Dataset Information

Antiviral activity of N-(4-hydroxyphenyl) retinamide (4-HPR) against Zika virus.

ABSTRACT: The rapid spread of Zika virus (ZIKV) in recent years has highlighted the severe diseases associated with ZIKV infection, such as Guillain-Barré syndrome in adults and microcephaly in newborns; yet no vaccines or antivirals currently exist to prevent or treat ZIKV infection. We and others have previously identified N-(4-hydroxyphenyl) retinamide (fenretinide or 4-HPR) as an antiviral compound that inhibits dengue virus 2 (DV2) and other flaviviruses by limiting the steady-state accumulation of viral RNA. Here we show that 4-HPR potently inhibits ZIKV in mammalian cell culture and significantly reduces both serum viremia and brain viral burden in a murine model of ZIKV infection. Consistent with previous observations with dengue virus, this antiviral activity is associated with a significant reduction in the steady-state abundance of viral genomic RNA. We show this reduction is due to a major decrease in the rate of viral RNA synthesis, though not via direct inhibition of the activity of the viral replicase. These results establish 4-HPR's mode of action against DV and ZIKV and, taken with previous clinical trials that established 4-HPR's safety and tolerability, illustrate the potential utility of 4-HPR as an agent for treatment of ZIKV infection.

SUBMITTER: Pitts JD

PROVIDER: S-EPMC5703041 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Antiviral activity of N-(4-hydroxyphenyl) retinamide (4-HPR) against Zika virus.

Pitts Jared D JD Li Pi-Chun PC de Wispelaere Melissanne M Yang Priscilla L PL

Antiviral research 20171016

The rapid spread of Zika virus (ZIKV) in recent years has highlighted the severe diseases associated with ZIKV infection, such as Guillain-Barré syndrome in adults and microcephaly in newborns; yet no vaccines or antivirals currently exist to prevent or treat ZIKV infection. We and others have previously identified N-(4-hydroxyphenyl) retinamide (fenretinide or 4-HPR) as an antiviral compound that inhibits dengue virus 2 (DV2) and other flaviviruses by limiting the steady-state accumulation of v ...[more]

PMID: 29051080

Similar Datasets

Project description:There is currently no knowledge of how the emerging human pathogen Zika virus (ZIKV) interacts with the antiviral endoribonuclease L (RNase L) pathway during infection. Since activation of RNase L during infection typically limits virus production dramatically, we used CRISPR-Cas9 gene editing technology to knockout (KO) targeted host genes involved in the RNase L pathway to evaluate the effects of RNase L on ZIKV infection in human A549 cells. RNase L was activated in response to ZIKV infection, which degraded ZIKV genomic RNA. Surprisingly, despite viral genome reduction, RNase L activity did not reduce ZIKV infectious titers. In contrast, both the flavivirus dengue virus and the alphavirus Sindbis virus replicated to significantly higher titers in RNase L KO cells compared to wild-type (WT) cells. Using MAVS/RNase L double KO cells, we demonstrated that the absence of increased ZIKV production in RNase L KO cells was not due to compensation by enhanced type I interferon transcripts to thus inhibit virus production. Finally, when synthetic double-stranded RNA was detected by OAS3 to induce RNase L antiviral activity prior to ZIKV infection, we observed reduced ZIKV replication factory formation, as well as a 42-fold reduction in virus yield in WT but not RNase L KO cells. This study proposes that ZIKV evades RNase L antiviral activity by generating a viral genome reservoir protected from RNase L cleavage during early infection, allowing for sufficient virus production before RNase L activation is detectable.IMPORTANCE With the onset of the 2015 ZIKV outbreak, ZIKV pathogenesis has been of extreme global public health interest, and a better understanding of interactions with the host would provide insight into molecular mechanisms driving the severe neurological outcomes of ZIKV disease. Here is the initial report on the relationship between ZIKV and the host oligoadenylate synthetase-RNase L (OAS-RNase L) system, a potent antiviral pathway effective at restricting replication of diverse viruses. Our study elucidated a unique mechanism whereby ZIKV production is impervious to antiviral RNase L activity, through a mechanism of viral RNA protection that is not mimicked during infection with numerous other RNase L-activating viruses, thus identifying a distinct replication strategy potentially important for ZIKV pathogenesis.

Dataset Information

Antiviral activity of N-(4-hydroxyphenyl) retinamide (4-HPR) against Zika virus.

Publications

Antiviral activity of N-(4-hydroxyphenyl) retinamide (4-HPR) against Zika virus.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets