| Title | Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects. | ||
| Author | Jurgeit, Andreas; McDowell, Robert; Moese, Stefan; Meldrum, Eric; Schwendener, Reto; Greber, Urs F | ||
| Journal | PLoS Pathog | Publication Year/Month | 2012 |
| PMID | 23133371 | PMCID | PMC3486884 |
| Affiliation | 1.Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland. | ||
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.