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.

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

“…Niclosamide appears to work by killing tapeworms on contact. It is speculated that niclosamide, as an antiviral, acts as a proton carrier to target acidic endosomes, leading to neutralization of cellular endolysosomal pH that will interfere with pH-dependent virus entry [51]. In our studies, niclosamide inhibited virus growth not only at early stage, but more importantly, at 24 h pi ( Figure 4H).…”

“…They are also employed as antivirals against several viruses [51][52][53][54]. In addition, an independent qHTS recently identified niclosamide as a potent anti-ZIKV drug, but with unknown mechanism [55].…”

Potential Therapeutics: Toe Hold in the Fight against Zika Virus

“…It is known to inhibit several viruses in culture systems, including the Japanese encephalitis flavivirus does not need to be capitalized (JEV) [38,39]. Niclosamide's broad antiviral activity has been attributed to its ability to neutralize endolysosomal pH and interfere with pH-dependent membrane fusion [40] which is an essential step in the common virus entry pathway. It seems that inhibition by niclosamide occurs at a post-entry step, such as replication [40,41].…”

“…Niclosamide's broad antiviral activity has been attributed to its ability to neutralize endolysosomal pH and interfere with pH-dependent membrane fusion [40] which is an essential step in the common virus entry pathway. It seems that inhibition by niclosamide occurs at a post-entry step, such as replication [40,41]. Niclosamide is a category B drug, which indicates that no risk to fetuses has been found in animal studies due to its low toxicity in mammals [42].…”

Uncoating of non-enveloped viruses

“…This has been shown with drugs blocking the vacuolar ATPase or by neutralizing endosomes with a biophysical protonophore mechanism [19]. Chemical cues are confined to specific compartments, for example low pH in endosomes, oxido-reducing conditions in the ER, or the cytosol with very low calcium ions and reducing conditions.…”