Tetracyclines proposed as treatment for COVID-19

In a letter to the editor of Pharmacotherapy , Mohit Sodhi, MSc, and Mahyar Etminan, PharmD, from the Department of Ophthalmology and Visual Sciences at the University of British Columbia, Vancouver, Canada outline evidence supporting the therapeutic potential of tetracyclines as a treatment for patients with COVID-19. The letter was published online on April 8, 2020. https://accpjournals.onlinelibrary.wiley.com/doi/abs/10.1002/phar.2395 The rationale for using tetracyclines considers the lipophilic nature of the tetrayclines along with their ability to inhibit matrix metalloproteinases (MMPs), anti-inflammatory properties and possible antiviral activity. Furthermore, the authors cite the relative safety of tetracyclines compared with other agents that are being considered to treat COVID-19, including antimalarial and antiretroviral drugs. Describing the tetracyclines as a potential treatment for COVID-19 “that is hiding in plain sight”, Sodhi and Etminan urge researchers to consider investigating the efficacy of this available therapy. Reviewing the activity of tetracyclines, the authors explain that they chelate zinc compounds on MMPs. Because coronaviruses depend on those enzymes for survival, cell infiltration, cell-to-cell adhesion, and replication, Sodhi and Etminan postulated that tetracyclines might inhibit viral replication within the host. As further support for the antiviral activity of tetracyclines, they cited reports indicating that tetracyclines might have activity for inhibiting RNA replication on positive-sense single stranded RNA, like SARS-CoV-2, the COVID-19 viral pathogen. The evidence includes findings from one in vitro study showing that doxycycline inhibited dengue virus serine protease, viral replication and viral entry into cultured cells and another showing a 70% decrease in retroviral load when a murine retrovirus producing cell line was incubated with doxycycline. Anti-inflammatory activity of tetracyclines is well-recognised and includes the ability to downregulate expression of several inflammatory cytokines that have been shown to be significantly elevated in lung tissue exposed to the coronavirus causing the infection known as SARS. In addition, chemically modified tetracyclines have been shown to induce apoptosis of mast cells that release a host of pro-inflammatory mediators. The effect on mast cells may be particularly relevant for treating COVID-19 considering evidence that mast cell proliferation within respiratory submucosa is induced by coronaviruses. The lipophilic nature of tetracyclines favors their distribution into lung tissue and is also significant because SARS-CoV-2 has a lipophilic outer shell. Suggesting that tetracyclines might be useful treatment for pulmonary complications of COVID-19, the authors cite a preclinical study in which a chemically-modified tetracycline prevented sepsis induced by acute respiratory distress syndrome.

Tags: covid-19 research