Polyamine depletion of cells reduces the infectivity of herpes simplex virus but not the infectivity of sindbis virus

Pohjanpelto, Pirkko; Sekki, Akseli; Hukkanen, Veijo; Bonsdorff, Carl-Henrik von

doi:10.1016/0024-3205(88)90501-2

Cited by 18 publications

(17 citation statements)

References 11 publications

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“…Small-molecule inhibition of cellular polyamine synthesis suggests that polyamines are important for the replication of several DNA viruses. Inhibition of polyamine synthesis with difluoromethylornithine (DFMO) results in a block of both HSV and HCMV replication (43,44). Additionally, work characterizing the effects of polyamines on vaccinia virus demonstrated that a late step in the viral life cycle, beyond transcription or translation, is affected by methylglyoxal bis(guanylhydrazone) (MGBG), an inhibitor of S-adenosylmethionine decarboxylase (SAMDC) (Fig.…”

Section: Polyamines In the Replication Of Dna Virusesmentioning

confidence: 99%

Polyamines and Their Role in Virus Infection

Mounce

Olsen

Vignuzzi

et al. 2017

Microbiol Mol Biol Rev

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Polyamines are small, abundant, aliphatic molecules present in all mammalian cells. Within the context of the cell, they play a myriad of roles, from modulating nucleic acid conformation to promoting cellular proliferation and signaling. In addition, polyamines have emerged as important molecules in virus-host interactions. Many viruses have been shown to require polyamines for one or more aspects of their replication cycle, including DNA and RNA polymerization, nucleic acid packaging, and protein synthesis. Understanding the role of polyamines has become easier with the application of small-molecule inhibitors of polyamine synthesis and the use of interferon-induced regulators of polyamines. Here we review the diverse mechanisms in which viruses require polyamines and investigate blocking polyamine synthesis as a potential broad-spectrum antiviral approach.

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Section: Polyamines In the Replication Of Dna Virusesmentioning

confidence: 99%

Polyamines and Their Role in Virus Infection

Mounce

Olsen

Vignuzzi

et al. 2017

Microbiol Mol Biol Rev

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“…We had previously observed that CHIKV and Zika virus (ZIKV) were sensitive to polyamine depletion (4), and to expand on these data, we used a related virus, Sindbis virus, which is a close relative to CHIKV but was shown in a previous study to not be affected by DFMO treatment (19). BHK-21 cells were pretreated with 500 M DFMO and infected at an MOI of 0.1, and the titers measured over a time course of infection ( Fig.…”

Section: Dfmo Limits the Replication Of Diverse Rna Virusesmentioning

confidence: 99%

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

Mounce

Cesaro

Moratorio

et al. 2016

J Virol

112

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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...

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“…Similar to the PCIs, MGBG was equally effective at inhibiting the replication of wild-type or drug-resistant HSV-1 strains (Greco et al, 2005). As a caveat of these experiments, it should be noted that previous experiments had shown that depletion of polyamines resulted in either inhibition (Raina et al, 1981;Pohjanpelto et al, 1988) or no effect (McCormick & Newton, 1975;Tyms et al, 1979) on HSV-1 replication.…”

Section: Other Cellular Targetsmentioning

confidence: 89%

“…Polyamines such as spermine have long been known to play major roles in the replication cycle of HSV-1 (Gibson & Roizman, 1971), and had even been shown to be required for efficient production of infectious HSV-1 virions (Pohjanpelto et al, 1988). A proteomics study identified several proteins the expression of which was induced, or at least not inhibited, during HSV infection (Greco et al, 2000).…”

Section: Other Cellular Targetsmentioning

confidence: 97%

Five Years of Progress on Cyclin-Dependent Kinases and other Cellular Proteins as Potential Targets for Antiviral Drugs

Schang

St.Vincent

Lacasse

2006

Antivir Chem Chemother

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In 1997-1998, the pharmacological cyclin-dependent kinase (CDK) inhibitors (PCIs) were independently discovered to inhibit replication of human cytomegalovirus, herpes simplex virus type 1 and HIV-1. The results from small clinical trials against cancer were then suggesting that PCIs could be safe enough to be used clinically. It was thus hypothesized that PCIs could have the potential to be developed as novel antivirals targeting cellular proteins. Consequently, Antiviral Chemistry & Chemotherapy published in 2001 the first review on the potential of CDKs, and cellular proteins in general, as potential targets for antivirals. The viral functions inhibited by PCIs, or their cellular targets, were then just starting to be characterized. The antiviral spectrum of PCIs and their effects on viral disease were still mostly untested. Even their actual specificity was not yet completely characterized. In addition, cellular proteins were not accepted as valid targets for antivirals. Significant progress has been made in the last 5 years in understanding the antiviral activities of PCIs and the potential roles of cellular proteins in general as targets for antivirals. The first clinical trials of the antiviral activities of PCIs and other inhibitors of cellular protein kinases have now been scheduled. Herein, we review the progress made since the publication of the first review on PCIs as potential antiviral drugs and on CDKs, and cellular proteins in general, as potential targets for antiviral drugs. We also highlight the major issues that still need to be addressed before PCIs or other drugs targeting cellular proteins can be developed as clinical antivirals.

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Polyamine depletion of cells reduces the infectivity of herpes simplex virus but not the infectivity of sindbis virus

Cited by 18 publications

References 11 publications

Polyamines and Their Role in Virus Infection

Polyamines and Their Role in Virus Infection

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

Five Years of Progress on Cyclin-Dependent Kinases and other Cellular Proteins as Potential Targets for Antiviral Drugs

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