Anti-viral activity
Strikingly, several reports have revealed promising antiviral effects of
tetracyclines in infections caused by RNA viruses (Figure 1 B), such as
HIV, Dengue virus, Japanese encephalitis virus and others. It has been
suggested that tetracyclines could interact and stabilize dsRNA (Dutta
and Basu, 2011), which are involved in viral replication and activate
host defense mechanisms, as observed with minocycline in HIV infection
(Szeto et al., 2010). Regarding SARS-CoV2, several of its functions are
associated with the host MMPs, and may be susceptible to tetracyclines’
MMP inhibitory activity. Bioinformatic analysis to prioritise drug
repurposing candidates based on reported activities and molecular
docking with SARS-CoV2 proteins have predicted potential anti-viral
activity for several tetracycline analogs (Wu et al., 2020). Docking
studies propose binding of doxycycline to the human Adaptor-Associated
Kinase 1 (AAK1) and the viral ADP-ribose phosphatase (ADPRP) (Sayed et
al., 2020), involved in viral endocytosis and replication, respectively.
It has also been proposed that tetracycline and doxycycline could act as
inhibitors of ACE2-spike binding (Sachdeva et al., 2020; Zhao and
Patankar, 2021), and doxycycline and minocycline as inhibitors of the
SARS-CoV-2 main protease (Mpro) (Bharadwaj et al.,
2020). In fact, experimental evidence of tetracycline’s direct antiviral
effect against SARS-CoV2 has already been reported. Doxycycline has
shown to reduce viral entry and replication in Vero E6 cells infected
with SARS-CoV-2 with a EC50 of 4.5 ± 2.9 µM (Gendrot et
al., 2020), which is compatible with the bioavailability of current
formulations. Furthermore, tetracyclines could also attain antiviral
activity indirectly. Viruses exploit the mitochondria machinery and
aerobic glycolysis of infected cells, which could also be susceptible to
the impact of tetracyclines on mitochondrial dynamics, mainly due to
calcium buffering.