A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID, 2025, Bader et al

https://www.nature.com/articles/s41467-025-57905-4
Abstract

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 has highlighted the vulnerability of a globally connected population to zoonotic viruses. The FDA-approved coronavirus antiviral Paxlovid targets the essential SARS-CoV-2 main protease, Mpro.

Whilst effective in the acute phase of a COVID infection, Paxlovid cannot be used by all patients, can lead to viral recurrence, and does not protect against post-acute sequelae of COVID-19 (PASC), commonly known as long COVID, an emerging significant health burden that remains poorly understood and untreated.

Alternative antivirals that are addressing broader patient needs are urgently required. We here report our drug discovery efforts to target PLpro, a further essential coronaviral protease, for which we report a novel chemical scaffold that targets SARS-CoV-2 PLpro with low nanomolar activity, and which exhibits activity against PLpro of other pathogenic coronaviruses.

Our lead compound shows excellent in vivo efficacy in a mouse model of severe acute disease. Importantly, our mouse model recapitulates long-term pathologies matching closely those seen in PASC patients. Our lead compound offers protection against a range of PASC symptoms in this model, prevents lung pathology and reduces brain dysfunction. This provides proof-of-principle that PLpro inhibition may have clinical relevance for PASC prevention and treatment going forward.

Paragraph breaks added.

 

Fig. 3: WEHI-P8 improves disease outcome in an acute mouse model of severe disease.

a WEHI-P8 was selected for mouse in vivo efficacy due to its favourable ADME properties. b Calculated unbound plasma concentration of WEHI-P8 in male C57BL/6 (WT) mice following oral administration at 100 mg/kg. c Schematic showing treatment regime used in d-g. Mice were treated at 6 h, 24 h and 48 h with euthanasia performed at 72 h post-infection. WT 7-9 week-old mice were infected with SARS-CoV-2 P21 (see Supplementary Fig. 7a) and treated with either vehicle, PLT (Paxlovid-like treatment: 56 mg/kg nirmatrelvir, 19 mg/kg ritonavir), or WEHI-P8 (100 mg/kg or 150 mg/kg) (see schematic and Methods d,e At 3 days port-infection (dpi), mice were monitored for d viral burden and e percent weight change compared to initial weight; nvehicle = 7, nPLT = 7, nP8-100 = 8, nP8-150 = 8 mice per group. Mean ± SD. f Haematoxylin and eosin (H&E) and immunohistochemistry (IHC) stained lungs are shown. Markers used for each cell type are indicated in brackets and images are representative of 4 animals per condition. Scale bars = 100 µm. g Levels of cytokines and chemokines measured by ELISA of lung homogenates from mice infected with SARS-CoV-2 P21; nvehicle = 7, nPLT = 7, nP8-100 = 8, nP8-150 = 8 mice per group; boxplots depict the median and interquartile range (IQR). Whiskers extend to the furthest data point within 1.5 times the IQR from each box end. P-values are indicated above each group and were determined by eone-way ANOVA with Tukey’s multiple comparisons tests d after log10 transformation and g Two-sided wilcoxon rank-sum test, with Bonferroni adjustment for multiple comparisons; **p < 0.01, ***p < 0.001. Exact P-values for Fig. 3g are provided in the Source Data file. Source data are provided as a Source Data file. Figure 3c Partially created in BioRender93.

 

Importantly, they gave the mice the treatment before they were infected.

 

This study uses a mouse model that might actually not be too bad. It has not just lung issues but immune, gut and microglia too. I'm really excited about using animal models for me/cfs because I think we desperately need to ramp up how much data we have to get some leads on etiology. Humans are accurate but slow. Blood cells in the lab haven't got us too far yet. Maybe mice will help us narrow down the types of thing we should be looking for in people.

Another great thing about this study is it is based in the same hospital complex as @MelbME in our city's incredible bio precinct. possibility of synergy!

 

That seems to indicate that it will be relevant to the people with PASC who do not have ME/CFS like disease - the ones with pathology. That might be a plus for reducing such pathology but I don't see this being a model for ME/CFS.

 

https://www.eurekalert.org/news-releases/1079816

News Release 8-Apr-2025
Tackling the ‘silent pandemic’: breakthrough study puts first long COVID treatment on horizon
Peer-Reviewed Publication

Walter and Eliza Hall Institute


image:

COVID-19 is caused by the SARS-CoV-2 virus. This image shows antibodies (shown in orange and purple) binding to ‘spike proteins’ on the surface of SARS-CoV-2 virus (shown in teal and yellow). Spike proteins are critical for SARS-CoV-2 to enter human cells, and this can be blocked by specific antibodies – breaking the infection cycle.

Credit: WEHI

view more


Credit: WEHI

Researchers have shown a new drug compound can prevent long COVID symptoms in mice – a landmark finding that could lead to a future treatment for the debilitating condition.

The world-first study found mice treated with the antiviral compound, developed by a multidisciplinary research team at WEHI, were protected from long term brain and lung dysfunction – key symptoms of long COVID.

Researchers hope the unprecedented results could lead to clinical trials and the first treatment for the disease in the future.


At a glance

• WEHI researchers have developed a drug compound that can protect mice from contracting long COVID symptoms.
  
  
• The world-first study also found the compound can treat acute COVID with better efficacy than Paxlovid – the leading treatment currently approved for COVID-19.
  
  
• It’s hoped the results could lead to clinical trials and an oral treatment for long COVID in the future.

Long COVID, also known as post-acute sequelae of COVID-19 (PASC), is a chronic condition characterised by symptoms that last for weeks or months after contracting COVID-19.

It is a significant health burden that remains poorly understood – with symptoms ranging from breathing difficulties, 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.

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.

The research is supported by the Medical Research Future Fund, the Wellcome Trust and generous philanthropic donations for COVID research and translation.

Chief Investigators: Professor Guillaume Lessene, Dr Marcel Doerflinger and Professor David Komander.



Journal
Nature Communications

DOI
10.1038/s41467-025-57905-4

Method of Research
Observational study

Subject of Research
Animals

Article Title
A novel PLpro inhibitor improves outcomes in a pre-clinical model of long COVID

Article Publication Date
3-Apr-2025