Curcumin inhibits the replication of enterovirus 71 in vitro

Abstract

Human enterovirus 71 (EV71) is the main causative pathogen of hand, foot, and mouth disease (HFMD) in children. The epidemic of HFMD has been a public health problem in Asia-Pacific region for decades, and no vaccine and effective antiviral medicine are available. Curcumin has been used as a traditional medicine for centuries to treat a diversity of disorders including viral infections. In this study, we demonstrated that curcumin showed potent antiviral effect again EV71. In Vero cells infected with EV71, the addition of curcumin significantly suppressed the synthesis of viral RNA, the expression of viral protein, and the overall production of viral progeny. Similar with the previous reports, curcumin reduced the production of ROS induced by viral infection. However, the antioxidant property of curcumin did not contribute to its antiviral activity, since N-acetyl-l-cysteine, the potent antioxidant failed to suppress viral replication. This study also showed that extracellular signal-regulated kinase (ERK) was activated by either viral infection or curcumin treatment, but the activated ERK did not interfere with the antiviral effect of curcumin, indicating ERK is not involved in the antiviral mechanism of curcumin. Unlike the previous reports that curcumin inhibited protein degradation through ubiquitin–proteasome system (UPS), we found that curcumin had no impact on UPS in control cells. However, curcumin did reduce the activity of proteasomes which was increased by viral infection. In addition, the accumulation of the short-lived proteins, p53 and p21, was increased by the treatment of curcumin in EV71-infected cells. We further probed the antiviral mechanism of curcumin by examining the expression of GBF1 and PI4KB, both of which are required for the formation of viral replication complex. We found that curcumin significantly reduced the level of both proteins. Moreover, the decreased expression of either GBF1 or PI4KB by the application of siRNAs was sufficient to suppress viral replication. We also demonstrated that curcumin showed anti-apoptotic activity at the early stage of viral infection. The results of this study provide solid evidence that curcumin has potent anti-EV71 activity. Whether or not the down-regulated GBF1 and PI4KB by curcumin contribute to its antiviral effect needs further studies.

Identification of GBF1 as a cellular factor required for hepatitis E virus RNA replication

“…Several viruses of the Picornaviridae , Coronaviridae , and Flaviviridae families rely on GBF1 for their replication (Belov et al, ; Carpp, Rogers, Moritz, & Aitchison, ; Goueslain et al, ; Lanke et al, ; Liang, Zheng, Bao, & Zhang, ; Qin et al, ; van der Linden et al, ; Verheije et al, ; Wang, Du, & Jin, ). However, it has been shown that GBF1 is not involved in the formation of poliovirus, mouse hepatitis coronavirus, and HCV replication complexes but rather in their maturation or activity (Belov et al, ; Goueslain et al, ; Verheije et al, ).…”

“…GBF1 also participates in Golgi morphogenesis and lipid droplet metabolism (Jackson & Bouvet, ). In addition, GBF1 is hijacked by several positive‐strand RNA viruses including Picornaviridae , Coronaviridae , and Flaviviridae members for their replication (Belov et al, ; Carpp et al, ; Goueslain et al, ; Lanke et al, ; Liang et al, ; Qin et al, ; van der Linden et al, ; Verheije et al, ; Wang et al, ). For instance, GBF1 was shown to interact with poliovirus and coxsackievirus B3 (CVB3) non‐structural protein 3A (Wessels et al, ; Wessels et al, ).…”

Biological properties of metal complexes of curcumin

“…Curcumin has shown antiviral activity against numerous viruses including dengue virus (serotype 2), human immunodeficiency virus, Japanese encephalitis virus, pseudorabies virus, vaccinia virus, parainfluenza virus type 3 (PIV‐3), feline infectious peritonitis virus (FIPV), vesicular stomatitis virus (VSV), herpes simplex virus (HSV), flock house virus (FHV), respiratory syncytial virus (RSV), hepatitis viruses, influenza type A virus (IAV), Ebola virus, and arthropod‐borne viruses . Different possible mechanisms have been reported for curcumin's antiviral properties such as functioning as an HIV‐1 integrase inhibitor , degrading viral Tat protein , inhibiting proteases , inhibiting viral entry , inhibiting virus attachment to cells , and inhibiting viral replication . Antiviral properties of several metal complexes have been reported .…”

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

“…We further carefully investigated the inhibition mechanism of the best antiviral agent, Cur‐CQDs‐180, against EV71, although elucidating the exact molecular interactions of the specific functional groups of CQDs and EV71 virions is difficult. Previous studies have demonstrated that antiviral curcumin could interact directly with many proteins, such as DNA polymerase, cell survival proteins, focal adhesion kinase, proteasome, thioredoxin reductase, protein kinase, lipoxygenase, carrier proteins, and tubulin . Therefore, in addition to blocking the viral attachment, the pleiotropic activities of curcumin against viral infection have been demonstrated to emanate from its multiple functions pertaining to a wide range of molecular targets, such as transcription regulation, the activation of intracellular signaling cascades, and the promotion of antioxidative activity.…”

“…A recent study revealed that curcumin inhibits arthropod‐borne viral infection with Zika and chikungunya viruses by interrupting the binding of viruses on the cell surface . Another study indicated that a high dosage of curcumin exhibited antiapoptotic ability at the early stage of viral infection of EV71 . However, curcumin could not exert a significant effect on the entry of nonenveloped viruses, such as EV71, into host cells, and its antiviral activities were thus limited.…”