Abstract
Infection of immunocompromised individuals with normally benign opportunistic viruses is a major health burden globally. Infections with viruses such as Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), Kaposi’s sarcoma virus (KSHV), adenoviruses (AdV), BK virus (BKPyV), John Cunningham virus (JCPyV), and human papillomavirus (HPV) are significant concerns for the immunocompromised, including when these viruses exist as a co-infection with human immunodeficiency virus (HIV). These viral infections are more complicated in patients with a weakened immune system, and often manifest as malignancies resulting in significant morbidity and mortality. Vaccination is not an attractive option for these immune compromised individuals due to defects in their adaptive immune response. Verdinexor is part of a novel class of small molecules known as SINE (Selective Inhibitor of Nuclear Export) compounds. These small molecules demonstrate specificity for the nuclear export protein XPO1, to which they bind and block function, resulting in sequestration of XPO1-dependent proteins in the nucleus of the cell. In antiviral screening, verdinexor demonstrated varying levels of efficacy against all of the aforementioned viruses including previously with HIV. Studies by other labs have discussed likely mechanisms of action for verdinexor (ie. XPO1-dependence) against each virus. GLP toxicology studies suggest that anti-viral activity can be achieved at a tolerable dose range, based on the safety profile of a previous phase 1 clinical trial of verdinexor in healthy human volunteers. Taken together, these results indicate verdinexor has the potential to be a broad spectrum antiviral for immunocompromised subjects for which vaccination is a poor option.
Highlights
Immunocompromised patients demonstrate susceptibility to latent opportunistic infections, when concurrently infected with human immunodeficiency virus (HIV)
XPO1 mediates the nuclear export of the HIV Rev protein and associated RNA species and we have shown that treatment with verdinexor and other Selective Inhibitor of Nuclear Export (SINE) compounds results in forced nuclear retention of Rev-GFP fusion at a50% effective concentration (EC50) of 160nM [8], and anti-HIV activity in PBMCs from healthy donors at an EC50 = 116 ± 54nM [8]
Verdinexor was screened against a broad range of viruses commonly associated with an immunocompromised state, including: Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), Kaposi’s sarcoma virus (KSHV), adenoviruses (AdV), BK virus (BKPyV), John Cunningham virus (JCPyV), and human papillomavirus (HPV)
Summary
Immunocompromised patients demonstrate susceptibility to latent opportunistic infections, when concurrently infected with HIV. XPO1 mediates the nuclear export of the HIV Rev protein and associated RNA species and we have shown that treatment with verdinexor and other SINE compounds results in forced nuclear retention of Rev-GFP fusion at a50% effective concentration (EC50) of 160nM [8], and anti-HIV activity in PBMCs from healthy donors at an EC50 = 116 ± 54nM [8]. Inhibition of the exportin-1 (XPO1) mediated nuclear transport by clinical stage orally bioavailable small molecule inhibitors (SINE) prevented the nuclear export of the late intron-containing RNA species by preventing the interaction of Rev with XPO-1 and suppressed viral replication [7, 10]. We demonstrate the antiviral properties of verdinexor against opportunistic dsDNA viruses These data, along with our previous HIV observations, suggest that verdinexor may be able to safely inhibit multiple concurrent viral infections commonly associated with pathology in immunocompromised individuals. We believe these data justify the evaluation of verdinexor in small animal models of viral diseases that demonstrated the highest sensitivity to verdinexor in this screen
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