Strategies to develop antivirals against enterovirus 71

Kuo, Rei-Lin; Shih, Shin‐Ru

doi:10.1186/1743-422x-10-28

Cited by 51 publications

(44 citation statements)

References 78 publications

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“…Inhibitors have been reported for distinct targets of EV71 and its closely related rhinovirus, as summarized in a recent review (11). Pleconaril, picodavir, and BPROZ-194 were shown to target viral capsid protein VP1 (12)(13)(14).…”

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confidence: 99%

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Deng

Yeo

et al. 2014

J Virol

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Enterovirus 71 (EV71) is a major viral pathogen in China and Southeast Asia. There is no clinically approved vaccine or antiviral therapy for EV71 infection. NITD008, an adenosine analog, is an inhibitor of flavivirus that blocks viral RNA synthesis. Here we report that NITD008 has potent antiviral activity against EV71. In cell culture, the compound inhibits EV71 at a 50% effective concentration of 0.67 M and a 50% cytotoxic concentration of 119.97 M. When administered at 5 mg/kg in an EV71 mouse model, the compound reduced viral loads in various organs and completely prevented clinical symptoms and death. To study the antiviral mechanism and drug resistance, we selected escape mutant viruses by culturing EV71 with increasing concentrations of NITD008. Resistance mutations were reproducibly mapped to the viral 3A and 3D polymerase regions. Resistance analysis with recombinant viruses demonstrated that either a 3A or a 3D mutation alone could lead to resistance to NITD008. A combination of both 3A and 3D mutations conferred higher resistance, suggesting a collaborative interplay between the 3A and 3D proteins during viral replication. The resistance results underline the importance of combination therapy required for EV71 treatment.

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confidence: 99%

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Deng

Yeo

et al. 2014

J Virol

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“…Several reviews have dealt with anti-enterovirus 71 synthetic small molecules [1][2][3][4][5][6][7]. This review gives an overview of 58 natural products (NPs), semi-synthetic NPs and NP-derived compounds from natural sources during the last decade (2005-2015) which exhibit anti-enterovirus 71 (EV71) activities.…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, exploring anti-EV71 agents is important. Several strategies have been used to develop antiviral drugs on the basis of the molecular characteristics of the virus [4]. Currently, no direct targeting vaccines or antivirals are available to treat severe EV71 infections.…”

Section: Introductionmentioning

confidence: 99%

Anti-Enterovirus 71 Agents of Natural Products

Wang

et al. 2015

Molecules

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“…According to the life cycle of EV-A71, several steps might be vulnerable for inhibiting viral replication, including attachment, uncoating, RNA replication and viral assembly. 7 Pleconaril was found to substitute for natural acyl compounds in binding into the hydrophobic pocket within VP1, which leads to an alteration in virion structure and prevents the conformational change needed for uncoating. 3,8 The so-called WIN compounds (named from Winthrop-based companies) and derivatives were modified and synthesized based on pleconaril and some of them were able to reduce virus-induced CPE significantly.…”

Section: Introductionmentioning

confidence: 99%

In vitroandin vivostudies of a potent capsid-binding inhibitor of enterovirus 71

Chern

Hsieh

et al. 2016

J. Antimicrob. Chemother.

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Objectives: Enterovirus 71 (EV-A71) is an important pathogen that can cause severe neurological symptoms and even death. Our aim was to identify potent anti-EV-A71 compounds and study their underlying mechanisms and in vivo activity. Methods:We identified a potent imidazolidinone derivative (abbreviated to PR66) as an inhibitor of EV-A71 infection from the screening of compounds and subsequent structure-based modification. Time-course treatments and resistant virus selection of PR66 were employed to study the mode of mechanism of PR66. In vivo activity of PR66 was tested in the ICR strain of new-born mice challenged with EV-A71/4643/MP4.Results: PR66 could impede the uncoating process during viral infection via interaction with capsid protein VP1, as shown by a resistant virus selection assay. Using site-directed mutagenesis, we confirmed that a change from valine to phenylalanine in the 179th amino acid residue of the cDNA-derived resistant virus resulted in resistance to PR66. PR66 increased the virion stability of WT viruses, but not the PR66-resistant mutant, in a particle stability thermal release assay. We further showed that PR66 had excellent anti-EV-A71 activity in an in vivo mouse model of disease, with a dose-dependent increase in survival rate and in protection against virus-induced hind-limb paralysis following oral or intraperitoneal administration. This was associated with reductions of viral titres in brain and muscle tissues. Conclusions:We demonstrated here for the first time that an imidazolidinone derivative (PR66) could protect against EV-A71-induced neurological symptoms in vivo by suppressing EV-A71 replication. This involved binding to and restricting viral uncoating.

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Strategies to develop antivirals against enterovirus 71

Cited by 51 publications

References 78 publications

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Inhibition of Enterovirus 71 by Adenosine Analog NITD008

Anti-Enterovirus 71 Agents of Natural Products

In vitroandin vivostudies of a potent capsid-binding inhibitor of enterovirus 71

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