WEHI scientists discovered a drug that blocks long COVID in mice and may improve acute treatment options beyond current antivirals like Paxlovid.
- WEHI researchers have developed a drug compound that protects mice from developing symptoms of long COVID.
- This groundbreaking study also showed that the compound treats acute COVID more effectively than Paxlovid, the current leading approved treatment.
- Researchers hope these results will pave the way for clinical trials and eventually lead to an oral treatment for long COVID.
Researchers have discovered that a new drug compound can prevent long COVID symptoms in mice, a major breakthrough that could pave the way for future treatment of this debilitating condition.
In this world-first study, mice treated with the antiviral compound, developed by a multidisciplinary team at WEHI, were protected from long-term brain and lung dysfunction, two hallmark symptoms of long COVID.
The research team hopes these groundbreaking results will lead to clinical trials and eventually the first approved treatment for the condition.
Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a chronic illness marked by symptoms that persist for weeks or months after the initial infection.
It is a significant health burden that remains poorly understood – with symptoms ranging from breathing difficulties to brain fog and chronic fatigue.
Despite millions of people worldwide reporting these symptoms, the cause of long COVID remains largely unknown and there is no approved treatment for the disease.
inflammation in mice during the long COVID stage of disease. The lungs on the right is healthier, showing the WEHI compound’s boosted efficacy. Credit: WEHI
Corresponding author and WEHI Laboratory Head, Dr Marcel Doerflinger, said the landmark results could be a turning point in the hunt for treatments to support people at risk of developing this condition.
“With 5% of people who contract COVID-19 going on to develop long COVID, the disease has morphed into a silent pandemic where millions are battling symptoms with more questions than answers,” Dr
Doerflinger said.
“Our pre-clinical studies have achieved something no currently approved therapy has done to date – preventing the most debilitating symptoms of long COVID in mice.
“While more research is needed to develop a drug that can be used in humans, seeing these milestone results in the unique mouse models developed at WEHI suggests this could be a real possibility in the future, which is incredibly exciting.”
Landmark discovery
While currently approved therapies for COVID-19 like Paxlovid target a critical coronavirus protein known as Mpro, WEHI researchers identified another protein, termed PLpro, as a promising drug target in 2020.
Professor David Komander has spent over 15 years studying the family of proteins that includes PLpro and co-led the large, multidisciplinary WEHI team that spearheaded the discovery of new PLpro
inhibitors.
To find a new drug compound that could target this critical protein, the team turned to the National Drug Discovery Centre (NDDC), headquartered at WEHI.
“Existing drugs had hit several hurdles to be effective in blocking PLpro in cells – our team wanted to see if we could find new ones capable of overcoming these barriers,” Prof Komander, a corresponding author and Division Head at WEHI, said.
“In order to do this, we screened over 400,000 compounds to see if we could uncover novel drug-like molecules that had potential against this protein.
“To have identified a drug target and then develop a novel drug compound against it in less than five years is an incredible feat that would have been impossible without the advanced technologies, speed and scale of the NDDC and multidisciplinary team at WEHI.”
Boosted efficacy
Dr Shane Devine, a co-first and corresponding author on the paper, said the team also found their novel compound can potentially treat acute COVID better than currently available antivirals for the
disease.
“Our study has provided the first evidence to prove PLpro is a powerful new drug target for COVID-19 treatments, while also showing its potential ability to treat the virus with unprecedented efficacy,” Dr Devine said.
Paxlovid is the leading COVID-19 treatment, but is currently only recommended for people who are considered at risk of severe disease.
A key limitation of this treatment is that it requires two compounds to interact with each other for the treatment to be effective – meaning it can also interfere with many other medications.
“Paxlovid and other antivirals in the market target Mpro and have these same issues, highlighting the urgent need for more research to enhance COVID-19 treatments that can provide greater access to more patients,” Dr Devine said.
“The SARS-CoV-2 virus also continues to mutate, meaning it’s only a matter of time until Paxlovid will no longer work. Our findings could lead to a future drug to help close these critical gaps.”
The project will continue collaborating with the Centre for Drug Candidate Optimisation (CDCO) and the Monash Institute of Pharmaceutical Sciences (MIPS) to evaluate the biopharmaceutical properties of this antiviral compound.
Reference: “A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID” by Stefanie M. Bader, Dale J. Calleja, Shane M. Devine, Nathan W. Kuchel, Bernadine G. C. Lu, Xinyu Wu, Richard W. Birkinshaw, Reet Bhandari, Katie Loi, Rohan Volpe, Yelena Khakham, Amanda E. Au, Timothy R. Blackmore, Liana Mackiewicz, Merle Dayton, Jan Schaefer, Lena Scherer, Angus T. Stock, James P. Cooney, Kael Schoffer, Ana Maluenda, Elizabeth A. Kleeman, Kathryn C. Davidson, Cody C. Allison, Gregor Ebert, Gong Chen, Kasiram Katneni, Theresa A. Klemm, Ueli Nachbur, Smitha Rose Georgy, Peter E. Czabotar, Anthony J. Hannan, Tracy L. Putoczki, Maria Tanzer, Marc Pellegrini, Bernhard C. Lechtenberg, Susan A. Charman, Melissa J. Call, Jeffrey P. Mitchell, Kym N. Lowes, Guillaume Lessene, Marcel Doerflinger and David Komander, 3 April 2025, Nature Communications.
DOI: 10.1038/s41467-025-57905-4
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11 Comments
Well, flying from Westchester Cnty NY to Lee Cnty Fla apparently is also a cure since long covid appears to the quiet observer to be a form of neurosis. It seemingly never affects power boat owners, motorcyclists or fishermen
I ride a 1200cc v twin and have suffered now for 5 years. Long Covid is like a slow poison death.
This is another cruel animal study, using a mouse model of post-COVID, which is a poor model for a human disease that lasts longer than the lifetime of mice. How do you assess, for example, brain fog in mice? And what kind of psychopath can cause this suffering to innocent animals who have the capacity to suffer? Mice are not good models for human disease. See my article, Of Mice and Men: The Problem with Studying Mice to Learn about Men. https://www.academia.edu/127948044/Of_Mice_and_Men_The_Problems_with_Studying_Mice_to_Learn_about_Men
In addition, the mice were fed standard rodent chow, which introduces metabolically-active compounds like pesticides, heavy metals, mycotoxins, and other contaminants, with uncontrolled levels of nutrients, as opposed to using a purified diet. See the study, Choice of Laboratory Rodent Diet May Confound Data Interpretation and Reproducibility. https://pubmed.ncbi.nlm.nih.gov/32258990/
Agree 100%
It will be like taking a sick cat to the vet and putting it down.
No. It will be like intentionally poisoning a perfectly healthy happy cat and THEN taking it to the vet to be put down. It’s cruel.
I would put down 1000 cats to be rid of Long COVID! Shut up about the cats, crazy cat lady!!!
No. It will be like intentionally poisoning a perfectly healthy happy cat and THEN euthanizing it. It’s cruel.
Sorry for the duplicate comment. I’m having problems with this webpage, and don’t see a way to delete comments.
Those with long covid desperately want a cure and want the govt to increase research funding
1. Long Covid is definitely NOT a form of neurosis, and approximately 5% of all Covid patients go on to develop it! It’s a serious disability for many of them, so please do not trivialize it/them.
OTOH, there certainly can be psychological ramifications, notably depression, as a RESULT of this illness. Doubtful that this qualifies as “neurosis”.
2. Yes, I agree that there is indeed cruelty involved in sacrificing many mice to gain medical knowledge, and we need to be grateful for these creatures, and hope that they are treated as humanely as possible.
(and yes, it’s icky–I’ve been vegetarian for over half a century)
That said, many human sufferers potentially benefit greatly from these experiments, and these little mammals have metabolisms that aren’t necessarily all that different from ours, so much of the information gleaned is indeed applicable. It’s noteworthy that, like us, a percentage of them do indeed go on to develop long covid, so, again, that demonstrates similarity and relevance.
Of course, the researchers themselves will have to conduct similar trials on human subjects to see if they get similar results, so likely it will be years before this treatment might be actually available.
(unsure how this discussion devolved into talking about cats, who have nothing to do with the study).