Structure and function of <i>cis</i>‐acting RNA elements of flavivirus

Liu, Zhongyu; Qin, Cheng‐Feng

doi:10.1002/rmv.2092

Cited by 23 publications

(23 citation statements)

References 100 publications

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“…The 5 and 3 UTRs are implicated in viral replication and pathogenesis [25]. The capsid (C) protein plays an essential role in viral assembly and replication [26].…”

Section: Groupmentioning

confidence: 99%

Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections

Blázquez

Saiz

2020

IJMS

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Protein kinases (PKs) are enzymes that catalyze the transfer of the terminal phosphate group from ATP to a protein acceptor, mainly to serine, threonine, and tyrosine residues. PK catalyzed phosphorylation is critical to the regulation of cellular signaling pathways that affect crucial cell processes, such as growth, differentiation, and metabolism. PKs represent attractive targets for drugs against a wide spectrum of diseases, including viral infections. Two different approaches are being applied in the search for antivirals: compounds directed against viral targets (direct-acting antivirals, DAAs), or against cellular components essential for the viral life cycle (host-directed antivirals, HDAs). One of the main drawbacks of DAAs is the rapid emergence of drug-resistant viruses. In contrast, HDAs present a higher barrier to resistance development. This work reviews the use of chemicals that target cellular PKs as HDAs against virus of the Flaviviridae family (Flavivirus and Hepacivirus), thus being potentially valuable therapeutic targets in the control of these pathogens.

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“…The 5 and 3 UTRs are implicated in viral replication and pathogenesis [25]. The capsid (C) protein plays an essential role in viral assembly and replication [26].…”

Section: Groupmentioning

confidence: 99%

Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections

Blázquez

Saiz

2020

IJMS

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“…The UFS may therefore be considered a switch for controlling the transition from viral translation to replication. It has also been proposed that the UFS acts as a structurally dynamic element to control NS5 recruitment during replication in a manner dependent on viral RNA levels [90], but this needs to be confirmed.…”

Section: Cyclization Of the Flavivirus Genomementioning

confidence: 99%

Information Encoded by the Flavivirus Genomes beyond the Nucleotide Sequence

Ramos-Lorente

Romero-López

Berzal‐Herranz

2021

IJMS

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The genus Flavivirus comprises numerous, small, single positive-stranded RNA viruses, many of which are important human pathogens. To store all the information required for their successful propagation, flaviviruses use discrete structural genomic RNA elements to code for functional information by the establishment of dynamic networks of long-range RNA–RNA interactions that promote specific folding. These structural elements behave as true cis-acting, non-coding RNAs (ncRNAs) and have essential regulatory roles in the viral cycle. These include the control of the formation of subgenomic RNAs, known as sfRNAs, via the prevention of the complete degradation of the RNA genome. These sfRNAs are important in ensuring viral fitness. This work summarizes our current knowledge of the functions performed by the genome conformations and the role of RNA–RNA interactions in these functions. It also reviews the role of RNA structure in the production of sfRNAs across the genus Flavivirus, and their existence in related viruses.

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“…1(a)). RNA regulatory elements are present in both the 5 0 UTR and the capsid gene, (reviewed in [27,28]), thus the beginning of the capsid gene (25 amino acids) must be duplicated before the reporter gene in order to preserve viral translation and replication (see Fig. 1(a)).…”

Section: Recombination-dependent Fatal Mutationsmentioning

confidence: 99%

Using recombination-dependent lethal mutations to stabilize reporter flaviviruses for rapid serodiagnosis and drug discovery

et al. 2020

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Background: Many flaviviruses are significant human pathogens that cause global public health threats. Developing research tools for studying and diagnosing these pathogens is a top priority. Reporter flaviviruses are useful tools for studying viral pathogenesis, diagnosing disease, and screening antiviral compounds. However, the stability of reporter flaviviruses has been challenged by viral RNA recombination, leading to deletion of the engineered reporter gene during viral replication. The instability of reporter viruses has limited their application to research and countermeasure development. Thus, new approaches to overcome the instability of reporter flaviviruses are critically needed to advance the flavivirus field. Methods: To create a stable flavivirus bearing a reporter gene, we engineered mutations in the viral capsid gene that are rendered virus-lethal upon recombination. Thus, only non-recombined reporter virus propagates. We tested this strategy using Zika virus (ZIKV) bearing a nano-luciferase (NanoLuc) gene and passaged both virus with capsid mutations and virus without mutations. Findings: The recombination-dependent lethal mutations succeeded in stabilizing the NanoLuc ZIKV through ten passages, while WT reporter virus showed instability as early as five passages. The stability of NanoLuc ZIKV was supported by RT-PCR, sequencing, focus forming assay, and luciferase assay. The success of this method was reconfirmed by also establishing a stable NanoLuc Yellow Fever 17D virus, indicating that the recombination-dependent lethal approach can be applied to other flaviviruses. To demonstrate the utility of the stable reporter viruses, we showed that NanoLuc ZIKV and YFV17D could be used to measure neutralizing antibody titers with a turnaround time as short as four hours. Importantly, the neutralizing antibody titers derived from the reporter virus assay were equivalent to those derived from the conventional plaque assay, indicating the new assay maintains the gold standard of serology testing. Furthermore, using a known inhibitor, we showed that the reporter viruses could be reliably used for antiviral evaluation. Interpretation: The study has developed a recombination-dependent lethal approach to produce stable reporter flaviviruses that may be used for rapid serodiagnosis, trans-gene delivery, vaccine evaluation, and antiviral discovery.

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Structure and function of cis‐acting RNA elements of flavivirus

Cited by 23 publications

References 100 publications

Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections

Potential for Protein Kinase Pharmacological Regulation in Flaviviridae Infections

Information Encoded by the Flavivirus Genomes beyond the Nucleotide Sequence

Using recombination-dependent lethal mutations to stabilize reporter flaviviruses for rapid serodiagnosis and drug discovery

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