tetano
Editor, Senior Moderator
PLoS Pathog. 2012 Oct;8(10):e1002976. doi: 10.1371/journal.ppat.1002976. Epub 2012 Oct 25.
Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects.
Jurgeit A, McDowell R, Moese S, Meldrum E, Schwendener R, Greber UF.
Source
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
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.
PMID:
23133371
[PubMed - in process]
PMCID:
PMC3486884
http://www.ncbi.nlm.nih.gov/pubmed/23133371
Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects.
Jurgeit A, McDowell R, Moese S, Meldrum E, Schwendener R, Greber UF.
Source
Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
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.
PMID:
23133371
[PubMed - in process]
PMCID:
PMC3486884
http://www.ncbi.nlm.nih.gov/pubmed/23133371