Naphthalene-based PLpro inhibitors show potential as COVID-19 therapeutics

A team of researchers has successfully demonstrated that a set of drug-like small molecules can inhibit the activity of a vital SARS-CoV-2 protein, which they say provides a promising path for new COVID-19 therapeutics.

From the University of Georgia (UGA), US, a team led by Professor Scott Pegan, director of the university’s Center for Drug Discovery, was the first to evaluate the SARS-CoV-2 protein PLpro, known to be essential in other coronaviruses for both its replication and its ability to suppress host immune function.

“The PLpro from SARS-CoV-2 behaved differently than its predecessor that caused the severe acute respiratory syndrome (SARS) outbreak in 2003. Specifically, our data suggests that the SARS-CoV-2 PLpro is less effective at its immune suppression roles,” said Pegan. “This may be one of the underlying reasons why the current virus is not as fatal as the virus from the 2003 outbreak… The COVID-19 virus infects, but people don’t run a fever before they are contagious, so there’s a lot of focus on how virulence factors like PLpro have been modified by nature to give the virus a better chance, from its perspective, to coexist with us.”

The team started to explore inhibitors designed to knock out PLpro and stop replication of the virus. They began with a series of compounds that were discovered 12 years ago and shown to be effective against SARS, but development was cut short since SARS had not reappeared.

“Obviously now we see the current coronavirus is probably going to be with us for a while – if not this one, then probably other types of coronaviruses,” Pegan said. “These compounds are a good starting point for therapeutic development. They have all the properties you would typically want to find in a drug and they have a history of not being considered toxic.”

These compounds, naphthalene-based PLpro inhibitors, are shown to be effective at halting SARS-CoV-2 PLpro activity as well as replication in cellular models. According to the researchers, they offer a potential rapid development path to generating PLpro-targeted therapeutics for use against SARS-CoV-2.

“The kind of small molecules that we’re developing are some of the first that are specifically designed for this coronavirus protease,” Pegan said. “Up till now, most therapeutic work against SARS has targeted another virulence factor, C3Lpro. This is a great start with a different target. Our hope is that we can turn this into a starting point for creating a drug that we can get in front of the US Food and Drug Administration (FDA).”

The study was published in Infectious Diseases.