Danish, Canadian & Italian Researchers Finds That The Antimicrobial Drug Atovaquone Has Antiviral Potential Against SARS-CoV-2 & Emerging VOCs!
: 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. Atovaquone is a chemical compound that belongs to the class of naphthoquinones Atovaquone is a hydroxy-1,4-naphthoquinone, an analog of ubiquinone, with antipneumocystic activity.
Besides being used to treat pneumocystis pneumonia, Atovaquone is also used alongside other drugs 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. https://pubs.acs.org/doi/full/10.1021/acsinfecdis.1c00278#
To date, the COVID-19 pandemic has had overwhelming impacts on healthcare systems and has claimed almost 5 million lives globally and infected almost 244 million individuals. The emerging novel variants of the SARS‑CoV‑2 harbor vaccine escape capacities; besides, some individuals may still face vaccine access inequity. Hence, repurposing of clinically approved, safe, accessible, and active drugs against SARS-CoV-2 is much anti
The U.S.FDA-approved molecule atovaquone/malarone may represent an effective therapeutic strategy in treating COVID-19, specifically for preventing infection among frontline workers and/or high-risk populations.
To date, Atovaquone (The active compound of malarone) has proven efficacy against Pneumocystis jirovecii pneumonia and as a fixed-dose combination with proguanil in preventing and treating malaria. This agent is a ubiquinol analog that affects parasitic mitochondrial functions without inhibiting the mammalian mitochondrial bc1 complex.
Atovaquone has an excellent safety profile and has been approved by the US Food and Drug Administration (FDA) to treat malaria. Recently, its potential broad-spectrum antiviral role has been described against arboviruses, including Zika, chikungunya, and dengue viruses.
Importantly the antiviral action of atovaquone is expressed through the inhibition of the pyrimidine biosynthesis pathway involved in viral RNA replication and the impedance of viral entry into host cells.
Furthermore, its efficacy in limiting the infectivity of the Middle East respiratory syndrome-related coronavirus (MERS-CoV) has been demonstrated in vitro.
This new COVID-19-Drugs-Atovaquone
study findings demonstrates the antiviral potential of atovaquone against the original SARS-CoV-2 strain and other variants of concern.
In the study, the antiviral potential of atovaquone was assessed following infection with SARS-CoV-2-spike-pseudotyped vesicular stomatitis virus (VSV) and wild-type (wtVSV), both expressing green fluorescent protein (GFP). In this study, VeroE6 cells were treated with various atovaquone concentrations; after that, the cells were infected with wtVSV-spike or wtVSV and were imaged for GFP as a proxy for infection rate. Additionally, cellular viability was evaluated 48 hours post-infection.
The study findings showed a dose-dependent block in the infectivity of both wtVSV and VSV-spike. It was noted that wtVSV was more toxic than VSV-spike, and there was a slight increase in cellular viability with atovaquone.
Subsequent quantitative polymerase chain reaction (qPCR) of the SARS-CoV-2 genome established that a concentration of 10 μM atovaquone was the most efficient in inhibiting viral replication. All concentrations of the drug prove to be non-toxic.
Significantly, a 105 −106 log-fold reduction in the production of viral progeny was observed in atovaquone-treated cells.
Also, immunofluorescence staining showed an almost complete absence of the intracellular SARS-CoV-2 spike protein after atovaquone treatment.
Importantly as well, the antiviral effect of the drug was retained in the human lung epithelial cell line Calu-3, with more than a 100-fold reduction in viral genome expression. The suppressed SARS-CoV-2 infectivity in the presence of atovaquone led to reduced virus-induced cytotoxicity of the infected Calu-3 cells.
Upon establishing atovaquone as a promising antiviral agent against the original SARS-CoV-2 strain, the antiviral capabilities of this agent were investigated against different variants of concern (VOCs) including the cluster 5 variant (mink variant), alpha variant, beta variant, and delta variant.
The study findings showed that treatment of VeroE6 hTMPRSS2 efficiently inhibited SARS-CoV-2 viral gene expression with the original viral strain and the mink variant.
Meanwhile, the antiviral capacity of atovaquone was expressed on alpha and beta variants.
However, despite this effect being slightly low on the SARS-CoV-2 delta variant, atovaquone could drastically interfere with the variant’s gene expression.
Also, an almost complete reduction of the intracellular SARS-CoV-2 spike protein for the different variants could be achieved with atovaquone treatment.
In order to further investigate whether atovaquone had a broad antiviral activity, the same experiments were performed on two mild human coronaviruses OC43 and 229E.
The findings showed that when Huh-7 and Caco-2 cells were treated with atovaquone, they exhibited reduced viral gene expressions. The antiviral activity of atovaquone was more pronounced against OC43 than 229E. Thus, the potent and broad-spectrum antiviral action of this agent could be confirmed against SARS-CoV-2 VOCs.
Significantly, atovaquone pretreatment of Calu-3 cells impeded the virus-induced inflammatory response which is known to render the “cytokine storm.” It was found that pretreatment for two hours inhibited RIG-I-induced antiviral gene levels, but not inflammatory gene levels.
The study findings indicate that atovaquone is a promising antiviral agent that benefits against SARS-CoV-2 infection by inhibiting viral replication and virus-induced inflammation at non-toxic concentrations in VeroE6 hTMPRSS2 cells and lung epithelial Calu-3 cells. Atovaquone interferes with the viral entry into the human host cells and appears to affect the intracellular phase of viral replication.
The research findings also revealed that this drug works both pre-and post-infection on SARS-CoV-2; and, therefore, can be used prophylactically and following exposure to the virus. Future studies should be directed towards investigating if the atovaquone-induced antiviral activity could result from cleavage of ACE2 through the TMPRSS2-mediated proteolytic activity and whether this drug could be used alone or as a combination treatment for COVID-19.
However, Thailand Medical News doubts that even if randomized clinical trials shows that the drug works, those elites in the United States including a group of Democrats and eugenic proponents in the United Kingdom along with certain big Pharma controlling the COVID-19 narratives will never allow it to see the light of day as an approved COVID-19 drug as their interest is only to peddle overpriced toxic drugs or therapeutics!
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