding in vitro
SARS-CoV-2-infected Vero E6 cells were incubated with varying concentrations of selinexor starting at 6 hours prior to the viral infection (preventative), at the time of viral infection (therapeutic), or at 0, 24, 36 and 48 hours post infection. Results from the test showed that selinexor has potent anti-SARS-CoV-2 activity in vitro, with 50% inhibition of SARS-CoV-2 replication at 10nM and 90% inhibition at 100nM in the Vero E6 cells. These tests also demonstrated that selinexor inhibited SARS-CoV-2 viral propagation in vitro even when added up to 48 hours after infection.
Selinexor demonstrated efficacy 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 (5mg/kg) or placebo (vehicle only) for 3 days starting 4 hours after infection. 3 Days after the SARS-CoV-2 infection, selinexor-treated animals had a mean viral RNA that was markedly lower than that of the placebo-treated animals. Compared to the placebo-treated group, selinexor has also significantly reduced inflammation in the respiratory system.
Selinexor inhibits inflammatory cytokine expression by lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMCs)
Elevated level of inflammatory cytokine is a key etiological feature and cause of death in patients infected with SARS-CoV-2. This study demonstrated that selinexor can significantly lower the ex vivo inflammatory cytokine release by LPS-stimulated human PBMCs.
About Antengene
Antengene Corporation Limited ("Antengene", SEHK: 6996.HK) is a leading clinical-stage R&D driven biopharmaceutical company focused on innovative medicines for oncology and other life-threatening diseases. Antengene aims to provide the most advanced anti-cancer drugs to patients in the Asia-Pacific Region and around the world. Since its establishment in 2017, Antengene has built a broad and expanding pipeline of clinical and pre-clinical stage assets through partnerships as well as in-house drug discovery, and obtained 15 investigational new drug (IND) approvals and submitted 6 new drug applications (NDA) in multiple markets in Asia Pacific. Antengene's vision is to "Treat Patients Beyond Borders". Antengene is focused on and committed to addressing significant unmet medical needs by discovering, developing and commercializing first-in-class/best-in-class therapeutics.
About Selinexor (XPOVIO®)
Selinexor is so far the first and only oral SINE compound approved by the FDA and is the first drug approved for the treatment of both MM and DLBCL. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple solid tumor indications, including liposarcoma and endometrial cancer. Antengene is currently conducting five late-stage clinical trials of selinexor for the treatment of MM, DLBCL, endometrial cancer, non-small cell lung cancer, and peripheral T and NK/T-cell lymphoma.
Reference
Kashyap T, Murray J, Walker CJ, Chang H, Tamir S, Hou B, Shacham S, Kauffman MG, Tripp RA, Landesman Y. Selinexor, a novel selective inhibitor of nuclear export, reduces SARS-CoV-2 infection and protects the respiratory system in vivo. Antiviral Res. 2021 Jun 19;192:105115.