Antibiotic licensed to treat bacterial infections has shown antiviral efficacy against COVID

Antibiotic licensed to treat bacterial infections has shown antiviral efficacy against COVID

An estimated 65.7% of the world’s population have already received at least one dose of a COVID-19 vaccine REUTERS/Phil Noble/File Photo

An estimated 65.7% of the world’s population has already received at least one dose of a COVID-19 vaccine. Although they have shown their essential role in reducing hospitalizations, they do not control the transmission of the virus and effective and affordable therapies against SARS-CoV-2 are still lacking. In this context, a study published in the open access journal PLOS pathogens by a team of scientists led by Sandrine Belouzard and Jean Dubuisson from Instituto Pasteur in Lille, France, suggested that clofoctol might be an effective treatment for SARS-CoV-2 infections in mice.

Obtaining antiviral treatment that is accessible and administrable on a large scale to all patients diagnosed at an early stage can help reduce the viral load in the respiratory tract and therefore the transmission of the disease. That’s why the reuse of clinically evaluated drugs can potentially offer a fast track for the rapid deployment of treatments for this type of emerging infectious disease.

The process of bringing a new drug to market is arduous; there are several stages of preclinical and clinical development that a drug candidate must successfully pass before it can be approved for human use. In the face of a public health emergency, such as the COVID-19 pandemic, the long delays associated with this process become more problematic. A drug development pathway for COVID-19 has focused on potential repurposing of existing drugs to treat patients.

A drug development pathway for COVID-19 has focused on the potential reuse of existing drugs to treat patients (Getty)
A drug development pathway for COVID-19 has focused on the potential reuse of existing drugs to treat patients (Getty)

Drugs that have previously received authorization for use in humans have already been tested for toxicity and tolerability in humans, so some preclinical testing may be skippedas well as the first clinical trials, which saves time,” explains dubuissonhead of the laboratory of the National Center for Scientific Research (CNRS) and one of the authors of the document.

Examples of existing drugs already being tested against SARS-CoV-2 include the antiretroviral drug lopinavir/ritonavir prescribed for the treatment of HIV, the antimalarial drug hydroxychloroquine, and the antiviral drug remdesivir. “Unfortunately, the clinical results of testing these drugs have been disappointing,” says Dubuisson. The first strategies used to explore the effectiveness of existing drugs against SARS-CoV-2 were based on a method known as targeted reuse. “People chose a single drug to test directly in humans, assuming it would have an antiviral effect,” says Dubuisson.

In the new study, read on PLoS Pathogens, Dubuisson and his colleagues took an alternative approach. “Our approach is different because there was no a priori hypothesis and we tested a very wide range of drugs used in medicine.“, he describes. The researchers used the Apteeus library, a collection of 1,942 licensed drugs, to perform high-content screening (HCS) on Vero-81 cells, an African monkey kidney cell line vulnerable to infection with SARS-CoV-2. . “After the first screen, among the 1,942 compounds tested, we identified a few dozen molecules with potential antiviral activity against SARS-CoV-2,” Dubuisson explained.

“After the first screen, among the 1,942 compounds tested, we identified a few dozen molecules with potential antiviral activity against SARS-CoV-2,” Dubuisson explained.

In total, the screen revealed 21 molecules that exhibited antiviral activity. These drugs have undergone further in vitro evaluation, exploring their clinical risk-benefit ratio and how their antiviral activity fared against different cellular entry mechanisms that SARS-CoV-2 may use to penetrate and infect cells. Three compounds, perphenazine, nitazoxanide, and clofoctol, were reported to demonstrate antiviral activity regardless of the SARS-CoV-2 entry route tested.

“Clofoctol was originally developed as an antibiotic to treat bacterial infections of the respiratory tract”explains the specialist. This compound was chosen for further evaluation against SARS-CoV-2 in animal studies due to its pharmacological properties: it has a high safety profile and accumulates in lung tissue at a higher concentration than in blood plasma. “Transgenic mice, genetically engineered to express human SARS-CoV-2 receptors, were treated with clofoctol after SARS-CoV-2 infection. This mouse model is a “classic” model for testing the antiviral activity of a drug in vivo”, adds Dubuisson.

The research team observed a decline in virus production in the mice's lungs two days after infection, in addition to reduced expression of inflammatory genes and reduced pathology in the lungs.
The research team observed a decline in virus production in the mice’s lungs two days after infection, in addition to reduced expression of inflammatory genes and reduced pathology in the lungs.

The research team observed a decline in virus production in the mice’s lungs two days after infection, in addition to reduced expression of inflammatory genes and reduced pathology in the lungs.. The long-term effects of clofoctol have not been evaluated, as the mice had to be sacrificed two days after treatment.

Dubuisson explains why: “Unlike humans, clofoctol is not as well tolerated in mice,” he says. Treatment had to be stopped early in the mice due to weight loss issues; however, humans can be safely treated with clofoctol for 10 days without experiencing major side effects.

Based on the results of this study, the researchers argued in the article’s discussion that there is a “strong case” for proposing clofoctol as “an affordable therapeutic candidate for the treatment of COVID-19 patients.” They added that because the drug is inexpensive, it could provide an opportunity to treat COVID-19 patients in resource-scarce settings. “The next step will be to test clofoctol in humans in a Phase III clinical trial,” Dubuisson concluded.

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