Identification of Chebulinic Acid and Chebulagic Acid as Novel Influenza Viral Neuraminidase Inhibitors.

Ping Li,Xiujuan Zhao,Ruikun Du,Xinyong Liu,Lin Wang,Peng Zhan,Xuewen Hou,Yanyan Wang,Qinghua Cui,Lijun Rong

doi:10.3389/fmicb.2020.00182

Abstract

The influenza A virus (IAV) causes seasonal epidemics and occasional but devastating pandemics, which are of a major public health concern. Although several antiviral drugs are currently available, there is an urgent need to develop novel antiviral therapies with different mechanisms of action due to emergence of drug resistance. In this study, two related compounds, chebulagic acid (CHLA) and chebulinic acid (CHLI), were identified as novel inhibitors against IAV replication. A reporter virus-based infection assay demonstrated that CHLA and CHLI exhibit no inhibitory effect on IAV entry or RNA replication during the virus replication cycle. Results of viral release inhibition assay and neuraminidase (NA) inhibition assay indicated that CHLA and CHLI exert their inhibitory effect on the NA-mediated viral release. Moreover, oseltamivir-resistance mutation NA/H274Y of NA is susceptible to CHLA or CHLI, suggesting a different mechanism of action for CHLA and CHLI. In summary, CHLA and CHLI are promising new NA inhibitors that may be further developed as novel antivirals against IAVs.

Highlights

Influenza vaccines and antiviral drugs are effective in preventing infection or ameliorating disease severity (Vasileiou et al, 2017)
To discover novel antiviral actives against influenza A viruses (IAVs), a library consisting of 352 natural product samples was prepared and screened using a phenotypic screening approach based on a reporter influenza A PR8-PB2-Gluc virus (Zhao et al, 2019) in a primary screen and confirmation screen
Since unripe pods of T. chebula exhibited a CC50 to Madin–Darby canine kidney (MDCK) cells of 255.1 ± 1.3 μg/mL, while ripe pods of T. chebula showed no obvious cytotoxicity at a high concentration as 500 μg/mL, it is likely that there is some difference between the compositions of the two natural product sample preparations

Summary

Introduction

Influenza vaccines and antiviral drugs are effective in preventing infection or ameliorating disease severity (Vasileiou et al, 2017). Influenza infection, as an acute respiratory disease caused by seasonal outbreaks and, periodically, pandemics of influenza viruses and accounting for up to 650,000 annual deaths globally (World Health Organization [WHO], 2018), remains a serious public health concern. This is partly due to the fact that current influenza vaccines can target only selected strains based on annual surveillance and prediction, which does not always match the circulating strains, leading to a sharp drop in vaccine efficacy (de Jong et al, 2000; Nachbagauer and Krammer, 2017). The development of antiviral drugs with different mechanisms of action is urgently needed against influenza viruses

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