A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

Callegaro, Sara; Perrone, Rosalba; Scalabrin, Matteo; Doria, Filippo; Palù, Giorgio; Richter, Sara N.

doi:10.1038/s41598-017-02667-3

Cited by 41 publications

(43 citation statements)

References 41 publications

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“…When we measured the infectivity of newly produced progeny virions by infectious center assays, the infectivity of both cell-associated virions and those released into the culture medium was more significantly reduced by treatment of NMM, but not by TMPyP2 ( Fig 7C ). The antiviral effect of G4-stabilizing ligands on herpes simplex virus-1 (HSV-1) has been reported [ 41 , 59 ]. Consistently, we also found that NMM treatment suppresses the growth of HSV-1 ( S3 Fig ).…”

Section: Resultsmentioning

confidence: 99%

Genome-wide analysis of regulatory G-quadruplexes affecting gene expression in human cytomegalovirus

et al. 2018

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G-quadruplex (G4), formed by repetitive guanosine-rich sequences, is known to play various key regulatory roles in cells. Herpesviruses containing a large double-stranded DNA genome show relatively higher density of G4-forming sequences in their genomes compared to human and mouse. However, it remains poorly understood whether all of these sequences form G4 and how they play a role in the virus life cycle. In this study, we performed genome-wide analyses of G4s present in the putative promoter or gene regulatory regions of a 235-kb human cytomegalovirus (HCMV) genome and investigated their roles in viral gene expression. We evaluated 36 putative G4-forming sequences associated with 20 genes for their ability to form G4 and for the stability of G4s in the presence or absence of G4-stabilizing ligands, by circular dichroism and melting temperature analyses. Most identified sequences formed a stable G4; 28 sequences formed parallel G4s, one formed an antiparallel G4, and four showed mixed conformations. However, when we assessed the effect of G4 on viral promoters by cloning the 20 putative viral promoter regions containing 36 G4-forming sequences into the luciferase reporter and monitoring the expression of luciferase reporter gene in the presence of G4-stabilizing chemicals, we found that only 9 genes were affected by G4 formation. These results revealed promoter context-dependent gene suppression by G4 formation. Mutational analysis of two potential regulatory G4s also demonstrated gene suppression by the sequence-specific G4 formation. Furthermore, the analysis of a mutant virus incapable of G4 formation in the UL35 promoter confirmed promoter regulation by G4 in the context of virus infection. Our analyses provide a platform for assessing G4 functions at the genomic level and demonstrate the properties of the HCMV G4s and their regulatory roles in viral gene expression.

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Section: Resultsmentioning

confidence: 99%

Genome-wide analysis of regulatory G-quadruplexes affecting gene expression in human cytomegalovirus

et al. 2018

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“…We have previously indicated the possible use of G4 ligands as antiviral compounds. Indeed, B19 and other G4 ligands were proven to hinder HSV-1 viral replication without affecting HSV-1 entry (Artusi et al, 2015;Callegaro et al, 2017). Here we further revealed that B19 strongly affects the expression of ICP4 protein acting on its own promoter, thus hampering all subsequent ICP4 transcriptional activities.…”

Section: Discussionmentioning

confidence: 99%

“…To gain further insights into the G4-dependent virus biology, we set out to identify viral/cellular proteins that could specifically interact with biotinylated G4forming HSV-1 sequences. We employed two sequences that have been previously reported to fold into G4s and be highly repeated within the HSV-1 genome: the 58 nt-long un2L2 and 66 nt-long gp054dL3 G4-folding oligonucleotides (Table S1), which are highly conserved and repeated within the terminal and internal repeat short regions (TRS and IRS, RS2) and the UL36 coding sequence (CDS, UL RS1), respectively (Artusi et al, 2015;Callegaro et al, 2017). Un2L2 is composed of 9 G-tracts, ranging from three to nine G bases each, gp054dL3 of ten G-tracts of 4-8 Gs each.…”

Section: Hsv-1 Transcription Factor Icp4 Binds To G4-folded Nucleic Amentioning

confidence: 99%

Transcription factor recruitment by parallel G-quadruplexes to promote transcription: the case of herpes simplex virus-1 ICP4

Frasson

Soldà

Nadai

et al. 2020

Preprint

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G-quadruplexes (G4s), four-stranded nucleic acid structures that adopt several distinctive conformations, are abundant at gene promoters and have been proposed as transcription regulatory elements. G4s form in the herpes simplex virus-1 (HSV-1) genome during its viral cycle. Here by cross-linking/pull-down assay we identified ICP4 as the protein that most interacts with viral G4s during infection. In vitro and in infected cells, ICP4 specifically and directly bound and unfolded parallel G4s, including those present in HSV-1 immediate early gene promoters, and consequently induced transcription. This mechanism was also exploited by ICP4 to promote its own transcription. By proximity ligation assay we visualized ICP4 interaction at the single G4 in cells. G4 ligands inhibited ICP4 binding to G4s. Our results indicate the existence of a well-defined G4-viral protein network that regulates the productive HSV-1 cycle. They also point to G4s as elements that recruit transcription factors to activate transcription in cells.

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“…Across different types of microbes, the modulation of transcription by G4s and its cascading effect on specific microbial phenotypes appears to be a common theme ( Figure 5). Inhibition of HSV-1 DNA replication ( Figure 4E) [78,79] HIV-1…”

Section: G4s As Antimicrobial Targetsmentioning

confidence: 99%

G-Quadruplexes: More Than Just a Kink in Microbial Genomes

Saranathan

Vivekanandan

2019

Trends in Microbiology

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G-quadruplexes (G4s) are noncanonical nucleic acid secondary structures formed by guanine-rich DNA and RNA sequences. In this review we aim to provide an overview of the biological roles of G4s in microbial genomes with emphasis on recent discoveries. G4s are enriched and conserved in the regulatory regions of microbes, including bacteria, fungi, and viruses. Importantly, G4s in hepatitis B virus (HBV) and hepatitis C virus (HCV) genomes modulate genes crucial for virus replication. Recent studies on Epstein-Barr virus (EBV) shed light on the role of G4s within the microbial transcripts as cis-acting regulatory signals that modulate translation and facilitate immune evasion. Furthermore, G4s in microbial genomes have been linked to radioresistance, antigenic variation, recombination, and latency. G4s in microbial genomes represent novel therapeutic targets for antimicrobial therapy.

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A core extended naphtalene diimide G-quadruplex ligand potently inhibits herpes simplex virus 1 replication

Cited by 41 publications

References 41 publications

Genome-wide analysis of regulatory G-quadruplexes affecting gene expression in human cytomegalovirus

Genome-wide analysis of regulatory G-quadruplexes affecting gene expression in human cytomegalovirus

Transcription factor recruitment by parallel G-quadruplexes to promote transcription: the case of herpes simplex virus-1 ICP4

G-Quadruplexes: More Than Just a Kink in Microbial Genomes

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