Inhibition of Polyamine Biosynthesis Is a Broad-Spectrum Strategy against RNA Viruses

Abstract

RNA viruses present an extraordinary threat to human health, given their sudden and unpredictable appearance, the potential for rapid spread among the human population, and their ability to evolve resistance to antiviral therapies. The recent emergence of chikungunya virus, Zika virus, and Ebola virus highlights the struggles to contain outbreaks. A significant hurdle is the availability of antivirals to treat the infected or protect at-risk populations. While several compounds show promise in vitro and in vivo, these outbreaks underscore the need to accelerate drug discovery. The replication of several viruses has been described to rely on host polyamines, small and abundant positively charged molecules found in the cell. Here, we describe the antiviral effects of two molecules that alter polyamine levels: difluoromethylornithine (DFMO; also called eflornithine), which is a suicide inhibitor of ornithine decarboxylase 1 (ODC1), and diethylnorspermine (DENSpm), an activator of spermidine/spermine N 1 -acetyltransferase (SAT1). We show that reducing polyamine levels has a negative effect on diverse RNA viruses, including several viruses involved in recent outbreaks, in vitro and in vivo. These findings highlight the importance of the polyamine biosynthetic pathway to viral replication, as well as its potential as a target in the development of further antivirals or currently available molecules, such as DFMO. IMPORTANCERNA viruses present a significant hazard to human health, and combatting these viruses requires the exploration of new avenues for targeting viral replication. Polyamines, small positively charged molecules within the cell, have been demonstrated to facilitate infection for a few different viruses. Our study demonstrates that diverse RNA viruses rely on the polyamine pathway for replication and highlights polyamine biosynthesis as a promising drug target. P olyamines are small, positively charged molecules, derived from arginine, that are involved in several cellular processes in mammalian and nonmammalian cells. Studies carried out on herpesviruses demonstrated that viral capsids contain significant amounts of polyamines that putatively neutralize charges on the viral DNA in order to facilitate compaction and encapsidation (1). Vaccinia virus (2) and bacteriophage R17 (3) also incorporate polyamines into virions. We recently demonstrated that chikungunya virus (CHIKV) and Zika virus (ZIKV), important pathogens responsible for serious outbreaks, rely on polyamines for both translation and transcription (4). The potential role of polyamines in virus replication and the possibility of targeting the polyamine biosynthetic pathway for more diverse array of RNA viruses, including those involved in outbreaks, has not been examined.Several drugs have been developed that can target the polyamine biosynthetic pathway. Perhaps the best known inhibitor is difluoromethylornithine (DFMO; also called eflornithine), an FDA-approved drug that is used to treat trypanosomiasis (5-7) and hirsutism (8), as wel...

Polyamines and Their Role in Virus Infection

“…Treatment of cells with DFMO significantly reduced viral titers, which were then rescued by replenishing polyamines exogenously (32,60,61). More recently, a report by Mounce et al expanded our knowledge of RNA viruses requiring polyamines for replication using DFMO depletion of cellular polyamines (62,63). The list of RNA viruses sensitive to polyamine depletion has been extended to include diverse families, including alphaviruses (chikungunya virus [CHIKV]), coronaviruses (Middle East respiratory syndrome [MERS] virus), enteroviruses (enterovirus A71 and poliovirus), flaviviruses (dengue virus serotype 1, Japanese encephalitis virus, and yellow fever virus), rhabdoviruses (rabies virus), and bunyaviruses (Rift Valley fever virus) (summarized in Table 1) (62,63).…”

“…More recently, a report by Mounce et al expanded our knowledge of RNA viruses requiring polyamines for replication using DFMO depletion of cellular polyamines (62,63). The list of RNA viruses sensitive to polyamine depletion has been extended to include diverse families, including alphaviruses (chikungunya virus [CHIKV]), coronaviruses (Middle East respiratory syndrome [MERS] virus), enteroviruses (enterovirus A71 and poliovirus), flaviviruses (dengue virus serotype 1, Japanese encephalitis virus, and yellow fever virus), rhabdoviruses (rabies virus), and bunyaviruses (Rift Valley fever virus) (summarized in Table 1) (62,63). Replication of each of these viruses was impacted to various degrees when polyamines were depleted with DFMO and rescued when polyamines were replenished exogenously.…”

Advances in Zika Virus Research: Stem Cell Models, Challenges, and Opportunities

“…Future studies are necessary to test these FDA approved drugs or clinical trial drug candidates in animal models for their efficacy as well as toxicity before moving to clinical trials. In addition to nonbiased large scale screens, studies based on mechanistic insights have also identified individual drugs and compounds that inhibit ZIKV replication and/or protect neural progenitors from cell death (Deng et al, 2016; Mounce et al, 2016; Onorati et al, 2016; Zmurko et al, 2016). Some of these compounds have been validated in animal models, but remain to be tested in the microcephaly model in vivo (Deng et al, 2016; Zmurko et al, 2016).…”

Repurposing host-based therapeutics to control coronavirus and influenza virus

“…Difluoromethylornithine (DFMO, also eflornithine), a polyamine inhibitor, has been approved by the FDA to treat African trypanosomiasis and cancer [110,111]. DFMO has been shown to reduce viral production of MERS-CoV 30-fold in Vero cells [112]. DFMO needs to be further studied to clarify its in vivo toxicity and efficacy.…”