Dengue virus (DENV), the causative agent of dengue fever, is a re-emerging infection predicted to cause up to 390 million infections globally each year (Bhatt et al., 2013). Despite its growing prevalence, there is no effective vaccine or antiviral agent available to combat DENV.
Here we describe a novel anti-DENV agent, fenretinide, which potently inhibits production of infectious virus. Fenretinide was found to be equally effective against all four serotypes of DENV (EC50 values ranging from 1.3 μM for DENV3, to 2.5 μM for DENV1), as well as against antibody-dependent enhanced infection (a widely regarded contributor to severe dengue disease; EC50 of 0.8 μM). Significantly, when dosed twice daily at 20 mg/kg, fenretinide resulted in a 70% survival rate in a lethal mouse model for DENV infection.
A loss of infectious virus correlated with reduced levels of viral non-structural proteins as well as reduced viral RNA levels, suggesting inhibition at the level of RNA replication.
Examination of the mode of action of this compound at the cellular level determined specific up-regulation of the pro-apoptotic PERK pathway within the unfolded protein response, with an 80-fold increase in GADD34 transcript levels observed after 24 h treatment in Huh7 cells.
Together, these data suggest that induction of a PERK-specific stress response following fenretinide treatment may lead to viral clearance.
Importantly, fenretinide has been used for the treatment of various cancers, providing important safety and pharmacological information regarding the use of this compound in humans. This study will provide an important platform for considering the future use of this compound to treat DENV-infected patients in a clinical setting.