Antiviral Potential of the Antimicrobial Drug Atovaquone against SARS-CoV-2 and Emerging Variants of Concern
Madalina E. Carter-Timofte, Rozanne Arulanandam, Naziia Kurmasheva, Kathy Fu, Geneviève Laroche, Zaid Taha, Demi van der Horst, Léna Cassin, Renée M. van der Sluis, Enrico Palermo, Daniele Di Carlo, David H. Jacobs, Glib Maznyi, Taha Azad, Ragunath Singaravelu, Fanghui Ren, Anne Louise Hansen, Manja Idorn, Christian K. Holm, Martin R. Jakobsen, Julien van Grevenynghe, John Hiscott, Søren R. Paludan, John C. Bell, Jean R. Séguin, Luc A. Sabourin, Marceline Côté, Jean‐Simon Diallo, Tommy Alain, David Olagnier
Abstract
The antimicrobial medication malarone (atovaquone/proguanil) is used as a fixed-dose combination for treating children and adults with uncomplicated malaria or as chemoprophylaxis for preventing malaria in travelers. It is an inexpensive, efficacious, and safe drug frequently prescribed around the world. Following anecdotal evidence from 17 patients in the provinces of Quebec and Ontario, Canada, suggesting that malarone/atovaquone may present some benefits in protecting against COVID-19, we sought to examine its antiviral potential in limiting the replication of SARS-CoV-2 in cellular models of infection. In VeroE6 expressing human TMPRSS2 and human lung Calu-3 epithelial cells, we show that the active compound atovaquone at micromolar concentrations potently inhibits the replication of SARS-CoV-2 and other variants of concern including the alpha, beta, and delta variants. Importantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model. Mechanistically, we demonstrate that the atovaquone antiviral activity against SARS-CoV-2 is partially dependent on the expression of TMPRSS2 and that the drug can disrupt the interaction of the spike protein with the viral receptor, ACE2. Additionally, spike-mediated membrane fusion was also reduced in the presence of atovaquone. In the United States, two clinical trials of atovaquone administered alone or in combination with azithromycin were initiated in 2020. While we await the results of these trials, our findings in cellular infection models demonstrate that atovaquone is a potent antiviral FDA-approved drug against SARS-CoV-2 and other variants of concern in vitro.