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

2012; Public Library of Science; Volume: 8; Issue: 10 Linguagem: Inglês

10.1371/journal.ppat.1002976

1553-7374

Andreas Jurgeit, Robert S. McDowell, Stefan Moese, Eric Meldrum, Reto A. Schwendener, Urs F. Greber,

Cytomegalovirus and herpesvirus research

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.