Polyamine Analog Diethylnorspermidine Restricts Coxsackievirus B3 and Is Overcome by 2A Protease Mutation In Vitro

Hulsebosch, Bridget; Mounce, Bryan C.

doi:10.3390/v13020310

Cited by 12 publications

(10 citation statements)

References 38 publications

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“…Interestingly, the enterovirus Coxsackievirus B3 (CVB3) develops mutations within its proteases as well as the capsid protein VP3 when polyamine synthesis is inhibited, suggesting a role for polyamines in protease activity and cellular attachment for enteroviruses [12][13][14] . Enteroviruses are small, non-enveloped, positive sense single-stranded RNA viruses a part of the picornavirus family that can cause a range of diseases from the mild cold to flaccid paralysis and dilated cardiomyopathy (DCM) 15,16 .…”

Section: Introductionmentioning

confidence: 99%

Polyamines and eIF5A hypusination facilitate SREBP2 translation and cholesterol synthesis to enhance enterovirus attachment and infection

Firpo

Petit

et al. 2021

Preprint

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Metabolism is key to cellular processes that underlie the ability of a virus to productively infect. Polyamines are small metabolites vital for many host cell processes including proliferation, transcription, and translation. Polyamine depletion also inhibits virus infection via diverse mechanisms, including inhibiting polymerase activity and viral translation. We showed that Coxsackievirus B3 (CVB3) attachment requires polyamines; however, the mechanism was unknown. Here, we report polyamines’ involvement in translation, through a process called hypusination, promotes expression of cholesterol synthesis genes by supporting SREBP2 translation, the master transcriptional regulator of cholesterol synthesis genes. Measuring bulk transcription, we found polyamines support expression of cholesterol synthesis genes, regulated by SREBP2. Polyamine depletion inhibits CVB3 by depleting cellular cholesterol. Exogenous cholesterol rescues CVB3 attachment, and mutant CVB3 resistant to polyamine depletion exhibits resistance to cholesterol perturbation. This study provides a novel link between polyamine and cholesterol homeostasis, a mechanism through which polyamines impact CVB3 infection.

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Section: Introductionmentioning

confidence: 99%

Polyamines and eIF5A hypusination facilitate SREBP2 translation and cholesterol synthesis to enhance enterovirus attachment and infection

Firpo

Petit

et al. 2021

Preprint

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“…shown that 2A protease mutation can result in CVB3 resistance to DENSpm. 59 Among the different screened drugs to inhibit CVB3 using different cell lines, it was found that dibucaine, pirlindole, and zuclopenthixol were able to inhibit CVB3 replication by targeting viral protein 2C. 60 Umifenovir is a broad-spectrum antiviral molecule that is active against human influenza A and B viruses by inhibiting virusendosome fusion.…”

Section: Other Moleculesmentioning

confidence: 99%

Combating coxsackievirus B infections

Nekoua

Mercier

Vergez

et al. 2022

Reviews in Medical Virology

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Coxsackieviruses B (CVB) are small, non‐enveloped, single‐stranded RNA viruses belonging to the Enterovirus genus of the Picornaviridae family. They are common worldwide and cause a wide variety of human diseases ranging from those having relatively mild symptoms to severe acute and chronic pathologies such as cardiomyopathy and type 1 diabetes. The development of safe and effective strategies to combat these viruses remains a challenge. The present review outlines current approaches to control CVB infections and associated diseases. Various drugs targeting viral or host proteins involved in viral replication as well as vaccines have been developed and shown potential to prevent or combat CVB infections in vitro and in vivo in animal models. Repurposed drugs and alternative strategies targeting miRNAs or based on plant extracts and probiotics and their derivatives have also shown antiviral effects against CVB. In addition, clinical trials with vaccines and drugs are underway and offer hope for the prevention or treatment of CVB‐induced diseases.

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“…In polyamine-depleted conditions, CVB3 replication is significantly attenuated, both in vitro and using the in vivo mouse model 22 . By passaging CVB3 in polyaminedepleted cells, we previously observed four escape mutants, three in the viral protease 2A or 3C 23,24 , and one in the capsid protein VP3 20 , suggesting a role in viral attachment and/or entry.…”

Section: Introductionmentioning

confidence: 99%

Polyamines mediate enterovirus attachment directly and indirectly through cellular heparan sulfate synthesis

Bm¹,

et al. 2021

Preprint

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Productive viral infection begins with attachment to a susceptible cell, and viruses have evolved complex mechanisms to attach to and subsequently enter cells. Prior to engagement with a cellular receptor, viruses frequently interact with nonspecific attachment factors that can facilitate virus-receptor interactions and viral entry. Polyamines, small positively-charged molecules abundant in mammalian cells, mediate viral attachment, though the mechanism was not fully understood. Using the Coxsackievirus B3 (CVB3) enterovirus model system, we show that polyamines mediate viral attachment both directly and indirectly. The polyamine putrescine specifically enhances viral attachment to cells depleted of polyamines. Putrescine’s positive charge mediates its ability to enhance viral attachment, and polyamine analogs are less efficient at mediating viral attachment. In addition to this direct role of polyamines in attachment, polyamines facilitate the cellular expression of heparan sulfates, negatively-charged molecules found on the cell surface. In polyamine-depleted cells, heparan sulfates are depleted from the surface of cells, resulting in reduced viral attachment. We find that this is due to polyamines’ role in the process of hypusination of eukaryotic initiation factor 5A, which facilitates cellular translation. These data highlight the important role of polyamines in mediating cellular attachment, as well as their function in facilitating cellular heparan sulfate synthesis.

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Polyamine Analog Diethylnorspermidine Restricts Coxsackievirus B3 and Is Overcome by 2A Protease Mutation In Vitro

Cited by 12 publications

References 38 publications

Polyamines and eIF5A hypusination facilitate SREBP2 translation and cholesterol synthesis to enhance enterovirus attachment and infection

Polyamines and eIF5A hypusination facilitate SREBP2 translation and cholesterol synthesis to enhance enterovirus attachment and infection

Combating coxsackievirus B infections

Polyamines mediate enterovirus attachment directly and indirectly through cellular heparan sulfate synthesis

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