Inhibition of CRM1-mediated nuclear export of influenza A nucleoprotein and nuclear export protein as a novel target for antiviral drug development.

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.

• Authors: Nopporn Chutiwitoonchai, Takafumi Mano, Michinori Kakisaka, Hirotaka Sato, Yasumitsu Kondoh, Hiroyuki Osada, Osamu Kotani, Masaru Yokoyama, Hironori Sato, Yoko Aida
• Journal: Virology (Virology) Vol. 507 Pg. 32-39 (07 2017) ISSN: 1096-0341 [Electronic] United States
• PMID: 28399435 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antiviral Agents
• Karyopherins
• Nucleoproteins
• Receptors, Cytoplasmic and Nuclear
• exportin 1 protein

Topics

• Active Transport, Cell Nucleus (drug effects)
• Antiviral Agents (pharmacology)
• Cell Line
• Cell Nucleus (metabolism, virology)
• Humans
• Influenza A virus (genetics, metabolism)
• Influenza, Human (metabolism, virology)
• Karyopherins (antagonists & inhibitors, genetics, metabolism)
• Nucleoproteins (genetics, metabolism)
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors, genetics, metabolism)