Amantadine inhibits hepatitis A virus internal ribosomal entry site-mediated translation in human hepatoma cells

Yokosuka, Osamu; Imazeki, Fumio; Fujiwara, Keiichi; Nagao, Keiichi; Saisho, Hiromitsu

doi:10.1016/j.bbrc.2005.03.212

Cited by 33 publications

(56 citation statements)

References 47 publications

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“…Its effect on RNA viruses suggested a therapeutic potential in chronic hepatitis C [2], probably by a specific antiviral effect on the function of the hepatitis C virus (HCV) p7 protein [3,4], a potential target for antiviral drug therapy [5]. A recent study showed that amantadine could suppress internal ribosomal entry site (IRES)-dependent translation in Huh7 cells containing HCV replicon RNA [6].…”

Section: Introductionmentioning

confidence: 98%

Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI)

Maynard

Pradat

Bailly

et al. 2006

Journal of Hepatology

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Section: Introductionmentioning

confidence: 98%

Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI)

Maynard

Pradat

Bailly

et al. 2006

Journal of Hepatology

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“…The genome includes 5′ non-translated region (5′NTR), one open reading frame encoding structural (VP4, VP2, VP3, VP4 and 2A) and non-structural proteins (2B, 2C, 3A, 3B, 3C and 3D), and 3′NTR [1]. HAV genome translation could be initiated by cap-independent mechanism through HAV internal ribosomal entry-site (IRES) with a pyrimidine-rich tract, which is located at the down-stream part of 5′NTR [2]. HAV is still a major cause of acute hepatitis [3], [4].…”

Section: Introductionmentioning

confidence: 99%

“…Small interfering RNAs against HAV genome are also varieties of DAAs [16]–[18]. Several broad-target HTAs, examples of which include interferon-α, interferon-β, interferon-λ1 and amantadine, have been developed and tested against HAV [2], [19]–[25]. These compounds could inhibit HAV IRES-dependent translation as well as HAV replication [2], [21], [22].…”

Section: Introductionmentioning

confidence: 99%

“…Several broad-target HTAs, examples of which include interferon-α, interferon-β, interferon-λ1 and amantadine, have been developed and tested against HAV [2], [19]–[25]. These compounds could inhibit HAV IRES-dependent translation as well as HAV replication [2], [21], [22]. HTAs of the targeted group are more precise in that they act on key host enzymes or cellular factors that are required for the viral lifecycle [9].…”

Section: Introductionmentioning

confidence: 99%

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Suppression of La Antigen Exerts Potential Antiviral Effects against Hepatitis A Virus

Jiang

Nakamoto

et al. 2014

PLoS ONE

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BackgroundDespite the development and availability of hepatitis A virus (HAV) vaccine, HAV infection is still a major cause of acute hepatitis that occasionally leads to fatal liver disease. HAV internal ribosomal entry-site (IRES) is one of the attractive targets of antiviral agents against HAV. The aim of the present study is to evaluate the impact of La, one of the cellular proteins, on HAV IRES-mediated translation and HAV replication.Methods and FindingsWe investigated the therapeutic feasibility of siRNAs specific for cellular cofactors for HAV IRES-mediated translation in cell culture. It was revealed that siRNA against La could inhibit HAV IRES activities as well as HAV subgenomic replication. We also found that the Janus kinase (JAK) inhibitors SD-1029 and AG490, which reduce La expression, could inhibit HAV IRES activities as well as HAV replication.ConclusionsInhibition of La by siRNAs and chemical agents could lead to the efficient inhibition of HAV IRES-mediated translation and HAV replication in cell culture models. La might play important roles in HAV replication and is being exploited as one of the therapeutic targets of host-targeting antivirals.

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“…Recently, amantadine has been found to inhibit HCV IRES translation when used at above clinically-relevant concentrations [26] . Amantadine also suppresses HAV IRES translation [27] . However, in both reports, amantadine also suppressed cap-dependent translation activity, in a rabbit reticulocyte-based in vitro transcription/translation assay system or in human hepatoma-derived cell lines.…”

Section: Amantadine Can Inhibit Ires-mediated Translation Without Affmentioning

confidence: 99%

Amantadine as a regulator of internal ribosome entry site

et al. 2008

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Aim: Studies of eukaryotes have yielded 2 translation initiation mechanisms: a classical cap-dependent mechanism and a cap-independent mechanism proceeding through the internal ribosomal entry site (IRES). We hypothesized that it might be possible to identify compounds that may distinguish between cap-dependent translation and cap-independent IRES-mediated translation. Methods: To facilitate compound screening, we developed bicistronic reporter constructs containing a β-galactosidase gene (β-gal) and a secreted human placental alkaline phosphatase (SEAP) reporter gene. Following transcription, the β-gal gene is translated by a cap-dependent mechanism, while SEAP expression is controlled by the IRES derived from either enterovirus 71 (EV-71) or encephalomyocarditis virus (EMCV). This assay could potentially identify compounds that inhibit SEAP expression (cap-independent) without affecting β-gal activity (cap-dependent). Results: Using a bicistronic plasmid-based transient transfection assay in the COS-1 cells, we identified amantadine, a compound that inhibited the IRES of EV71-and EMCV-mediated cap-independent translation but did not interfere with cap-dependent translation when the dose of amantadine was lower than 0.25 mg/mL. Conclusion: These results imply that amantadine may distinguish between cap-dependent translation and cap-independent IRES-mediated translation and can be used to regulate gene expression at a translational level.

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Amantadine inhibits hepatitis A virus internal ribosomal entry site-mediated translation in human hepatoma cells

Cited by 33 publications

References 47 publications

Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI)

Amantadine triple therapy for non-responder hepatitis C patients. Clues for controversies (ANRS HC 03 BITRI)

Suppression of La Antigen Exerts Potential Antiviral Effects against Hepatitis A Virus

Amantadine as a regulator of internal ribosome entry site

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