Inhibition of fatty acid synthase by amentoflavone reduces coxsackievirus B3 replication

Wilsky, Steffi; Sobotta, Katharina; Wiesener, Nadine; Pilas, Johanna; Althof, Nadine; Münder, Thomas; Wutzler, Peter; Henke, Andreas

doi:10.1007/s00705-011-1164-z

Cited by 57 publications

(44 citation statements)

References 54 publications

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“…Dynamin 2 protein encoded by DNM2 is required for CVB3 entry (Patel et al 2009). Fatty acid synthase encoded by FASN is required for CVB3 replication (Wilsky et al 2012). OSBP and SACM1L are required for sterol/PI(4)P exchange at the ERGolgi interface, and rhinovirus and enterovirus, which belong to Picornaviridae like CVB3, use these processes for viral replication (Mesmin et al 2013;Roulin et al 2014;Strating et al 2015).…”

Section: Dnm2 Fasn Osbp and Sacm1l Are Known To Be Important For Ementioning

confidence: 99%

Arrayed CRISPR screen with image-based assay reliably uncovers host genes required for coxsackievirus infection

Lee

Kim

et al. 2018

Genome Res.

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Pooled CRISPR screens based on lentiviral systems have been widely applied to identify the effect of gene knockout on cellular phenotype. Although many screens were successful, they also have the limitation that genes conferring mild phenotypes or those essential for growth can be overlooked, as every genetic perturbation is incorporated in the same population. Arrayed screens, on the other hand, incorporate a single genetic perturbation in each well and could overcome these limitations. However, arrayed screens based on siRNA-mediated knockdown were recently criticized for low reproducibility caused by incomplete inhibition of gene expression. To overcome these limitations, we developed a novel arrayed CRISPR screen based on a plasmid library expressing a single guide RNA (sgRNA) and disrupted 1514 genes, encoding kinases, proteins related to endocytosis, and Golgi-localized proteins, individually using 4542 sgRNAs (three sgRNAs per gene). This screen revealed host factors required for infection by coxsackievirus B3 (CVB3) from Picornaviridae, which includes human pathogens causing diverse diseases. Many host factors that had been overlooked in a conventional pooled screen were identified for CVB3 infection, including entry-related factors, translational initiation factors, and several replication factors with different functions, demonstrating the advantage of the arrayed screen. This screen was quite reliable and reproducible, as most genes identified in the primary screen were confirmed in secondary screens. Moreover, ACBD3, whose phenotype was not affected by siRNA-mediated knockdown, was reliably identified. We propose that arrayed CRISPR screens based on sgRNA plasmid libraries are powerful tools for arrayed genetic screening and applicable to larger-scale screens.

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Section: Dnm2 Fasn Osbp and Sacm1l Are Known To Be Important For Ementioning

confidence: 99%

Arrayed CRISPR screen with image-based assay reliably uncovers host genes required for coxsackievirus infection

Lee

Kim

et al. 2018

Genome Res.

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“…For example, DENV and WNV recruit fatty acid synthase (FASN), the key enzyme in FA biogenesis, to VRCs[44,55,56]. In line with a requirement for de novo FA biosynthesis, several viruses, including enteroviruses, DENV, WNV and HCV, are sensitive to pharmacological inhibition of FASN and in some cases upregulate FASN[44,53,[55][56][57][58][59][60].…”

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confidence: 99%

Viral rewiring of cellular lipid metabolism to create membranous replication compartments

Strating

Kuppeveld

2017

Current Opinion in Cell Biology

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Positive-strand RNA (+RNA) viruses (e.g. poliovirus, hepatitis C virus, dengue virus, SARS-coronavirus) remodel cellular membranes to form so-called viral replication compartments (VRCs), which are the sites where viral RNA genome replication takes place. To induce VRC formation, these viruses extensively rewire lipid metabolism. Disparate viruses have many commonalities as well as disparities in their interactions with the host lipidome and accumulate specific sets of lipids (sterols, glycerophospholipids, sphingolipids) at their VRCs. Recent years have seen an upsurge in studies investigating the role of lipids in +RNA virus replication, in particular of sterols, and uncovered that membrane contact sites and lipid transfer proteins are hijacked by viruses and play pivotal roles in VRC formation.

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“…The study showed that the mice infected with CVB3 had defects in their blood circulation, and viral replication was found in their heart and kidneys (Yin et al ., 2014). Although the anti-CVB3 activity of amentoflavone was also suggested to be mediated by the inhibition of fatty acid synthase expression (Wilsky et al ., 2012), amentoflavone possessed higher cytotoxicity with relatively weaker antiviral activity than the total flavonoid extracts from Selaginella moellendorffii Hieron (Yin et al ., 2014). Thus, it seems that there may be a synergistic effect exerted by flavonoids, or other antiviral compounds may be present in the total flavonoid extracts from Selaginella moellendorffii Hieron.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Activity of Chrysin Derivatives against Coxsackievirus B3 in vitro and in vivo

Song

Kwon

Jang

et al. 2015

Biomolecules & Therapeutics

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Chrysin is a 5,7-dihydroxyflavone and was recently shown to potently inhibit enterovirus 71 (EV71) by suppressing viral 3C protease (3Cpro) activity. In the current study, we investigated whether chrysin also shows antiviral activity against coxsackievirus B3 (CVB3), which belongs to the same genus (Enterovirus) as EV71, and assessed its ability to prevent the resulting acute pancreatitis and myocarditis. We found that chrysin showed antiviral activity against CVB3 at 10 μM, but exhibited mild cellular cytotoxicity at 50 μM, prompting us to synthesize derivatives of chrysin to increase the antiviral activity and reduce its cytotoxicity. Among four 4-substituted benzyl derivatives derived from C(5) benzyl-protected derivatives 7, 9–11 had significant antiviral activity and showed the most potent activity against CVB3 with low cytotoxicity in Vero cells. Intraperitoneal injection of CVB3 in BALB/c mice with 1×106 TCID50 (50% tissue culture infective dose) of CVB3 induced acute pancreatitis with ablation of acinar cells and increased serum CXCL1 levels, whereas the daily administration of 9 for 5 days significantly alleviated the pancreatic inflammation and reduced the elevation in serum CXCL1 levels. Collectively, we assessed the anti-CVB3 activities of chrysin and its derivatives, and found that among 4-substituted benzyl derivatives, 9 exhibited the highest activity against CVB3 in vivo, and protected mice from CVB3-induced pancreatic damage, simultaneously lowering serum CXCL1 levels.

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Inhibition of fatty acid synthase by amentoflavone reduces coxsackievirus B3 replication

Cited by 57 publications

References 54 publications

Arrayed CRISPR screen with image-based assay reliably uncovers host genes required for coxsackievirus infection

Arrayed CRISPR screen with image-based assay reliably uncovers host genes required for coxsackievirus infection

Viral rewiring of cellular lipid metabolism to create membranous replication compartments

Antiviral Activity of Chrysin Derivatives against Coxsackievirus B3 in vitro and in vivo

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