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.
Highlights
The discovery of antibiotics against microbes in the early 20th century has had a major impact on society and saved countless lives [1]
We found that pH-dependent human rhinovirus (HRV) using the low-density lipoprotein receptor (LDLR) family (HRV1A, 2), the intracellular adhesion molecule 1 (ICAM1) tropic major group (HRV14, 16) and the genetic groups A (HRV1A, 2 16) and B (HRV14) were sensitive to niclosamide at IC50 of 0.84 to 1.4 mM (Figure 1A, B and Figure S1A in Text S1)
Since we observed that niclosamide inhibited viruses, which were strongly pH dependent and less pH dependent, we investigated if niclosamide affected the phenotypes of early endosomes by staining for early endosomal antigen 1 (EEA1)
Summary
The discovery of antibiotics against microbes in the early 20th century has had a major impact on society and saved countless lives [1]. Classical antiviral strategies have targeted viral structural or enzymatic motifs with high specificity and potentially low side effects. HRVs comprise more than one hundred known serotypes They are the most frequent viral infections among humans and the predominant cause of the common cold [4]. HRV infections can pose severe health risks in patients with pre-existing airway conditions, including chronic obstructive pulmonary disease, asthma or cystic fibrosis. The minor group viruses comprise twelve members utilizing low-density lipoprotein receptor (LDLR) proteins for cell entry, and the major group uses the intracellular adhesion molecule 1 (ICAM1) [5]. These infections are typically pH-dependent and require the passage of viruses through acidic endosomal compartments. The recently discovered species C HRVs, which are prevalent in young children appear to use distinct but unknown attachment sites for infection [6]
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