Amiloride inhibits the initiation of Coxsackievirus and poliovirus RNA replication by inhibiting VPg uridylylation

Ogram, Sushma A.; Boone, Christopher D.; McKenna, Robert; Flanegan, James B.

doi:10.1016/j.virol.2014.06.025

Cited by 9 publications

(8 citation statements)

References 47 publications

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“…This finding was supported by structural studies of CVB3 in which 3D pol was cocrystalized with VPg and the peptide was found to be bound to the back of the thumb, again distant from the active site (59). One possible explanation of how VPg could be uridylylated at this site is that the nucleotidylylation reaction is carried out by a second molecule of 3D pol (59, 103, 151). Such a “trans” uridylylation mechanism was supported also from structural studies of the EV71 polymerase complexed with VPg, in which VPg bound at the bottom of the palm domain could not access the catalytic site (27).…”

Section: Initiation Of Protein-primed Picornavirus Rna Synthesismentioning

confidence: 99%

Initiation of protein-primed picornavirus RNA synthesis

Paul

Wimmer

2015

Virus Research

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Plus strand RNA viruses use different mechanisms to initiate the synthesis of their RNA chains. The Picornaviridae family constitutes a large group of plus strand RNA viruses that possess a small terminal protein (VPg) covalently linked to the 5’-end of their genomes. The RNA polymerases of these viruses use VPg as primer for both minus and plus strand RNA synthesis. In the first step of the initiation reaction the RNA polymerase links a UMP to the hydroxyl group of a tyrosine in VPg using as template a cis-replicating element (cre) positioned in different regions of the viral genome. In this review we will summarize what is known about the intiation reaction of protein-primed RNA synthesis by the RNA polymerases of the Picornaviridae. As an example we will use the RNA polymerase of poliovirus, the prototype of Picornaviridae. We will also discuss models of how these nucleotidylylated protein primers might be used, together with viral and cellular replication proteins and other cis-replicating RNA elements, during minus and plus strand RNA synthesis.

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Section: Initiation Of Protein-primed Picornavirus Rna Synthesismentioning

confidence: 99%

Initiation of protein-primed picornavirus RNA synthesis

Paul

Wimmer

2015

Virus Research

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“…As CVB3-TD virion RNA was shown to have covalently attached VPg, despite the fact that not all TD genomes have uridine as the 5′ nucleotide [ 50 ], the question arose as to whether the CRE-2C, which functions in the uridylation of VPg (reviewed by Paul and Wimmer [ 49 ]), is required for the replication of the TD CVB genomes. An inhibitor of VPg binding to the viral 3D polymerase, amiloride, decreases the initiation of enterovirus genome replication of both strands [ 112 ], an observation that verifies the process of nucleotidylation of VPg as being a part of the RNA initiation process. It has been shown that the disruption of the CVB3 CRE-2C structure via 16 mutations in the stem and loop ( Figure 6 ; mutations that did not alter the 2C amino acid sequence) inhibited the production of a cytopathic virus in cell culture, and generated double-stranded RF, but not single-stranded viral RNA, when replicons containing these mutations were transfected in cell culture [ 113 ].…”

Section: A Cis-acting Replication Element (Cre-2c) Plays a Role In Lo...mentioning

confidence: 99%

Persistent Enterovirus Infection: Little Deletions, Long Infections

Chapman

2022

Vaccines

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Enteroviruses have now been shown to persist in cell cultures and in vivo by a novel mechanism involving the deletion of varying amounts of the 5′ terminal genomic region termed domain I (also known as the cloverleaf). Molecular clones of coxsackievirus B3 (CVB3) genomes with 5′ terminal deletions (TD) of varying length allow the study of these mutant populations, which are able to replicate in the complete absence of wildtype virus genomes. The study of TD enteroviruses has revealed numerous significant differences from canonical enteroviral biology. The deletions appear and become the dominant population when an enterovirus replicates in quiescent cell populations, but can also occur if one of the cis-acting replication elements of the genome (CRE-2C) is artificially mutated in the element’s stem and loop structures. This review discusses how the TD genomes arise, how they interact with the host, and their effects on host biology.

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“…Amiloride (a diuretic drug) and its more potent derivative 5-(N-ethyl-N-isopropyl) amiloride (EIPA, Fig. 14B) were shown to inhibit CVB3 RNA replication in cell culture [29]. They compete with incoming nucleoside triphosphates (NTPs) and Mg 2+ .…”

Section: Inhibitors Of Replicationmentioning

confidence: 99%

Development of antiviral therapeutics combating coxsackievirus type B3 infection

Volobueva

Zarubaev

Lantseva

2021

Russian Journal of Infection and Immunity

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Enteroviruses are highly diverse group of single-stranded positive RNA viruses belonging to Enterovirus genus from Picornaviridae family. They are the most prevalent viruses in the world. Enteroviruses normally cause seasonal self-limiting infections but they are also known as causative infectious agents of encephalitis, myocarditis, poliomyelitis, acute heart failure and sepsis. Genetic plasticity of enteroviruses allows for widespread epidemics and sporadic outbreaks to occur (for example, outbreaks of Enterovirus D68 and Enterovirus 71). Type B Coxsackieviruses of Enterovirus B species is one of commonly identified infectious agents associated predominantly with mild upper respiratory and gastrointestinal illnesses. Nevertheless, Coxsackieviruses B3 infection can result in severe myocarditis leading ultimately to heart failure. The pathogenesis of Coxsackieviruses B3 induced myocarditis is well studied, and it is mediated by both direct injury mediated by viral proteases and indirect damage secondary to host immune responses. There are no approved direct antiviral medications for the treatment of enteroviral infection in particular Coxsackieviruses B3 myocardial infection to date. Neither are there ongoing clinical trials in the field of Coxsackieviruses B3 infection treatment or prophylaxis. Available treatment strategies are mainly supportive to stabilize the patient condition and to relieve discomforts. Possibly, the relatively small market for anti-enteroviral drugs prevents pharma industry from new drug development. The lifecycle of Coxsackieviruses B3 have been extensively studied and attractive targets for drug design are known. The aim of the present review is to describe the current state of the field of antiviral drug design against Coxsackieviruses B3 infection with special focus on direct-acting antivirals, though host factor-targeting inhibitors (including compounds from medicinal plant extracts) are mentioned too. The following categories of direct Coxsackieviruses B3 inhibitors are discussed in details: capsid binders (pleconaril and its derivatives), viral 3C protease inhibitors (rupintrivir and its analogs), drugs, targeting the viral replication (both nucleoside analogs and non-nucleoside inhibitors). Results of drug repurposing screens for amiloride, benzerazide, dibucaine and fluoxetine are also included.

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Amiloride inhibits the initiation of Coxsackievirus and poliovirus RNA replication by inhibiting VPg uridylylation

Cited by 9 publications

References 47 publications

Initiation of protein-primed picornavirus RNA synthesis

Initiation of protein-primed picornavirus RNA synthesis

Persistent Enterovirus Infection: Little Deletions, Long Infections

Development of antiviral therapeutics combating coxsackievirus type B3 infection

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