Niclosamide as an antiviral agent
Niclosamide’s role in anti-viral host defense was first reported by Jurgeit et al., (2010) by the use of a monoclonal antibody against viral dsRNA during image-based screening of infected cells. Niclosamide was shown to neutralize acidic membrane bound compartments via a proton carrier mode of action (protonophore) in vesicles as well as in protein-free liposomes (Jurgeit et al., 2012). Blockade of the acidification of the endolysosomal compartments, without affecting vacuolar ATPase, has been shown to inhibit infection with the human rhinovirus and influenza virus in a pH-dependent manner. The same mechanism was shown to mediate its antiviral efficacy against both Dengue and Zika viruses (Jung et al., 2019). A study found that niclosamide’s antiviral activity against Dengue virus was through a reduction of endosomal acidification and phosphorylation of AKT and p70SK (independent of mTOR) and against Zika virus through blocking the NS2B-NS3 interaction, thus highlighting its pleotropic antiviral effects (Kao et al., 2018; Zhong Li et al., 2017). Li et al., (2017) found that niclosamide is a broad-spectrum inhibitor against flaviviruses and also inhibited the replication of Ebola and Chikungunya viruses via the modulation of low pH-dependent cellular mechanisms of viral maturation (Peter B. Madrid et al., 2015; Mazzon et al., 2019). A systematic screen of FDA-approved drugs identified niclosamide as one of the most potent Ebola virus inhibitors, although its in vivo efficacy is yet to be confirmed in animal models (P. B. Madrid et al., 2015). Finally, niclosamide also inhibits the pathogenic beta-coronaviruses (N. C. Gassen et al., 2019; Wen et al., 2007; C. J. Wu et al., 2004; Yang et al., 2020) and reduced the replication of MERS-Co-V via a mechanism involving enhanced autophagy through inhibition of S-phase kinase-associated protein 2 (SKP2) (N. C. Gassen et al., 2019).