The antiparasitic drug niclosamide inhibits dengue virus infection by interfering with endosomal acidification independent of mTOR

by Jo-Chi Kao, Wei-Chun HuangFu, Tsung-Ting Tsai, Min-Ru Ho, Ming-Kai Jhan, Ting-Jing Shen, Po-Chun Tseng, Yung-Ting Wang, Chiou-Feng Lin 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 infectionin vitro andin vivo. Principle FindingNiclosamide effectively retarded DENV-induced infectionin 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 niclosam...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research