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Virology. 2017 Apr 8;507:32-39. doi: 10.1016/j.virol.2017.04.001. [Epub ahead of print]
Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development.
Chutiwitoonchai N1, Mano T1, Kakisaka M1, Sato H1, Kondoh Y2, Osada H2, Kotani O3, Yokoyama M3, Sato H3, Aida Y4.
Author information
Abstract
An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function.
Copyright ? 2017 Elsevier Inc. All rights reserved.
KEYWORDS:
Chromosome region maintenance 1; Influenza A virus; Nuclear export protein; Nuclear export signal; Nucleoprotein
PMID: 28399435 DOI: 10.1016/j.virol.2017.04.001
Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development.
Chutiwitoonchai N1, Mano T1, Kakisaka M1, Sato H1, Kondoh Y2, Osada H2, Kotani O3, Yokoyama M3, Sato H3, Aida Y4.
Author information
Abstract
An anti-influenza compound, DP2392-E10 based on inhibition of the nuclear export function of the viral nucleoprotein-nuclear export signal 3 (NP-NES3) domain was successfully identified by our previous high-throughput screening system. Here, we demonstrated that DP2392-E10 exerts its antiviral effect by inhibiting replication of a broad range of influenza A subtypes. In regard to the molecular mechanism, we revealed that DP2392-E10 inhibits nuclear export of both viral NP and nuclear export protein (NEP). More specifically, in vitro pull-down assays revealed that DP2392-E10 directly binds cellular CRM1, which mediates nuclear export of NP and NEP. In silico docking suggested that DP2392-E10 binds at a region close to the HEAT9 and HEAT10 domains of CRM1. Together, these results indicate that the CRM1-mediated nuclear export function of influenza virus represents a new potential target for antiviral drug development, and also provide a core structure for a novel class of inhibitors that target this function.
Copyright ? 2017 Elsevier Inc. All rights reserved.
KEYWORDS:
Chromosome region maintenance 1; Influenza A virus; Nuclear export protein; Nuclear export signal; Nucleoprotein
PMID: 28399435 DOI: 10.1016/j.virol.2017.04.001