Tetracycline as an inhibitor to the SARS‐CoV‐2

Abstract

The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) remains an extant threat against public health on a global scale. Cell infection begins when the spike protein of SARS‐CoV‐2 binds with the human cell receptor, angiotensin‐converting enzyme 2 (ACE2). Here, we address the role of tetracycline as an inhibitor for the receptor‐binding domain (RBD) of the spike protein. Targeted molecular investigation show that tetracycline binds more favorably to the RBD (−9.40 kcal/mol) compared to doxycycline (−8.08 kcal/mol), chloroquine (−6.31 kcal/mol), or gentamicin (−4.83 kcal/mol) while inhibiting attachment to ACE2 to a greater degree (binding efficiency of 2.98 kcal/(mol nm 2 ) for tetracycline–RBD, 5.16 kcal/(mol nm 2 ) for doxycycline–RBD, 5.59 kcal/(mol nm 2 ) for chloroquine–RBD, and 7.02 kcal/(mol nm 2 ) for gentamicin–RBD. Stronger inhibition by tetracycline is verified with nonequilibrium PMF calculations, for which the tetracycline–RBD complex exhibits the lowest free energy profile along the dissociation pathway from ACE2. Tetracycline binds to tyrosine and glycine residues on the viral contact interface that are known to modulate molecular recognition and bonding affinity. These RBD residues also engage in significant hydrogen bonding with the human receptor ACE2. The ability to preclude cell infection complements the anti‐inflammatory and cytokine suppressing capability of tetracycline; this may reduce the duration of ICU stays and mechanical ventilation induced by the coronavirus SARS‐CoV‐2.

Doxycycline Inhibition of a Pseudotyped Virus Transduction Does Not Translate to Inhibition of SARS-CoV-2 Infectivity

“…Gendrot and collaborators employed the IHUMI-3 strain for which genomic data are not available, thus making it difficult to establish the degree of widespread of the virus and its comparison with other strains. Our SPR data indicated that doxycycline did not interact with relevant binding sites of S or ACE2 proteins, as instead suggested by an in silico study [ 15 ]. It cannot be excluded that it may affect, at least on the pseudotyped retroviral vector, the integrity of the virus lipidic envelope, suggested to be important for the virus integrity [ 32 ].…”

“…In silico docking studies suggested a direct interaction of tetracyclines with the RBD, which can result in inhibition of the RBD–ACE2 complex [ 15 ] and reported their ability to inhibit 3CLpro [ 16 ], thus interfering with virus internalization and replication. This antiviral activity was confirmed in a study on Vero E6 cells infected with a clinically isolated SARS-CoV-2 strain (IHUMI-3) showing that doxycycline, at concentrations compatible with the circulating levels reached after oral or intravenous administration, inhibited virus entry and replication [ 17 ].…”

Doxycycline inhibition of a pseudotyped virus transduction does not translate to inhibition of SARS-CoV-2 infectivity

“…Gendrot and collaborators employed the IHUMI-3 strain for which genomic data are not available thus making difficult to establish the degree of widespread of the virus and its comparison with other strains. Doxycycline did not interact with relevant binding sites of S or ACE2 proteins, as instead suggested by an in-silico study (14). It cannot be excluded that it may affect, at least on the pseudotyped retroviral vector, the integrity of the virus lipidic envelope, suggested to be important for the virus integrity (27).…”

“…In-silico docking studies suggested a direct interaction of tetracyclines with the RBD which can result in inhibition of the RBD-ACE2 complex (14), and reported their ability to inhibit 3CLpro (15), thus interfering with virus internalization and replication. This antiviral activity was confirmed in a study on Vero E6 cells infected with a clinically isolated SARS-CoV-2 strain (IHUMI-3) showing that doxycycline, at concentrations compatible with the circulating levels reached after oral or intravenous administration, inhibited virus entry and replication (16).…”

Tetracycline plus macrolide: A potential therapeutic regimen for COVID-19?

“…Tetracycline is also reported to inhibit the binding of the SARS-CoV-2 spike protein to angiotensinconverting enzyme 2 (ACE2) (3). Thus, infection of cells by SARS-CoV-2 may be inhibited.…”