A multidisciplinary research team at the Walter and Eliza Hall Institute of Medical Research (WEHI) has developed a groundbreaking drug compound that prevents long COVID symptoms in mice, marking a significant advancement toward potential treatments for this debilitating condition.
The world-first study demonstrated that mice treated with the novel antiviral compound were protected from long-term brain and lung dysfunction – key symptoms associated with long COVID, also known as post-acute sequelae of COVID-19 (PASC).
"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," said Dr. Marcel Doerflinger, Laboratory Head at WEHI and corresponding author of the study.
Long COVID remains poorly understood despite affecting millions worldwide. Symptoms can persist for weeks or months after initial infection, including breathing difficulties, brain fog, and chronic fatigue. Currently, there are no approved treatments specifically targeting this condition.
"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," Dr. Doerflinger added.
Novel Drug Target Shows Promise
While existing COVID-19 treatments like Paxlovid target the viral protein Mpro, WEHI researchers identified another protein, PLpro, as a promising alternative drug target in 2020.
Professor David Komander, who has studied the family of proteins that includes PLpro for over 15 years, co-led the team that discovered new PLpro inhibitors. To identify effective compounds, the researchers utilized the National Drug Discovery Centre (NDDC) 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," explained Professor Komander. "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."
The development of this novel compound in less than five years represents an extraordinary achievement in drug discovery, made possible by the advanced technologies and multidisciplinary expertise at WEHI.
Superior Efficacy Against Acute COVID
Beyond its potential for preventing long COVID, the research team discovered that their novel compound may treat acute COVID more effectively than currently available antivirals.
"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," said Dr. Shane Devine, co-first and corresponding author on the paper.
Paxlovid, the leading COVID-19 treatment, has significant limitations. It is only recommended for high-risk patients and requires two compounds to interact for effectiveness, which can interfere with 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 noted.
Another advantage of targeting PLpro is addressing viral mutations. As Dr. Devine explained, "The SARS-CoV-2 virus 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."
Compelling Visual Evidence
The efficacy of the WEHI compound was visually demonstrated through comparative analysis of mouse lungs. Lungs treated with a drug similar to Paxlovid showed significant dark red areas indicative of damage and inflammation during the long COVID stage. In contrast, lungs treated with the WEHI compound appeared healthier, providing clear evidence of the compound's superior efficacy.
Path Forward
While these results are promising, researchers emphasize that more work is needed to develop a drug suitable for human use. The project will continue through collaborations 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 philanthropic donations for COVID research and translation. Chief investigators include Professor Guillaume Lessene, Dr. Marcel Doerflinger, and Professor David Komander.
If successful in future clinical trials, this compound could become the first approved treatment specifically targeting long COVID, offering hope to millions suffering from this condition worldwide.
