title: Niclosamide is a proton carrier and targets acidic endosomes with broad antiviral effects.
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.
authors.affiliation: Institute of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Jurgeit
authors.forename: Robert
authors.initials: R
authors.lastname: McDowell
authors.forename: Stefan
authors.initials: S
authors.lastname: Moese
authors.forename: Eric
authors.initials: E
authors.lastname: Meldrum
authors.forename: Reto
authors.initials: R
authors.lastname: Schwendener
authors.forename: Urs F
authors.initials: UF
authors.lastname: Greber
mesh_terms: D000969:Antinematodal Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D018699:Coated Vesicles / Q000187:drug effects; D004357:Drug Synergism; D011992:Endosomes / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D018942:Macrolides / Q000494:pharmacology; D009534:Niclosamide / Q000737:chemistry / Q000494:pharmacology*; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000502:physiology; D012327:RNA Virus Infections / Q000188:drug therapy / Q000517:prevention & control; D012229:Rhinovirus / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000969:Antinematodal Agents; D000998:Antiviral Agents; D008081:Liposomes; D018942:Macrolides; C040929:bafilomycin A1; D009534:Niclosamide