Evaluation of antiviral activity of AR-12 against Enterovirus 71 in vitro

Abstract

Epidemics of Enterovirus 71 (EV71) infection is a significant public health problem in the Asia-Pacific region. EV71 infection usually manifests as Hand, Foot and Mouth Disease (HFMD) in young children under the age of 5. In some patients, the disease can deteriorate rapidly with potentially fatal neurological and systemic complications with long-term sequelae. Although two EV71 vaccines have recently been approved by the China Food and Drug Administration for use in human, there are limited treatment options for treating unvaccinated patients. In this study, the antiviral activity of AR-12 (OSU-03012) against EV71 was evaluated. AR-12 is a cyclooxygenase-2 celecoxib derivative, which is a broad-spectrum drug possessing anticancer, antibacterial, antifungal and antiviral activities. Previous studies have shown that AR-12 inhibits viral replication by interfering with host kinase pathways, dysregulating the functions of multiple chaperone proteins, and/or inducing autophagy. In this study, AR-12 was shown to reduce EV71 viral load in RD (rhabdomyosarcoma) and SF268 (glioblastoma) cells. The 50% cytotoxicity concentration, 50% effective concentration, and selectivity index of AR-12 against EV71 in RD cells were 3.62 μM, 1.10 μM, and 3.29, respectively. These data suggest AR-12 is a potential anti-EV71 drug candidate suitable for further development and optimization. Further investigations should be conducted to determine the antiviral mechanism of AR-12 against EV71 and treatment effects in suitable animal models. (Scientific Language) Epidemics of Enterovirus 71 (EV71) infections have been a significant public health problem in the Asia-Pacific region. EV71 infection commonly presents as Hand, Foot and Mouth Disease (HFMD). In some young children under the age of 5 years, severe neurological and systemic complications may occur. Although two EV71 vaccines have recently been approved by the China Food and Drug Administration for use in human, only a limited proportion of the susceptible population has been vaccinated so far. As there are limited treatment options available for EV71 infection, the antiviral activity of a potential anti-EV71 drug, AR-12, was evaluated in this thesis. AR-12 has broad-spectrum activities against cancer, bacteria, fungi, and viruses. The drug may inhibit virus replication by affecting the activities of host cell signalling pathways and other cellular components that are responsible for correct assembly and folding of protein, inducing degradation, and recycling of misfolded viral proteins. In this study, AR-12 was shown to reduce EV71 viral load in multiple cell lines. The concentration of AR-12 required to inhibit EV71 replication was lower than the drug concentration that caused toxicity in these cells. These data suggested AR-12 might be a potential anti-EV71 drug candidate for further development. Further investigations should be conducted to determine the antiviral mechanism of AR-12 against EV71. (Layman Language)