Spotlight on Therapeutics: Is PLpro the secret weapon for defeating coronaviruses?

More than seven million people died from complications caused by the most recent global coronavirus outbreak, the COVID-19 pandemic in 2020.

This number may have been much smaller if we’d had effective antiviral treatments available earlier – that’s the focus of the project led by The Walter and Eliza Hall Institute for Medical Research’s Dr Shane Devine and his team. By taking a novel approach to antiviral therapy, researchers aim to create a library of ‘shelf-ready’ new antiviral compounds – so that antiviral therapies can be developed much faster when the next coronavirus pandemic hits. 

There are seven main coronaviruses that can infect humans, all of which have emerged over the past 20 years as the global population has grown. These include SARS-1, MERS, and SARS-2, which causes COVID-19.

When the COVID-19 pandemic hit, researchers relied on isolated compounds from the SARS-1 outbreak 20 years prior to begin developing the antiviral medicine “Paxlovid”. A gamechanger next time around would be to have more compounds with broad spectrum-efficacy available to work with as the starting point to fast-track an effective medicine.

Current treatments, such as Paxlovid, target the main protease in coronaviruses, but this project is exploring the relatively understudied papain-like protease (PLpro) protein, which could open the door to a new class of broad-spectrum antivirals that are effective against multiple strains of coronaviruses.

What is PLpro?

PLpro is one of two essential proteases involved in coronavirus replication – without it, infection is impossible. Until recently, it remained largely unexplored as a therapeutic target.

Dr Devine's team is developing compounds that specifically target PLpro, and creating novel inhibitors designed to block its function across multiple coronavirus strains.

“We already have a subset of compounds that work to block PLpro in COVID-19 and some other coronaviruses. We’re in the early stages of testing, but we’re seeing promising results against multiple coronaviruses,” said Dr Devine.

“Compared to current antivirals, our compounds bind differently to the PLpro protein and will potentially avoid limitations of current therapeutics. If we successfully develop a PLpro-inhibitor drug, we think it would have broader application across larger patient cohorts,” Dr Devine explained.

What is the blue sky vision?

“If we had a library of shelf-ready PLpro-inhibiting compounds available before the next pandemic hits, things like lockdowns could be a thing of the past because we could develop new medicines quickly,” Dr Devine said.

Such a resource would give researchers a solid starting point from which to develop drugs, and the more information we can discover about each specific compound, the further ahead we’ll be.

“We are making PLpro inhibitors that will literally stop coronavirus in its tracks. An effective treatment for coronaviruses would completely change pandemic management and greatly enhance Australia's sovereign capability and security,” Dr Devine concluded.

Project title: Antivirals targeting papain-like protease (PLpro)

Chief Investigator: Dr Shane Devine

Co-Investigators: Prof David Komander, Mr Dale Calleja, Prof Guillaume Lessene and A/Prof Kym Lowes.

Spotlight on Therapeutics: This content series profiles the projects and people behind the Cumming Global Centre for Pandemic Therapeutics innovative research.