Inhibition of enterovirus 71 replication and viral 3C protease by quercetin

Abstract

BackgroundEnterovirus 71 (EV71) is one of the major causative agents of hand, foot, and mouth disease (HFMD), which is sometimes associated with severe central nervous system disease in children. There is currently no specific medication for EV71 infection. Quercetin, one of the most widely distributed flavonoids in plants, has been demonstrated to inhibit various viral infections. However, investigation of the anti-EV71 mechanism has not been reported to date.MethodsThe anti-EV71 activity of quercetin was evaluated by phenotype screening, determining the cytopathic effect (CPE) and EV71-induced cells apoptosis. The effects on EV71 replication were evaluated further by determining virus yield, viral RNA synthesis and protein expression, respectively. The mechanism of action against EV71 was determined from the effective stage and time-of-addition assays. The possible inhibitory functions of quercetin via viral 2Apro, 3Cpro or 3Dpol were tested. The interaction between EV71 3Cpro and quercetin was predicted and calculated by molecular docking.ResultsQuercetin inhibited EV71-mediated cytopathogenic effects, reduced EV71 progeny yields, and prevented EV71-induced apoptosis with low cytotoxicity. Investigation of the underlying mechanism of action revealed that quercetin exhibited a preventive effect against EV71 infection and inhibited viral adsorption. Moreover, quercetin mediated its powerful therapeutic effects primarily by blocking the early post-attachment stage of viral infection. Further experiments demonstrated that quercetin potently inhibited the activity of the EV71 protease, 3Cpro, blocking viral replication, but not the activity of the protease, 2Apro, or the RNA polymerase, 3Dpol. Modeling of the molecular binding of the 3Cpro-quercetin complex revealed that quercetin was predicted to insert into the substrate-binding pocket of EV71 3Cpro, blocking substrate recognition and thereby inhibiting EV71 3Cpro activity.ConclusionsQuercetin can effectively prevent EV71-induced cell injury with low toxicity to host cells. Quercetin may act in more than one way to deter viral infection, exhibiting some preventive and a powerful therapeutic effect against EV71. Further, quercetin potently inhibits EV71 3Cpro activity, thereby blocking EV71 replication.

Flavonoids as Antiviral Agents for Enterovirus A71 (EV-A71)

“…Quercetin was also investigated for its anti-apoptotic potential against virus-induced cell death. Quercetin was able to prevent the viral spread induced by apoptosis, thus making it a dual action antiviral agent [82].…”

High Amplification of the Antiviral Activity of Curcumin through Transformation into Carbon Quantum Dots

“…Our results suggest that Cur‐CQDs‐180 can inhibit ROS formation and the resultant p38 kinase activation induced by EV71, which agrees with the reports that highly antioxidative polyphenols, flavonoids, and terpenoids mediated to alleviate enterovirus infections . A further report indicated that natural compounds with high ROS scavenging activity could inhibit EV71‐induced cyclooxygenase‐2 (COX‐2) expression and regulate prostaglandin E‐2 (PGE 2 ) release by activating multiple inflammatory signaling pathways . PGE 2 plays a central role in inflammatory responses, and COX is the rate‐limiting enzyme that governs the first two steps in the synthesis of PGE 2 .…”

Research on active compounds regarding SGMD for the treatment of COVID-19 based on network pharmacology and molecular docking

“…Quercetin can reduce the apoptosis rate of rat alveolar cells and inhibit in ammation by suppressing the expression of TGF-β1, TNF-α and so on [12]. In addition, studies have shown that quercetin also has a great diversity of pharmacological activities like antioxidation [13][14][15], antitumor [16][17][18][19], antiviral [20][21][22][23] and immunoregulation [24][25][26]. The pharmacological effects of irisolidone include anti-in ammatory, antioxidation, antibacterial and antitumor impacts [27].…”