CNBP Binds and Unfolds In Vitro G-Quadruplexes Formed in the SARS-CoV-2 Positive and Negative Genome Strands

Bezzi, G; Piga, Ernesto J.; Binolfi, Andrés; Armas, Pablo

doi:10.3390/ijms22052614

Cited by 43 publications

(57 citation statements)

References 97 publications

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“…The urge of feasible therapies has boosted researchers worldwide to search for new strategies to fight the virus: one of these is the use of G4s as novel antiviral targets. Several bioinformatics tools were employed to assess the presence of PQSs within the SARS-CoV-2 RNA genome, showing very low enrichment in G4s [8,[99][100][101]. Nonetheless, the identified PQSs were shown to fold into two-layered G4s and to be located within the open reading frames (ORFs) 1ab and 3a, spike, membrane, and nucleocapsid genes, suggesting that RNA G4s could be involved in the regulation of viral replication, assembly, and immune-response modulation [99].…”

Section: Application Of G4 Ligands In Emerging Viruses: the Case Of Sars-cov-2mentioning

confidence: 99%

“…In addition, in constructs including the G4 regions upstream the GFP gene, G4 ligands treatment reduced GFP expression [102]. SARS-CoV-2 RNA G4s were found to be targeted and unwound by the cellular protein CNBP, disclosing new aspects in the virus/host interplay: since CNBP expression is enhanced in response to viral infections, the protein/G4 interaction could be targeted for antiviral purposes [101]. The SARS-Unique Domain (SUD) of SARS-CoV Nsp3 protein had been previously shown to interact with G4s, and this interaction was proposed to be crucial for SARS genome transcription/replication [103].…”

Section: Application Of G4 Ligands In Emerging Viruses: the Case Of Sars-cov-2mentioning

confidence: 99%

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G-Quadruplex Targeting in the Fight against Viruses: An Update

Ruggiero

Zanin

Terreri

et al. 2021

IJMS

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G-quadruplexes (G4s) are noncanonical nucleic acid structures involved in the regulation of key cellular processes, such as transcription and replication. Since their discovery, G4s have been mainly investigated for their role in cancer and as targets in anticancer therapy. More recently, exploration of the presence and role of G4s in viral genomes has led to the discovery of G4-regulated key viral pathways. In this context, employment of selective G4 ligands has helped to understand the complexity of G4-mediated mechanisms in the viral life cycle, and highlighted the possibility to target viral G4s as an emerging antiviral approach. Research in this field is growing at a fast pace, providing increasing evidence of the antiviral activity of old and new G4 ligands. This review aims to provide a punctual update on the literature on G4 ligands exploited in virology. Different classes of G4 binders are described, with emphasis on possible antiviral applications in emerging diseases, such as the current COVID-19 pandemic. Strengths and weaknesses of G4 targeting in viruses are discussed.

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Section: Application Of G4 Ligands In Emerging Viruses: the Case Of Sars-cov-2mentioning

confidence: 99%

Section: Application Of G4 Ligands In Emerging Viruses: the Case Of Sars-cov-2mentioning

confidence: 99%

G-Quadruplex Targeting in the Fight against Viruses: An Update

Ruggiero

Zanin

Terreri

et al. 2021

IJMS

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“…Alternatively, these compounds were also found to compete with the host cell or viral proteins for binding to these structures with frequently inhibitory but occasionally also stimulatory effects on their reproduction 32,33 .…”

Section: Introductionmentioning

confidence: 99%

Targeting G-quadruplexes in the rhinovirus genome by Pyridostatin inhibits uncoating and highlights a critical role for sodium ions.

Real-Hohn

Groznica

Kontaxis

et al. 2021

Preprint

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The ~ 2.4 µm long rhinovirus ss(+)RNA genome consists of roughly 7,200 nucleotides. It is tightly folded to fit into the ~ 22 nm diameter void in the protein capsid. In addition to previously predicted secondary structural elements in the RNA, using the QGRS mapper, we revealed the presence of multiple quadruplex forming G-rich sequences (QGRS) in the RV-A, B, and C clades, with four of them being exquisitely conserved. The biophysical analyses of ribooligonucleotides corresponding to selected QGRS demonstrate G-quadruplex (GQ) formation in each instance and resulted in discovering another example of an unconventional, two-layer zero-nucleotide loop RNA GQ stable at physiological conditions. By exploiting the temperature-dependent viral breathing to allow diffusion of small compounds into the virion, we demonstrate that the GQ-binding compounds PhenDC3 and pyridostatin (PDS) uniquely interfere with viral uncoating. Remarkably, this inhibition was entirely prevented in the presence of K+ but not Na+, despite the higher GQ stabilising effect of K+. Based on virus thermostability studies combined with ultrastructural imaging of isolated viral RNA, we propose a mechanism where Na+ keeps the encapsidated genome loose, allowing its penetration by PDS to promote the transition of QGRS sequestered in alternative metastable structures into GQs. The resulting conformational change then materialises in a severely compromised RNA release from the proteinaceous shell. Targeting extracellularly circulating RVs with GQ-stabilisers might thus become a novel way of combating the common cold.

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“…Treatment of Ebola with TMPyP4 evidently inhibits L gene expression [21]. Recently, bioinformatics analysis identified G4-forming sequences in the SARS-CoV-2 genome [23,24]. In addition, treatment with PDP reduced the SARS-CoV-2 N expression in vitro and in vivo by targeting the RNA G4 structure in SARS-CoV-2 [25].…”

Section: Introductionmentioning

confidence: 99%

G-Quadruplexes Formation at the Upstream Region of Replication Origin (OriL) of the Pseudorabies Virus: Implications for Antiviral Targets

Zhu

Liu

Zhang

2021

Viruses

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Pseudorabies virus (PRV) is the causative agent of Aujeszky’s disease, which still causes large economic losses for the swine industry. Therefore, it is urgent to find a new strategy to prevent and control PRV infection. Previous studies have proven that guanine (G)-rich DNA or RNA sequences in some other viruses’ genomes have the potential to form G-quadruplex (G4), which serve as promising antivirus targets. In this study, we identified two novel G4-forming sequences, OriL-A and OriL-S, which are located at the upstream origin of replication (OriL) in the PRV genome and conserved across 32 PRV strains. Circular dichroism (CD) spectroscopy and a gel electrophoresis assay showed that the two G-rich sequences can fold into parallel G4 structures in vitro. Moreover, fluorescence resonance energy transfer (FRET) melting and a Taq polymerase stop assay indicated that the G4 ligand PhenDC3 has the capacity to bind and stabilize the G4. Notably, the treatment of PRV-infected cells with G4-stabilizer PhenDC3 significantly inhibited PRV DNA replication in host cells but did not affect PRV’s attachment and entry. These results not only expand our knowledge about the G4 characteristics in the PRV genome but also suggest that G4 may serve as an innovative therapeutic target against PRV.

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CNBP Binds and Unfolds In Vitro G-Quadruplexes Formed in the SARS-CoV-2 Positive and Negative Genome Strands

Cited by 43 publications

References 97 publications

G-Quadruplex Targeting in the Fight against Viruses: An Update

G-Quadruplex Targeting in the Fight against Viruses: An Update

Targeting G-quadruplexes in the rhinovirus genome by Pyridostatin inhibits uncoating and highlights a critical role for sodium ions.

G-Quadruplexes Formation at the Upstream Region of Replication Origin (OriL) of the Pseudorabies Virus: Implications for Antiviral Targets

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