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.