Mechanism of action against SARS-CoV-2
The antiviral activity of niclosamide against SARS-CoV-2 is complex and
involves multiple cellular processes as illustrated in Figure 1.
SARS-CoV-2 uses the angiotensin converting enzyme-2 (ACE-2) as a
cellular entry receptor in permissive cells of the respiratory tract and
the spike proteins initiate the merging of the viral envelope with the
host cell cytomembrane (Zhou et al., 2020). Following receptor binding
and conformational changes in the spike protein, cathepsin L mediates
proteolysis within endosomes leading to viral entry into host cells
(Beniac, Andonov, Grudeski, & Booth, 2006). The protonophoric activity
of niclosamide that causes endosomal neutralization can also interfere
with viral entry and prevent viral genome release into the cytosol thus
further limiting SARS-CoV-2 replication (Jurgeit et al., 2012). Garret
et al., (2021) recently demonstrated that the total lipid profile is
amplified during SARS-CoV-2 infection in VeroE6 cells and treatment with
niclosamide led to a reduction in lipids available for virus production.
Additionally, in primary human lung cells and intestinal organoids
niclosamide enhances autophagy, thus further attenuating SARS-CoV-2
replication (Nils C. Gassen et al., 2021).
Syncytia formation in SARS-CoV-2 infected pneumocytes has been observed
in COVID-19 lungs. To identify inhibitors of spike-driven syncytia
formation, a high-content microscopy-based screening of more than 3,000
compounds was conducted (L. Braga et al., 2021). The screen identified
efficacious drugs that inhibited viral replication, with one of the most
potent being niclosamide. Niclosamide also has potent bronchodilatory
effects, inhibits excessive mucus production and down-regulates the
release of pro-inflammatory cytokines such as IL-8 by inhibiting TMEM16A
(Cabrita, Benedetto, Schreiber, & Kunzelmann, 2019). Due to its effects
on intracellular calcium levels, niclosamide can inhibit other cytokines
and could therefore play an important role in controlling the cytokine
storm and acute respiratory distress syndrome (ARDS) in acutely ill
COVID-19 patients. The above studies show several plausible mechanisms
of action of niclosamide against COVID-19, including prevention of viral
entry, prevention of viral replication via autophagy inhibition and
finally, inhibition of spike-driven syncytia formation. In conclusion,
these studies have confirmed potent, multi-faceted and pleiotropic
activity of niclosamide against SARS-CoV-2, targeting multiple aspects
of the viral life cycle.