Inhibition of enterovirus 71 replication and the viral 3D polymerase by aurintricarboxylic acid

Hung, Hui-Chen; Chen, Tzu‐Chun; Fang, Ming-Yu; Yen, Kuei‐Jung; Shih, Shin‐Ru; Hsu, Ju Wei; Tseng, Ching‐Ping

doi:10.1093/jac/dkp502

Cited by 58 publications

(52 citation statements)

References 36 publications

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“…This is consistent with recent studies with HeLa and RD cells and yeasts (33,57), in which overexpression of EV71 2A did not affect the growth of these cells. In 2A-expressing HeLa cells and yeasts, the newly identified transcriptional activity of 2A protease may also regulate some cellular genes to benefit viral replication (57) Certain inhibitors, such as ATA, and RNA interference (RNAi) against 3D have been used as antiviral strategies to suppress EV71 transcription and replication (8,9), as the 3D protein serves as an RNA-dependent RNA polymerase for initial de novo transcription with a poly(C) template and genomic RNA through EV71 VP protein binding and uridylylation (62,63). To our knowledge, there has been no report describing a host interaction with 3D during EV71 infection.…”

Section: Discussionmentioning

confidence: 99%

Enterovirus 71 Proteins 2A and 3D Antagonize the Antiviral Activity of Gamma Interferon via Signaling Attenuation

Wang

Chen

Chang

et al. 2015

J Virol

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Enterovirus 71 (EV71) infection causes severe mortality involving multiple possible mechanisms, including cytokine storm, brain stem encephalitis, and fulminant pulmonary edema. Gamma interferon (IFN-␥) may confer anti-EV71 activity; however, the claim that disease severity is highly correlated to an increase in IFN-␥ is controversial and would indicate an immune escape initiated by EV71. This study, investigating the role of IFN-␥ in EV71 infection using a murine model, showed that IFN-␥ was elevated. Moreover, IFN-␥ receptor-deficient mice showed higher mortality rates and more severe disease progression with slower viral clearance than wild-type mice. E nterovirus 71 (EV71) is a single-stranded RNA virus in the Picornaviridae family. The EV71 genome encodes four structural proteins, VP1 to VP4, and seven nonstructural proteins, 2A to 2C and 3A to 3D (1). Numerous studies have investigated the functions of viral proteins in viral replication and virulence (2). During EV71 infection, capsid VP proteins mediate virus entry by binding to cellular receptors, human scavenger receptor class B and P-selectin glycoprotein ligand 1 (3). Additionally, VP proteins participate in the assembly of viral particles (4). The 3C protein, a chymotrypsin-like protease, reduces host cell transcription dramatically by inhibiting cell polyadenylation (5) and induces caspase-regulated neural cell apoptosis (6). To develop specific anti-EV71 drugs, a number of small molecules targeting viral proteins have been designed, such as the 3C inhibitor rupintrivir and the 3D inhibitor aurintricarboxylic acid (ATA) (7-9).EV71 infection typically causes mild, self-limiting hand-footand-mouth disease; however, patients sometimes have significant morbidity and mortality resulting from hemorrhagic pulmonary edema following acute central nervous system-related cardiopulmonary failure and brain stem encephalitis (2,10,11). In addition to the direct cytotoxicity caused by EV71 infection (12-16) and the resultant virulence factors (6, 17), host factors such as the aberrant production of cytokines that is detected during EV71-associated pulmonary edema can also lead to disease. In infected

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Section: Discussionmentioning

confidence: 99%

Enterovirus 71 Proteins 2A and 3D Antagonize the Antiviral Activity of Gamma Interferon via Signaling Attenuation

Wang

Chen

Chang

et al. 2015

J Virol

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“…For group B coxsackieviruses (B1 to B5) and polioviruses 1 and 3, infectious virus titers were determined by plaque assays on monolayers of HeLa-RW cells (22,25). Viral quantification of enterovirus A71 (EV-A71), coxsackievirus A9, and echoviruses 6, 7, 9, 11, 25, and 30 was accomplished using a 50% tissue culture infective dose (TCID 50 ) (26) assay modified from an EV-A71 protocol (27).…”

Section: Cells and Virusesmentioning

confidence: 99%

Discovery of Structurally Diverse Small-Molecule Compounds with Broad Antiviral Activity against Enteroviruses

Zuo

Kye

Quinn

et al. 2016

Antimicrob Agents Chemother

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Antiviral drugs do not currently exist for the treatment of enterovirus infections, which are often severe and potentially lifethreatening. We conducted high-throughput molecular screening and identified a structurally diverse set of compounds that inhibit the replication of coxsackievirus B3, a commonly encountered enterovirus. These compounds did not interfere with the function of the viral internal ribosome entry site or with the activity of the viral proteases, but they did drastically reduce the synthesis of viral RNA and viral proteins in infected cells. Sequence analysis of compound-resistant mutants suggests that the viral 2C protein is targeted by most of these compounds. These compounds demonstrated antiviral activity against a panel of the most commonly encountered enteroviruses and thus represent potential leads for the development of broad-spectrum anti-enteroviral drugs.

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“…As a pervious reports of other antiviral compound expressed, that DTrip-22 and aurintricarboxylic acid are EV71 3D polymerase inhibitors (Chen et al, 2009;Hung et al, 2010) and T-705RTP is an influenza A virus RdRp inhibitor ( Furuta et al, 2013). All these results indicate that a large amount of compound is required to inhibit RdRp activity for in vitro assays.…”

Section: Discussionmentioning

confidence: 60%

BPR-3P0128 inhibits RNA-dependent RNA polymerase elongation and VPg uridylylation activities of Enterovirus 71

et al. 2014

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Inhibition of enterovirus 71 replication and the viral 3D polymerase by aurintricarboxylic acid

Abstract: Overall, the findings in this study suggest that ATA is able to effectively inhibit EV71 replication through interfering with the viral 3D polymerase.

Cited by 58 publications

References 36 publications

Enterovirus 71 Proteins 2A and 3D Antagonize the Antiviral Activity of Gamma Interferon via Signaling Attenuation

Enterovirus 71 Proteins 2A and 3D Antagonize the Antiviral Activity of Gamma Interferon via Signaling Attenuation

Discovery of Structurally Diverse Small-Molecule Compounds with Broad Antiviral Activity against Enteroviruses

BPR-3P0128 inhibits RNA-dependent RNA polymerase elongation and VPg uridylylation activities of Enterovirus 71

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