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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.Author SummaryCurrent antiviral approaches are directed against specific viral targets but are limited in their broad-spectrum potential. Targeting host pathways, on the other hand can have broad antiviral effects, albeit with possible side effects. Here, we report the mode of antiviral action of a small chemical compound, niclosamide. Niclosamide belongs to the salicylanilides, and has been FDA approved to treat parasitic helminthic infestations in humans since decades. In recent years, niclosamide was shown to have anti-neoplastic and antiviral effects. We screened a library of FDA-approved chemicals, and found that niclosamide is an entry inhibitor for a number of pH-dependent respiratory viruses, including influenza virus and human rhinoviruses. Cell biological and biochemical analyses and intracellular pH measurements showed that niclosamide neutralizes acidic membrane-bounded compartments. Niclosamide did not affect the vacuolar ATPase but acted as a protonophore, both in vesicles isolated from cells, and protein-free liposome assays. It blocked rhinovirus infections synergistically with the proton ATPase inhibitor bafilomycin A1. Niclosamide targets endosomes by a mode of action distinct from that of endosomal pH neutralizing agents, such as chloroquine, which accumulates in acidic endosomes.

  

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