Could 6′,6′-difluoro-aristeromycin (DFA) have broad-spectrum antiviral potential against coronaviruses?

Coronaviruses have caused zoonotic outbreaks throughout history. In the last two decades of this century alone, we have seen the emergence of three highly pathogenic coronaviruses: the severe acute respiratory syndrome (SARS), the Middle East respiratory syndrome (MERS), and the severe acute respiratory syndrome 2 (SARS-CoV-2), which is the causative pathogen of the current coronavirus disease 2019 (COVID-19) pandemic. SARS and MERS share similarities with SARS-CoV-2, and exploring common weaknesses could aid in the development of therapeutics for COVID-19.

Researchers at the Leiden University Medical Center demonstrated that low-micromolar concentrations of 6′,6′-difluoro24 aristeromycin (DFA), an adenosine nucleoside analog, strongly inhibits the replication of Middle East respiratory syndrome coronavirus (MERS-CoV) in a cell-based infection assay.

The team’s study, which appeared on the pre-print server bioRxiv*, shows promise in finding a potential broad-spectrum antiviral compound against coronaviruses.

Coronavirus outbreaks

The emergence of the severe acute respiratory syndrome coronavirus (SARS-CoV-1) in China in 2003 and the MERS-CoV in Saudi Arabia in 2012 highlights the potential pandemic threat posed by this type of zoonotic pathogens. About a decade apart, these outbreaks cause global health crises that take a toll on the healthcare system.

Due to the nature of these viral pathogens and the severity of the diseases caused by these coronaviruses, the World Health Organization (WHO) provided priority status to them. This status allows for the urgent development of prophylactic and therapeutic treatment strategies.

In late December 2019, a novel coronavirus emerged in China, causing the current pandemic. To date, more than 167 million individuals worldwide have been infected by SARS-CoV-2, while over 3.46 million have died. The SARS-CoV-2 pandemic and its burden on public health globally emphasizes the critical nature of finding highly effective anti-coronavirus drugs.

There are currently various drug classes under evaluation as inhibitors of coronavirus replication, including those targeting viral functions such as viral proteases and the RNA polymerase.

DFA inhibits MERS-CoV

The research team used cell-based assays for MERS-CoV-2, SARS-CoV, chikungunya, and Zika virus replication in the current study. The team described the potential of a set of adenosine and selenadenosine analogs for inhibiting these pathogens.

They derived these compounds from aristeromycin, a popular carbocyclic nucleoside compound inhibiting S-adenosyl-L-homocysteine hydrolase (SAH hydrolase or SAHH). It also has antiviral, anti-cancer, and anti-toxoplasma properties.

Further, these aristeromycin derivatives are nucleoside analogs made to target viral RNA-dependent RNA polymerase and indirectly target the methylation of viral RNA by inhibiting the host SAH hydrolase.

The researchers evaluated a library of more than 80 adenosine and selenoadenosine analogs to arrive at the study findings that were previously considered for its antiviral activity against MERS-CoV, SARS-CoV, and mouse hepatitis virus (MHV) using cell-based cytopathic effect (CPE) reduction assays.

From there, the team has identified DFA as the most potent inhibitor of MERS-CoV and SARS-CoV replication. It is also found to be more effective in decreasing the progeny titers of MERS-CoV than those of SARS-CoV-1, when treating Vero cells with DFA.

Using two-independent cell-based assays, a dose-response assay, and a CPE-reduction assay, the researchers assessed the antiviral activity of DFA against MERS-CoV in a more detailed way.

From this library, we identified 6′,6′-difluoro-aristeromycin (DFA) as the aristeromycin derivative that inhibited MERS-CoV replication most efficiently in cell-based assays,” the team explained in the study.

The team hypothesizes that DFA affects viral cap methylation by inhibiting the viral enzymes or binding to the SAH hydrolase. They examined the antiviral activity of DFA against the other betacoronaviruses and revealed that it has a limited effect on their replication.

Nevertheless, our results justify the further characterization of DFA derivatives as an inhibitor of MERS-CoV replication,” they added.

To date, there is a lack of antiviral drugs that are effective against human coronavirus infections, including the MERS-CoV that is endemic in the Middle East, the current SARS-CoV-2 pandemic, and potential future zoonotic coronaviruses.

The current study sheds light on the need to investigate novel drug targets and identify antiviral compounds with potential multivalent activity against coronaviruses. Though finding that DFA has potential as a broad-spectrum antiviral agent, further studies are still needed.

Meanwhile, the team combined the results with a previous study showing that DFA can inhibit Zika virus and chikungunya. The team urged scientists to look at DFA, not only for coronaviruses but also for other viral infections.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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