Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects |
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Authors: | Andreas Jurgeit Robert McDowell Stefan Moese Eric Meldrum Reto Schwendener Urs F Greber |
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Institution: | 1. Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.; 2. 3-V Biosciences Inc., Menlo Park, California, United States of America.; 3. Institute of Molecular Cancer Research, University of Zurich, Zurich, Switzerland.; UCLA, United States of America, |
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Abstract: | Viruses use a limited set of host pathways for infection. These pathways represent bona fide antiviral targets with low likelihood of viral resistance. We identified the salicylanilide niclosamide as a broad range antiviral agent targeting acidified endosomes. Niclosamide is approved for human use against helminthic infections, and has anti-neoplastic and antiviral effects. Its mode of action is unknown. Here, we show that niclosamide, which is a weak lipophilic acid inhibited infection with pH-dependent human rhinoviruses (HRV) and influenza virus. Structure-activity studies showed that antiviral efficacy and endolysosomal pH neutralization co-tracked, and acidification of the extracellular medium bypassed the virus entry block. Niclosamide did not affect the vacuolar H+-ATPase, but neutralized coated vesicles or synthetic liposomes, indicating a proton carrier mode-of-action independent of any protein target. This report demonstrates that physico-chemical interference with host pathways has broad range antiviral effects, and provides a proof of concept for the development of host-directed antivirals. |
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