Abstract
Highly pathogenic influenza viruses pose a serious public health threat to humans. Although vaccines are available, new antivirals are needed to efficiently control disease progression and virus transmission due to the emergence of drug-resistant viral strains. In this study, we describe the anti-viral properties of Soloxolone methyl (SM) (methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien-30-oate, a chemical derivative of glycyrrhetinic acid) against the flu virus. Anti-flu efficacy studies revealed that SM exhibits antiviral activity against the H1N1 influenza A virus in a dose-dependent manner causing a more than 10-fold decrease in virus titer and a reduction in the expression of NP and M2 viral proteins. In a time-of-addition study, SM was found to act at an early stage of infection to exhibit an inhibitory effect on both the attachment step and virus uptake into cells. Also, in infected cells SM downregulates the expression of the inflammatory cytokines IL-6 and TNF-α. In infected mice, SM administered intranasally prior to and after infection significantly decreases virus titers in the lung and prevents post-challenge pneumonia. Together, these results suggest that Soloxolone methyl might serve as an effective therapeutic agent to manage influenza outbreaks and virus-associated complications, and further preclinical and clinical investigation may be warranted.
Highlights
Viral respiratory infections are the most common diseases experienced by people of all ages
We reported that Soloxolone methyl (methyl 2-cyano-3,12-dioxo-18βH-olean-9(11),1(2)-dien30-oate, or SM) a semisynthetic derivative, obtained by direct modification of the A- and C-rings of glycyrrhetinic acid (GLA) (Fig. 1), possesses high antiproliferative and pro-apoptotic activities with respect to different cancer cell lines[18,19]
SM inhibits the growth of H1N1 influenza A in Madin-Darby canine kidney cells (MDCK) and A549 cells
Summary
Viral respiratory infections are the most common diseases experienced by people of all ages. The appearance of drug-resistant influenza viruses is caused either by a mutation in the active site of the NA, which alters its sensitivity to inhibitors[13], or a mutation in influenza virus hemagglutinin (HA), decreasing the affinity of HA for cellular receptors and allowing efficient release of progeny virions from infected cells almost regardless of NA activation status[13]. These reasons limit the future utility of commonly used NA inhibitors, highlighting the urgent need for new classes of anti-influenza agents to combat potential human influenza pandemics
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