Naproxen Exhibits Broad Anti-influenza Virus Activity in Mice by Impeding Viral Nucleoprotein Nuclear Export

Abstract

Summary: Naproxen is a non-steroidal anti-inflammatory drug that has previously been shown to exert antiviral activity against influenza A virus by inhibiting nucleoprotein (NP) binding to RNA. Here, we show that naproxen is a potential broad, multi-mechanistic anti-influenza virus therapeutic, as it inhibits influenza B virus replication both in vivo and in vitro. The anti-influenza B virus activity of naproxen is more efficient than that of the commonly used neuraminidase inhibitor oseltamivir in mice. Furthermore, the NP of influenza B virus (BNP) has a higher binding affinity to naproxen than influenza A virus NP (ANP). Specifically, naproxen targets the NP at residues F209 (BNP) and Y148 (ANP). This interaction antagonizes the nuclear export of NP normally mediated by the host export protein CRM1. This study reveals a crucial mechanism of broad-spectrum anti-influenza virus activity of naproxen, suggesting that the existing drug naproxen may be used as an anti-influenza drug. : Zheng et al. show that the over-the-counter anti-inflammatory drug naproxen exerts broad-spectrum antiviral activity against influenza A and B viruses by blocking the nuclear export of the viral nucleoproteins (NPs). Nuclear retention of NP impedes influenza replication, thereby stunting viral progression. Naproxen effectively protects mice against influenza B virus infection. Keywords: influenza virus, nucleoprotein, naproxen, nuclear export, CRM1, vRNP