A new multinational research involving medical scientists from Aarhus University-Denmark, Istituto Pasteur Italia-Cenci Bolognetti Foundation-Italy, University of Ottawa-Canada and Ottawa Hospital Research Institute-Canada has found that the U.S, FDA approved antimicrobial drug Atovaquone has antiviral potential against the SARS-CoV-2 coronavirus and emerging VOCs and could be repurposed to treat COVID-19.
Atovaquone, sold under the brand name Mepron, is a quinone antimicrobial medication for the prevention and treatment of Pneumocystis jirovecii pneumonia and is belongs to the class of naphthoquinones (hydroxy-1,4-naphthoquinone), an analog of ubiquinone, with antipneumocystic activity and it’s used to treat toxoplasmosis, malaria and babesia.
At present, 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, the study team 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, the study findings showed 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.
Significantly, atovaquone retained its full antiviral activity in a primary human airway epithelium cell culture model.
Mechanistically, the study team demonstrated 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 awaiting the results of these trials, this present study 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.
The study findings were published in the peer reviewed journal: ACS Infectious Disease.
Atovaquone, the active compound of malarone, has been used in humans since 1999, both as a treatment for Pneumocystis jirovecii pneumonia (5,6) and as a fixed-dose combination with proguanil for treating and preventing malaria. (7,8) Atovaquone is an ubiquinol analogue, which targets the formation of the bc1 complex as part of the mitochondrial electron transport chain and leads to a collapse in mitochondrial functions. (9−12)
Importantly, atovaquone only affects parasitic mitochondrial functions without inhibiting the mammalian mitochondrial bc1 complex. (10) Treatment with this compound further results in changes in the concentration of metabolites within the pyrimidine biosynthetic pathway as well as the inhibition of purine biosynthesis. (12−15)
Given its excellent safety profile, atovaquone is a popular and widely used Food and Drug Administration (FDA)-approved drug for the treatment of malaria.
As recently as 2019, however, atovaquone has also been described as a potential broad-spectrum antiviral drug, particularly active against arboviruses including Zika virus, chikungunya virus, and dengue virus. (16,17) In the case of viral infections, atovaquone is believed to act early against infections, potentially by targeting viral RNA replication, through a mechanism involving the inhibition of the pyrimidine biosynthesis pathway, (16) or viral entry, by interfering with viral glycoprotein-mediated membrane fusion. (17)
Additionally, atovaquone was demonstrated to have some efficacy in vitro in limiting the infectivity of the coronavirus MERS-CoV. (18)
Early on and as the pandemic progressed in the provinces of Quebec and Ontario in Canada, several anecdotal observations suggested that patients taking the antimalaria medication had either beneficial or protective effects against COVID-19. This was observed in multiple contexts (each case is described in the Supplemental Text), including first-line responders working in outbreak establishments as well as elderly individuals.
In particular, malarone regimen seemed to revert the COVID-positive status in several patients. In addition, malarone taken prophylactically appeared to be effective at protecting hospital workers and long-term care home employees for extended periods against SARS-CoV-2 infections where severe outbreaks occurred.
Follow-up investigations found that none of the patients reported any serious side effects with malarone or atovaquone taken in a prophylactic or therapeutic manner. Notably, none tested positive following or while being on malarone despite some being at elevated risk. These anecdotal cases proposed that the active compound atovaquone may be of use in preventing coronavirus infection or alleviating disease symptoms.
Importantly, two clinical trials, one at the University of Texas Southwestern Medical Center and the other at the HonorHealth Research Institute in Arizona, were initiated last year (2020) to test atovaquone in combination with azithromycin in patients with confirmed COVID-19. One trial is now completed but the results are yet to be published (NCT04456153), while the other continues to actively recruit participants (NCT04339426).
Collectively, these clinical observations prompted us to evaluate the antiviral capacity of atovaquone in relevant cellular models of infection against the original SARS-CoV-2 and other variants of concern. Our findings demonstrate the strong antiviral potential of this FDA-approved molecule in limiting the infectivity and replication of the original SARS-CoV-2 and other variants of concern in lung epithelial cells and a primary human airway epithelial cell culture model in vitro.
Although this study does not directly confirm the efficacy of the drug in humans, the potent antiviral effects obtained in vitro suggest that atovaquone/malarone may represent an effective therapeutic option repurposed for the treatment of COVID-19, particularly to protect frontline workers and/or high-risk populations.