A Quinolinone Compound Inhibiting the Oligomerization of Nucleoprotein of Influenza A Virus Prevents the Selection of Escape Mutants.

Juliann Nzembi Makau,Hiroki Otaki,Takeshi Ishikawa,Ken Watanabe,Satoshi Mizuta,Yuji O Kamatari,Noriyuki Nishida

doi:10.3390/v12030337

Abstract

The emergence of resistance to currently available anti-influenza drugs has heightened the need for antivirals with novel mechanisms of action. The influenza A virus (IAV) nucleoprotein (NP) is highly conserved and essential for the formation of viral ribonucleoprotein (vRNP), which serves as the template for replication and transcription. Recently, using in silico screening, we identified an antiviral compound designated NUD-1 (a 4-hydroxyquinolinone derivative) as a potential inhibitor of NP. In this study, we further analyzed the interaction between NUD-1 and NP and found that the compound interferes with the oligomerization of NP, which is required for vRNP formation, leading to the suppression of viral transcription, protein synthesis, and nuclear export of NP. We further assessed the selection of resistant variants by serially passaging a clinical isolate of the 2009 H1N1 pandemic influenza virus in the presence of NUD-1 or oseltamivir. NUD-1 did not select for resistant variants after nine passages, whereas oseltamivir selected for resistant variants after five passages. Our data demonstrate that NUD-1 interferes with the oligomerization of NP and less likely induces drug-resistant variants than oseltamivir; hence, it is a potential lead compound for the development of novel anti-influenza drugs.

Highlights

Influenza A viruses (IAVs) cause seasonal infections that lead to hundreds of thousands of hospitalizations and deaths annually
These results indicate that NUD-1 and naproxen interfered with the formation of high-molecular-weight NP oligomers
Because NP oligomerization is important for the formation of the viral ribonucleoprotein (vRNP) complex, the transcription template in influenza virus, we investigated whether NUD-1 interferes with transcription activity

Summary

Introduction

Influenza A viruses (IAVs) cause seasonal infections that lead to hundreds of thousands of hospitalizations and deaths annually. Antiviral drugs are important for treatment once infection has occurred, especially in the cases of novel viruses that are not targeted by seasonal vaccines. Over the last two decades, two classes of antiviral drugs, namely, M2 ion channel and neuraminidase inhibitors, have been used globally for influenza management. Widespread resistance to these antivirals has been reported [1,2]. New drugs targeting the RNA polymerase complex were approved for clinical use, whereas others are in clinical development [3]. In 2014, Japan approved favipiravir for Viruses 2020, 12, 337; doi:10.3390/v12030337 www.mdpi.com/journal/viruses

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