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).