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Drug repurposing of N‐acetyl cysteine as antiviral against dengue virus infection

G. Sreekanth,Jutatip Panaampon,Aroonroong Suttitheptumrong,Aporn Chuncharunee,Jintana Bootkunha,P. Yenchitsomanus,T. Limjindaporn

Published 2019 in Antiviral Research

ABSTRACT

Abstract Liver injury is one of the hallmark features of severe dengue virus (DENV) infection since DENV can replicate in the liver and induce hepatocytes to undergo apoptosis. N‐acetyl cysteine (NAC), which is a clinically‐used drug for treating acetaminophen toxicity, was found to benefit patients with DENV‐induced liver injury; however, its mechanism of action remains unclear. Accordingly, our aim was to repurpose NAC in the preclinical studies to investigate its mechanism of action. Time of addition experiments in HepG2 cells elucidated effectiveness of NAC to reduce infectious virion at pre‐, during‐ and post infection. In DENV‐infected mice, NAC improved DENV‐associated clinical manifestations, including leucopenia and thrombocytopenia, and reduced liver injury and hepatocyte apoptosis. Interestingly, we discovered that NAC significantly reduced DENV production in HepG2 cells and in liver of DENV‐infected mice by induction of antiviral responses via interferon signaling. NAC treatment in DENV‐infected mice helped to maintain antioxidant enzymes and redox balance in the liver. Therefore, NAC reduces DENV production and oxidative damage to ameliorate DENV‐induced liver injury. Taken together, these findings suggest the novel therapeutic potential of NAC in DENV‐induced liver injury and recommend evaluating its efficacy and safety in humans with DENV‐induced liver injury. HighlightsNAC was repurposed in preclinical studies to identify its mechanism of action in DENV‐induced liver injury.NAC influenced the stages of viral life cycle in DENV‐infected HepG2 cells.NAC reduced DENV production in the HepG2 cells and the liver of DENV‐infected mice by exerting antiviral responses.NAC helped to maintain the antioxidant enzymes and to reduce JNK phosphorylation in the liver of DENV‐infected mice.

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