Effect of exportin 1/XPO1 nuclear export pathway inhibition on coronavirus replication

Abstract

Nucleocytoplasmic transport of proteins using XPO1 (exportin 1) plays a vital role in cell proliferation and survival. Many viruses also exploit this pathway to promote infection and replication. Thus, inhibiting XPO1-mediated nuclear export with selective inhibitors activates multiple antiviral and anti-inflammatory pathways. The XPO1 inhibitor, Selinexor, is an FDA-approved anticancer drug predicted to have antiviral function against many viruses, including SARS-CoV-2. Unexpectedly, we observed that pretreatment of cultured human cells with Selinexor actually enhanced protein expression and replication of coronaviruses, including SARS-CoV-2. Knockdown of cellular XPO1 protein expression significantly enhanced the replication of coronaviruses in human cells. We further demonstrate that Selinexor treatment reduced the formation of unique cytoplasmic antiviral granules that include RNA helicase DHX9 in the virus-infected cells. These results, for the first time, show that the anti-cancer drug Selinexor enhances the replication of coronaviruses in human cells in vitro and thus should be further explored in vivo for the potential impact on the dual use for anticancer and antiviral therapy.

Beyond oncology: Selinexor’s journey into anti-inflammatory treatment and long-term management

“…Furthermore, Selinexor modulates immune responses by controlling the release of inflammatory cytokines, potentially alleviating cytokine storms commonly associated with severe COVID-19 cases through the inhibition of NF-kB pathways and direct effects on STAT3 and IL-6 transcription (37). Conversely, research by Rahman et al suggests that pretreatment with Selinexor may enhance coronavirus replication, including in SARS-CoV-2 and mouse hepatitis virus (MHV), illustrating the complex effects of Selinexor on viral replication and inflammation, and underscoring the necessity for precise administration timing (40,43).…”