Niclosamide Is a Proton Carrier and Targets Acidic Endosomes with Broad Antiviral Effects

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. © 2012 jurgeit et al.