Neutralization of Acidic Intracellular Vesicles by Niclosamide Inhibits Multiple Steps of the Dengue Virus Life Cycle In Vitro.

Abstract

Dengue fever is one of the most important mosquito-borne viral infections in large parts of tropical and subtropical countries and is a significant public health concern and socioeconomic burden. There is an urgent need to develop antivirals that can effectively reduce dengue virus (DENV) replication and decrease viral load. Niclosamide, an antiparasitic drug approved for human use, has been recently identified as an effective antiviral agent against a number of pH-dependent viruses, including flaviviruses. Here, we reveal that neutralization of low-pH intracellular compartments by niclosamide affects multiple steps of the DENV infectious cycle. Specifically, niclosamide-induced endosomal neutralization not only prevents viral RNA replication but also affects the maturation of DENV particles, rendering them non-infectious. We found that niclosamide-induced endosomal neutralization prevented E glycoprotein conformational changes on the virion surface of flaviviruses, resulting in the release of non-infectious immature virus particles with uncleaved pr peptide from host cells. Collectively, our findings support the potential application of niclosamide as an antiviral agent against flavivirus infection and highlight a previously uncharacterized mechanism of action of the drug.

• Authors: Eunhye Jung, Sangwoo Nam, Hyeryeon Oh, Sangmi Jun, Hyun-Joo Ro, Baek Kim, Meehyein Kim, Yun Young Go
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 8682 (06 18 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31213630 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Viral Envelope Proteins
• E protein TH Sman, Dengue virus
• Niclosamide

Topics

• Animals
• Antiviral Agents (pharmacology)
• Cell Line
• Cell Line, Tumor
• Chlorocebus aethiops
• Cytoplasmic Vesicles (chemistry, drug effects, virology)
• Dengue Virus (drug effects, genetics, growth & development)
• Endosomes (chemistry, drug effects, virology)
• Humans
• Hydrogen-Ion Concentration
• Intracellular Space (chemistry, drug effects, virology)
• Life Cycle Stages (drug effects)
• Niclosamide (pharmacology)
• Vero Cells
• Viral Envelope Proteins (genetics, metabolism)
• Virion (drug effects, genetics, growth & development)
• Virus Replication (drug effects, genetics)