Breakthrough drug prevents long COVID symptoms in mice

Researchers at the Walter and Eliza Hall Institute of Medical Research (WEHI) have shown that a new drug compound can prevent long COVID symptoms in mice. The researchers hope their results, which have been published in the journal Nature Communications, could lead to clinical trials and the first treatment for the disease 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. Yet despite millions of people worldwide reporting these symptoms — ranging from breathing difficulties to brain fog and chronic fatigue — the cause of long COVID remains largely unknown and there is no approved treatment for the disease.

“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 WEHI Laboratory Head Dr Marcel Doerflinger, corresponding author on the new study.

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 multidisciplinary WEHI team that spearheaded the discovery of new PLpro inhibitors.

“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,” said Komander, who is a Division Head at WEHI.

“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 [National Drug Discovery Centre] and multidisciplinary team at WEHI.”

The team’s study found that mice treated with the antiviral compound were protected from long-term brain and lung dysfunction — key symptoms of long COVID. According to Doerflinger, this could be a turning point in the hunt for treatments to support people at risk of developing the condition.

“Our preclinical studies have achieved something no currently approved therapy has done to date — preventing the most debilitating symptoms of long COVID in mice,” he said.

“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.”

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. Paxlovid is the leading COVID-19 treatment, but it has a key limitation in 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,” 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.”

Image caption: 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. Image credit: WEHI.