Ugonin J Acts as a SARS-CoV-2 3C-like Protease Inhibitor and Exhibits Anti-inflammatory Properties.

Wei-Chung Chiou,Hsu-Feng Lu,Tein-Yao Chang,Jinn-Moon Yang,Nung-Yu Hsu,Yuan-Fan Chin,Cheng Huang,Ping-Cheng Liu,Jir-Mehng Lo,Yeh B Wu

doi:10.3389/fphar.2021.720018

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes severe “flu-like” symptoms that can progress to acute respiratory distress syndrome (ARDS), pneumonia, renal failure, and death. From the therapeutic perspective, 3-chymotrypsin-like protein (3CLpro) is a plausible target for direct-acting antiviral agents because of its indispensable role in viral replication. The flavonoid ugonin J (UJ) has been reported to have antioxidative and anti-inflammatory activities. However, the potential of UJ as an antiviral agent remains unexplored. In this study, we investigated the therapeutic activity of UJ against SARS-CoV-2 infection. Importantly, UJ has a distinct inhibitory activity against SARS-CoV-2 3CLpro, compared to luteolin, kaempferol, and isokaempferide. Specifically, UJ blocks the active site of SARS-CoV-2 3CLpro by forming hydrogen bonding and van der Waals interactions with H163, M165 and E166, G143 and C145, Q189, and P168 in subsites S1, S1′, S2, and S4, respectively. In addition, UJ forms strong, stable interactions with core pharmacophore anchors of SARS-CoV-2 3CLpro in a computational model. UJ shows consistent anti-inflammatory activity in inflamed human alveolar basal epithelial A549 cells. Furthermore, UJ has a 50% cytotoxic concentration (CC50) and a 50% effective concentration (EC50) values of about 783 and 2.38 µM, respectively, with a selectivity index (SI) value of 329, in SARS-CoV-2-infected Vero E6 cells. Taken together, UJ is a direct-acting antiviral that obstructs the activity of a fundamental protease of SARS-CoV-2, offering the therapeutic potential for SARS-CoV-2 infection.

Highlights

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, giving rise to coronavirus disease 2019 (COVID-19), has threatened global public health and has had profound effects on the economy, psychology, and human behaviors (Chen et al, 2020)
Previous studies demonstrated that boceprevir inhibits the proteolytic activity of SARS-CoV-2 3-chymotrypsinlike protein (3CLpro) (Fu et al, 2020; Ma et al, 2020; Pathak et al, 2021)
Based on the therapeutic experience with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), it is reasonable to believe that drug combinations and cocktails can offer substantial clinical benefits in the context of the COVID-19 pandemic (Weisberg et al, 2020)

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, giving rise to coronavirus disease 2019 (COVID-19), has threatened global public health and has had profound effects on the economy, psychology, and human behaviors (Chen et al, 2020). Infection with SARS-CoV-2 causes severe “flu-like” symptoms that can progress to acute respiratory distress syndrome (ARDS), pneumonia, renal failure, and death (Harrison et al, 2020). Widespread inflammation in the lungs and excessive immune responses have been observed in severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) infections (Fajgenbaum and June, 2020; Harrison et al, 2020; Quan et al, 2020)

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