The Second-generation XPO1 Inhibitor Eltanexor Inhibits Human Cytomegalovirus (HCMV) Replication By Promoting Type Ⅰ Interferon Response

Human cytomegalovirus(HCMV)is a ubiquitous opportunistic pathogen and can be life-threatening for immunocompromised individuals.Currently no vaccine is available for prevention of HCMV associated diseases.Most of available antiviral drugs approved for HCMV treatment are designed to target viral DNA synthesis.Many literatures have showed these drugs lead to emerging of resistant viral variants in patients.Therefore,it is urgent to find new drugs for treating these resistant viruses.Here we have showen Eltanexor,a second-generation of Selective Inhibitor of Nuclear Export(SINE),effectively inhibit HCMV infection.Eltanexor inhibits HCMV replication in human foreskin fibroblasts in a dose dependent manner.This drug does not significantly inhibit viral entry and trafficking of viral genome,but inhibits the transcription and translation of some viral immediate early genes and all early and late genes,and abolishes production of infectious virions.Our study reveals that Eltanexor inhibits viral replication in a continuous fashion.Furthermore,we find Eltanexor enhances the expression of IFNβ in CMV-infected cells,which couples with nuclear localization of interferon regulatory factor 3(IRF3).Our study reveals a novel mechanism by which Eltanexor inhibits viral replication.Importance: HCMV is a life-threatening pathogen for many immunocompromised individuals and can cause severe consequence from congenital infections in pregnant women.Current antiviral drugs are faced with low bioavailability and constant emerging of resistant viral variants.It is important to find a new drug which can treat drug-resistant viruses.Our strategy is to target a conserved nuclear-cytoplasm shuttling protein XPO-1that is essential for viral replication.In this report,we describe that a safe secondgeneration SINE,Eltanexor,inhibits viral replication in a continuous fashion.In addition,we reveal that Eltanexor enhances type I interferon production,which represents a breakthrough of understanding the mechanism by which Eltanexor inhibits viral replication as well as cancers.