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논문 상세정보

Abstract

BackgroundThe antiparasitic agent niclosamide has been demonstrated to inhibit the arthropod-borne Zika virus. Here, we investigated the antiviral capacity of niclosamide against dengue virus (DENV) serotype 2 infection in vitro and in vivo.Principle findingNiclosamide effectively retarded DENV-induced infection in vitro in human adenocarcinoma cells (A549), mouse neuroblastoma cells (Neuro-2a), and baby hamster kidney fibroblasts (BHK-21). Treatment with niclosamide did not retard the endocytosis of DENV while niclosamide was unable to enhance the antiviral type I interferon response. Furthermore, niclosamide did not cause a direct effect on viral replicon-based expression. Niclosamide has been reported to competitively inhibit the mTOR (mammalian target of rapamycin), STAT3 (signal transducer and activator of transcription 3), and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) signaling pathways; however, selective inhibitors of those pathways did not reduce DENV infection. Similar to the vacuolar-type H+-ATPase inhibitor bafilomycin A1, both niclosamide and other protonophores, such as CCCP (carbonyl cyanide m-chlorophenyl hydrazone), and FCCP (carbonyl cyanide-p-trifluoromethoxyphenylhydrazone), effectively reduced endosomal acidification and viral dsRNA replication. Co-administration of a single dose of niclosamide partially decreased viral replication, viral encephalitis, and mortality in DENV-infected ICR suckling mice.SignificanceThese results demonstrate that niclosamide diminishes viral infection by hindering endosomal acidification.Author summaryDengue and severe dengue cause global health concerns annually. Without antiviral drugs, supportive care is the only treatment option for patients with DENV infection. A current vaccine has been approved for protection against DENV infection; however, the potential risks and challenges associated with the immunopathogenesis of DENV remain unresolved. For anti-dengue therapy, the repurposing of drugs with antimicrobial and anticancer properties is a possible pharmacological strategy. In this study, we evaluated the potential antiviral effects of the antiparasitic drug niclosamide, considering its current pharmacological efficacy against arthropod-borne Zika virus infection. Using in vitro and in vivo models of DENV infection, we demonstrated that one of the therapeutic effects of niclosamide is to significantly target endosomal acidification. Following safety screening, repurposing niclosamide treatment may facilitate the development of anti-dengue drugs in the near future.

  

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